CHEST GