MANAGEMENT OF VENOUS

THROMBOEMBOLISM

Speaker Abhishek Agrawal Moderator Dr Dharmendra Jain

Introduction

Pulmonary Embolism and Deep Venous Thrombosis are a part of the larger entity lsquoVenous Thromboembolismrsquo

VTE = DVT + PE

Pulmonary Embolism is known as The Great Masquerader

EpidemiologyIncidence of VTE is 15 per 1000 person years

Incidence of DVT is approximately twice as that of Pulmonary Embolism

Pulmonary embolism is the third most common cause of hospital-related death and the most common preventable cause of hospital-related death

About half the cases of VTE are idiopathic in nature

Lindblad B Eriksson A Bergqvist D Autopsy-verified pulmonary embolism in a surgical department Analysis of the period from 1951 to 1988 Br J Surg 199178(7)849-852

Braunwald 10th edition

Braunwald 10th edition

Modifiable Risk Factorsbull Obesitybull Metabolic syndromebull Cigarette smokingbull Hypertensionbull Abnormal lipid profilebull High consumption of red meat andbull low consumption of fish fruits andbull vegetables

Risk Factorsbull Advancing agebull Arterial disease including carotid and coronary diseasebull Personal or family history of venous thromboembolismbull Recent surgery trauma or immobility including strokebull Congestive heart failurebull Chronic obstructive pulmonary diseasebull Acute infectionbull Air pollutionbull Long-haul air travelbull Pregnancy oral contraceptive pills or postmenopausal hormone replacement

therapybull Pacemaker implantable cardiac defibrillator leads or indwelling central bull venous catheterbull Hypercoagulable states bull Factor V Leiden resulting in activated protein C resistance bull Prothrombin gene mutation 20210bull Antithrombin deficiencybull Protein C deficiency bull Protein S deficiency Antiphospholipid antibody syndrome

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Introduction

Pulmonary Embolism and Deep Venous Thrombosis are a part of the larger entity lsquoVenous Thromboembolismrsquo

VTE = DVT + PE

Pulmonary Embolism is known as The Great Masquerader

EpidemiologyIncidence of VTE is 15 per 1000 person years

Incidence of DVT is approximately twice as that of Pulmonary Embolism

Pulmonary embolism is the third most common cause of hospital-related death and the most common preventable cause of hospital-related death

About half the cases of VTE are idiopathic in nature

Lindblad B Eriksson A Bergqvist D Autopsy-verified pulmonary embolism in a surgical department Analysis of the period from 1951 to 1988 Br J Surg 199178(7)849-852

Braunwald 10th edition

Braunwald 10th edition

Modifiable Risk Factorsbull Obesitybull Metabolic syndromebull Cigarette smokingbull Hypertensionbull Abnormal lipid profilebull High consumption of red meat andbull low consumption of fish fruits andbull vegetables

Risk Factorsbull Advancing agebull Arterial disease including carotid and coronary diseasebull Personal or family history of venous thromboembolismbull Recent surgery trauma or immobility including strokebull Congestive heart failurebull Chronic obstructive pulmonary diseasebull Acute infectionbull Air pollutionbull Long-haul air travelbull Pregnancy oral contraceptive pills or postmenopausal hormone replacement

therapybull Pacemaker implantable cardiac defibrillator leads or indwelling central bull venous catheterbull Hypercoagulable states bull Factor V Leiden resulting in activated protein C resistance bull Prothrombin gene mutation 20210bull Antithrombin deficiencybull Protein C deficiency bull Protein S deficiency Antiphospholipid antibody syndrome

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

EpidemiologyIncidence of VTE is 15 per 1000 person years

Incidence of DVT is approximately twice as that of Pulmonary Embolism

Pulmonary embolism is the third most common cause of hospital-related death and the most common preventable cause of hospital-related death

About half the cases of VTE are idiopathic in nature

Lindblad B Eriksson A Bergqvist D Autopsy-verified pulmonary embolism in a surgical department Analysis of the period from 1951 to 1988 Br J Surg 199178(7)849-852

Braunwald 10th edition

Braunwald 10th edition

Modifiable Risk Factorsbull Obesitybull Metabolic syndromebull Cigarette smokingbull Hypertensionbull Abnormal lipid profilebull High consumption of red meat andbull low consumption of fish fruits andbull vegetables

Risk Factorsbull Advancing agebull Arterial disease including carotid and coronary diseasebull Personal or family history of venous thromboembolismbull Recent surgery trauma or immobility including strokebull Congestive heart failurebull Chronic obstructive pulmonary diseasebull Acute infectionbull Air pollutionbull Long-haul air travelbull Pregnancy oral contraceptive pills or postmenopausal hormone replacement

therapybull Pacemaker implantable cardiac defibrillator leads or indwelling central bull venous catheterbull Hypercoagulable states bull Factor V Leiden resulting in activated protein C resistance bull Prothrombin gene mutation 20210bull Antithrombin deficiencybull Protein C deficiency bull Protein S deficiency Antiphospholipid antibody syndrome

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Modifiable Risk Factorsbull Obesitybull Metabolic syndromebull Cigarette smokingbull Hypertensionbull Abnormal lipid profilebull High consumption of red meat andbull low consumption of fish fruits andbull vegetables

Risk Factorsbull Advancing agebull Arterial disease including carotid and coronary diseasebull Personal or family history of venous thromboembolismbull Recent surgery trauma or immobility including strokebull Congestive heart failurebull Chronic obstructive pulmonary diseasebull Acute infectionbull Air pollutionbull Long-haul air travelbull Pregnancy oral contraceptive pills or postmenopausal hormone replacement

therapybull Pacemaker implantable cardiac defibrillator leads or indwelling central bull venous catheterbull Hypercoagulable states bull Factor V Leiden resulting in activated protein C resistance bull Prothrombin gene mutation 20210bull Antithrombin deficiencybull Protein C deficiency bull Protein S deficiency Antiphospholipid antibody syndrome

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Risk Factorsbull Advancing agebull Arterial disease including carotid and coronary diseasebull Personal or family history of venous thromboembolismbull Recent surgery trauma or immobility including strokebull Congestive heart failurebull Chronic obstructive pulmonary diseasebull Acute infectionbull Air pollutionbull Long-haul air travelbull Pregnancy oral contraceptive pills or postmenopausal hormone replacement

therapybull Pacemaker implantable cardiac defibrillator leads or indwelling central bull venous catheterbull Hypercoagulable states bull Factor V Leiden resulting in activated protein C resistance bull Prothrombin gene mutation 20210bull Antithrombin deficiencybull Protein C deficiency bull Protein S deficiency Antiphospholipid antibody syndrome

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

DVTbull Distal (calf vein) DVT bull Most DVT starts in the calf In surgical patients thrombi often begin intra operatively In about half of

patients they resolve spontaneously within 72 hours but in one sixth of patients they extend to involve the proximal veins5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation5 The presence of symptoms and the extent of proximal progression are harbingers for an increased risk of PE

bull Proximal (popliteal and thigh) DVT bull Symptoms of DVT (pain swelling tenderness and redness) generally do not develop until there is

involvement of the proximal leg veins5 Massive thrombosis can result in vascular compromise and venous gangrene

bull About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis6 and 10 have symptomatic PE78 The prevalence of PE increases with age particularly above 70 years78

bull Without treatment a quarter of proximal DVT will propagate during the first 30 days one fifth regress and the rest will remain unchanged6 Without adequate treatment half the patients will experience recurrent symptomatic VTE within 3 months9

bull With adequate treatment regression of thrombus occurs during the first week and recanalisation and resolution of thrombus occurs in about half the patients generally within the first 3 months1011 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer In some cases thrombus extends into previously unaffected vein segments despite adequate anticoagulation but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Pathophysiology cont

PE has the following pathophysiological effects-

Increased pulmonary vascular resistance

Impaired gas exchange and hypoxemia

Alveolar hyperventilation

Increased airway resistance

Decreased pulmonary compliance

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Clinical Featuresbull Most common symptom ndash Dyspneabull Most common sign ndash Tachycardia

bull Otherwise unexplained dyspnea bull Chest pain either pleuritic or ldquoatypicalrdquo bull Anxietybull Cough

bull Tachypneabull Tachycardiabull Low-grade feverbull Left parasternal liftbull Tricuspid regurgitant murmur Accentuated P2 bull Hemoptysisbull Leg edema erythema tenderness

SYMPTOMS

SIGNS

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

PULOMONARY EMBOLISM

MASSIVE PE

SUBMASSIVE PE

MILD PE

i Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support not due to a cause other than PE

ii Pulselessness or iii Persistent profound bradycardia (heart

rate 40 bpm with signs or symptoms of shock)

i Without systemic hypotension (systolic blood pressure 111309990 mm Hg)

ii With either RV dysfunction or myocardial necrosis

Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE

Management of Massive and Submassive Pulmonary Embolism Iliofemoral Deep Vein Thrombosis and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association

Troponin I gt 09 ngmL or troponin T gt 01 ngmLBNP gt 90 pgmL or pro-NT BNP gt 500 pgmL

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Modified from Piazza G Goldhaber SZ Management of submassive pulmonary embolism Circulation 20101221124-9

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Chest X-Ray

HAMPTON HUMP

WESTERMARK SIGN

PALLArsquos SIGN

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Electrocardiogram

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

D-dimer The sensitivity of the d-dimer is gt80 for DVT (including

isolated calf DVT) and gt95 for PE A normal d-dimer is a useful ldquorule outrdquo test

Other causes of raised D-dimero Myocardial infarctiono Pneumoniao Sepsiso Cancer o Postoperative state o Second and Third trimester of pregnancy

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

CT ANGIOGRAPHY The overall negative predictive value of a chest CT scan was

994

The CT scan serves as a prognostic and diagnostic test

Right ventricular enlargement on CT portends a complicated hospital course

The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

When reviewing results of CT the clinician should look for the following bull Size location and extent of thrombusbull Other diagnoses that may coexist with PE or explain PE symptoms bull Pneumoniabull Atelectasisbull Pericardial effusionPneumothoraxbull Left ventricular enlargement

bull Pulmonary artery enlargement suggestive of pulmonary hypertension

bull Age of thrombus acute subacute chronicbull Location of thrombus pulmonary arteries pelvic veins deep leg

veins upper extremity veinsbull Right ventricular enlargementbull Contour of the interventricular septum whether it bulges toward

the left ventricle thus indicating right ventricular pressure overload Incidental masses or nodules in lung

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

EchocardiogramRight ventricular enlargement or hypokinesis especially free

wall hypokinesis with sparing of the apex (the McConnell sign)Interventricular septal flattening and paradoxical motion

toward the left ventricle resulting in a D-shaped left ventricle in cross section

Tricuspid regurgitationPulmonary hypertension with a tricuspid regurgitant jet

velocity gt26 msecLoss of respiratory-phasic collapse of the inferior vena cava

with inspirationDilated inferior vena cava without physiologic inspiratory

collapseDirect visualization of thrombus (more likely with

transesophageal echocardiography)

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Venous Ultrasonography DVT ----- loss of vein compressibility

If PE is suspected DVT can be considered a surrogate for PE

At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site

A negative result does not rule out the possibility of PE

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Other Modalities

Ventilation Perfusion Scanning

Pulmonary Angiography

Contrast Venography

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Differential Diagnosis Anxiety Pleurisy Costochondritis Pneumonia bronchitis asthma COPD Myocardial infarction Pericarditis Congestive heart failure Idiopathic pulmonary hypertension

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Clinical Decision RulesLow Clinical Likelihood of DVT if Point Score Is Zero or Less Moderate Likelihood if Score Is 1 to 2 High Likelihood if Score Is 3 or Greater

Clinical Variable DVT Score

Active cancer 1 Paralysis paresis or recent cast 1 Bedridden for gt3 days major surgery lt12 weeks 1

Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling gt3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT ndash2

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Wells Criteria for clinical likelihood of PE

High Probability if gt4 score points

Clinical Variable PE Score

Signs and symptoms of DVT 30 Alternative diagnosis less likely than PE 30

Heart rate gt100min 15 Immobilization gt3 days or surgery within 4 weeks 15

Prior PE or DVT 15 Hemoptysis 10 Cancer 10

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

WELLS Criteria for likelihood of PE

DVT - 3

Cancer - 1

Immobilization gt3 days or surgery within 4 weeks - 15

Prior PE or DVT ndash 15

Tachycardia ndash 15 Diagnosis other than PE - 3

Hemoptysis - 1

High Probability if gt4 score pointsLow Probability if lt=4 score points

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

TREATMENT

Oxygenation Hemodynamic stability Anticoagulation Fibrinolysis IVC filter Catheter Embolectomy Surgical Embolectomy

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

AnticoagulationHeparin is the corner stone of anticoagulation

Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop

The activated AT then inactivates coagulation factors thrombin (factor IIa) Xa IXa XIa and XIIa

Target the aPTT between 15 and 25 times the control valueThe therapeutic range of aPTT is 60 to 80 seconds

shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter thrombolysis or embolectomy

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Low Molecular Weight HeparinLMWHs consist of short chains of polysaccharide

(fragments of UFH)

It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin)

LMWH therapy is monitored by the anti-factor Xa assay measuring anti-factor Xa activity

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Heparin and LMWH - MOA

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Difference LMWH and UFHUFH LMWH

Unpredicatable response Significant protein binding Saturable clearance mechanism Inactivation by platelet factor 4

Predictable response Less protein binding Less inactivation by platelet factor 4

Less bioavailability More bioavailability

Short half life Long half life

Need of regular monitoring No need of regular monitoring

Risk of HIT Less risk of HIT

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

LMWH

In a trial of 672 patients with VTE and cancer those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a ldquobridgerdquo to warfarin 88 versus 174

Lee AY Levine MN Baker RI et al Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 349146 2003

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

When monitoring needed in LMWH

The plasma anti-Xa level may be useful in five situations (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies(2) LMWH dosing in obese patients(3) LMWH dosing in patients with renal dysfunction(4) pregnancy(5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

FONDAPARINUX bull Fondaparinux is an anticoagulant pentasaccharide that

specifically inhibits activated factor X By selectively binding to anti- thrombin fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin

bull Fixed-dose once-daily subcutaneous injection without the need for coagulation laboratory monitoring or dose adjust- ment

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

FONDAPARINUX - MOA

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

bull Uses-① The FDA has approved fondaparinux for initial treatment of

acute PE and acute DVT as a bridge to oral anticoagulation with warfarin

② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later)

③ At times fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin

The dose for VTE prophylaxis is a fixed low dose of 25 mg once daily regardless of body weight

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

WARFARINbull Warfarin is a vitamin K antagonist that prevents gamma-

carboxylation activation of coagulation factors II VII IX and Xbull Half life of factor VII is 6 hours whereas half life of factor II is 5

daysbull Its activity is measured by Prothrombin Time bull The full anticoagulant effect of warfarin may not be apparent

for 5 to 7 days even if the prothrombin time used to monitor warfarinrsquos effect becomes elevated more rapidly

bull For VTE patients the usual target INR range is between 20 and 30

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Warfarin - MOA

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Overlap of Warfarin and LMWHbull Warfarin monotherapy decreases the levels of two

endogenous anticoagulants proteins C and S thus increasing thrombogenic potential

bull Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days and preferably till the target INR is achieved 2 times 24 hours apart

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Starting dosebull Warfarin is traditionally dosed by an ldquoeducated guessrdquo coupled

with trial and errorbull One open-label randomized trial compared two warfarin ini-

tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE95 The median time to two consecutive target INRs was 5 days in both groups (P = 069)

bull Computer-assisted warfarin dosing can be used for better results

Quiroz R Gerhard-Herman M Kosowsky JM et al Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism Am J Cardiol 98535 2006

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Warfarin Interactions

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Novel Anticoagulantsbull Immediate onset of action bull Short half lifebull Administration in fixed doses without routine laboratory

coagulation monitoring bull Few drug-drug or drug-food interactions bull No bridging is needed with a parenteral anticoagulant when

they have to be stopped for any diagnostic or surgical procedure

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Dabigatranbull It is a direct thrombin inhibitor bull It has been proven noninferior to enoxaparin in three major

orthopedic surgery trials of total knee or hip arthroplasty

bull In a large-scale trial of acute VTE dabigatran was noninferior to warfarin

Wolowacz SE Roskell NS Plumb JM et al Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty A meta-analysis Thromb Haemost 10177 2009

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Rivaroxabanbull Rivaroxaban is a factor Xa inhibitorbull It has 80 bioavailabilitybull Half life is 5 to 9 hours bull It is approved for treatment of acute DVT and acute PE as

monotherapy bull Its efficacy has proven superior to enoxaparin to prevent VTE

after total knee and hip arthroplasty bull Both dabigatran and rivaroxaban are approved in Canada and

Europe for VTE prevention after knee or hip arthroplasty Eriksson BI Borris LC Friedman RJ et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 3582765 2008

Lassen MR Ageno W Borris LC et al Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty N Engl J Med 3582776 2008

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN

MODE Oral Oral Oral Oral

MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor

DoseVTE Prophylaxis

20 mg OD 25 mg BD - 110 mg on day 1 220mg OD

Dose VTE Treatment

15 mg BD X 3wks 20 mg OD

10 mg BD X 1wk 5 mg BD

60 mg OD 150 mg BD

Antidote ANDEXANAT ALFA

ANDEXANAT ALFA

ANDEXANAT ALFA

IDARUCIZUMAB

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Cancer and VTE ndash LMWH should be used as monotherapy

Unprovoked PEProximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 15 and 2

Optimal Duration of Anticoagulation

CLINICAL SETTING RECOMMENDATION First provoked PEproximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT

3 months

Second provoked VTE Uncertain

Second VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is resolved

Unprovoked PEProximal leg DVT Consider indefinite duration

First unprovoked calf DVT 3 months

Second unprovoked calf DVT Uncertain

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Recurrent VTEbull Recurrent VTE has a high fatality rate especially when it

occurs despite ongoing anticoagulation within the first week of diagnosis115

bull Even after completion of a 6-month course of anticoagulation the case fatality rate for recurrent PE remains high116

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

D-dimer in Recurrent VTEbull In the placebo group of the PREVENT trial D-dimer was

measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels

bull Howeveran overview of 1888 patients who had unprovoked VTE showed that they had a high 35 annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation127

Shrivastava S Ridker PM Glynn RJ et al D-dimer factor VIII coagulant activity low-intensity warfarin and the risk of recurrent venous thromboembolism J Thromb Haemost 41208 2006

Verhovsek M Douketis JD Yi Q et al Systematic review D-dimer to predict recurrent disease after stopping

anticoagulant therapy for unprovoked venous thromboembolism Ann Intern

Med 149481 W494 2008

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

bull In a separate meta-analysis of patients with idiopathic VTE those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 72 recurrence rate

bull No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation

Bruinstroop E Klok FA Van De Ree MA et al Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism A meta-analysis J Thromb Haemost 7611 2009

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

FIBRINOLYSISbull Successful fibrinolysis reverses right heart failure and may

result in a lower rate of death and recurrent PE by① Dissolving much of the anatomically obstructing pulmonary

arterial thrombus② Preventing the continued release of serotonin and other

neurohumoral factors that exacerbate pulmonary hypertension

③ Lysing much of the source of the thrombus in the pelvic or deep leg veins thereby decreasing the likelihood of recurrent PE

bull Wide windowbull Patients who receive thrombolysis up to 14 days after new

symptoms or signs maintain an effective response

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Fibrinolytic Agents

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Fibrinolytic AgentsFibrinolytic FDA

Indication for PE

Direct Plasminogen Activator

Dosage Fibrin Specificity

PAI Resistance

Streptokinase Yes No 250 000-IU IV bolus followed by100 000-IUh infusion for 12ndash24 h

- -

Urokinase Yes No 4400-IUkg bolus followed by 4400IU 1113099 kg11130991 1113099 h11130991 for 12ndash24 h

- -

Alteplase Yes Yes 100-mg IV infusion over 2 h

++ ++

Reteplase No Yes Double 10-U IV bolusdagger 30 min apart

+ +

Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30ndash50 mg with a 5-mg step every 10 kg from 111309960 to 111309990 kg)

+++ +++

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Use of Heparin before and after Thrombolysis

1 Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis

2 Proceed to order thrombolysis Use the US Food and Drug Administrationndashapproved regimen of alteplase 100 mg as a continuous infusion during 2 hours

3 Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT)

4 Infuse thrombolysis as soon as it becomes available 5 At the conclusion of the 2-hour infusion obtain a stat aPTT 6 If the aPTT is 80 seconds or less (which is almost always the case) 7 resume UFH as a continuous infusion without a bolus 8 If the aPTT exceeds 80 seconds hold off from resuming heparin for 4

hours and repeat the aPTT At this time the aPTT has virtually always declined to lt80 seconds If this is the case resume continuous infusion of intravenous UFH without a bolus

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Use of Heparin before and after Thrombolysis

STOP IV UFH INFUSION

Resume UFH as continous infusion

APTT gt 80 secAPTT lt 80 sec (almost always)

Obtain APTT after 2 hours of infusion

Give ALTEPLASE 100 mg IV over 2 hour infusion

Proceed to thrombolysis Do not delay thrombolysis for obtaining APTT

APTT will be lt 80 sec

Hold Heparin for 4 hours and repeat APTT

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Fibrinolysis in Submassive PEbull Death or hemodynamic collapse within 7 days of fibrinolysis is

reduced by 56 of patients with submassive PE

bull But risk of hemorrhagic stroke is 2 in firbrinolysed patients as compared with 02 in patients who only receive heparin

Reference

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

IVC FILTERS Indications -1) Contraindication to anticoagulation2) Complication to anticoagulants3) Failure to achieve target INR inspite of anticoagulation4) Free floating Ileo-femoral or IVC thrombus

2 types1) Permanent2) Retrievable

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Normal Venogram Various types of IVC filters

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Catheter Embolectomy

1) Thrombus fragmentation

2) Rheolytic thrombectomy

3) Suction thrombectomy

4) Rotational thrombectomyC

5) Conventional catheter-directed thrombolysis (CDT)

6) Pharmacomechanical thrombolysis (PMT)

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Limitations

1 Poor maneuverability

2 Mechanical hemolysis

3 Macroembolization

4 Microembolization

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

SURGICAL EMBOLECTOMY

bull Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis

bull Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale

bull Patients refractory to thrombolysis

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Prophylaxis for VTE

bull PE is the most preventable cause of in-hospital death

bull Mechanical Measures ndash Reduce DVT risk by 60

bull Intermittent pneumatic compression devicesbull Enhance endogenous fibrinolysisbull Increase venous blood flow and graduated

compression stockings

bull Graduated compression stockings

Urbankova J Quiroz R Kucher N et al Intermittent pneumatic compression and deep vein thrombosis prevention A meta-analysis in postoperative patients Thromb Haemost 941181 2005

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

Unconventional Approach

bull VITAMIN Ebull In Womenrsquos Health Study involving 39876 women

receiving 600 units of vitamin E bull 21 reduction in VTE was seenbull 44 reduction in patients having prior VTEbull 49 reduction in patients having Factor V Leiden mutation or the

prothrombin gene mutation bull Vitamin E may reduce VTE risk in women especially

those with a prior history of VTE or with a genetic predisposition

Glynn RJ Ridker PM Goldhaber SZ et al Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism Report from the Womenrsquos Health Study Circulation 1161497 2007

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71

STATINS

bull In the JUPITER study 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mgdL and hsCRP levels of 20 mgdL or higher were given Rosuvastatin 20mgdaybull Symptomatic VTE was reduced by 43 in the

Rosuvastatin group (P = 0007)

bull Thus Rosuvastatin appears to prevent VTE

Glynn RJ Danielson E Fonseca FA et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism N Engl J Med 3601851 2009

• MANAGEMENT OF VENOUS THROMBOEMBOLISM
• Introduction
• Epidemiology
• Modifiable Risk Factors
• Risk Factors
• DVT
• Slide 7
• Pathophysiology cont
• Slide 9
• Clinical Features
• Slide 11
• Slide 12
• Chest X-Ray
• Slide 14
• D-dimer
• CT ANGIOGRAPHY
• Slide 17
• Echocardiogram
• Slide 19
• Slide 20
• Venous Ultrasonography
• Other Modalities
• Differential Diagnosis
• Clinical Decision Rules
• Wells Criteria for clinical likelihood of PE
• Slide 26
• Slide 27
• Slide 28
• TREATMENT
• Anticoagulation
• Slide 31
• Low Molecular Weight Heparin
• Heparin and LMWH - MOA
• Difference LMWH and UFH
• LMWH
• When monitoring needed in LMWH
• FONDAPARINUX
• FONDAPARINUX - MOA
• Slide 39
• WARFARIN
• Warfarin - MOA
• Overlap of Warfarin and LMWH
• Starting dose
• Warfarin Interactions
• Novel Anticoagulants
• Dabigatran
• Rivaroxaban
• Slide 48
• Slide 49
• Slide 50
• Recurrent VTE
• D-dimer in Recurrent VTE
• Slide 53
• FIBRINOLYSIS
• Slide 55
• Fibrinolytic Agents
• Fibrinolytic Agents (2)
• Use of Heparin before and after Thrombolysis
• Use of Heparin before and after Thrombolysis (2)
• Slide 60
• Fibrinolysis in Submassive PE
• IVC FILTERS
• Slide 63
• Catheter Embolectomy
• Limitations
• SURGICAL EMBOLECTOMY
• Slide 67
• Prophylaxis for VTE
• Slide 69
• Unconventional Approach
• Slide 71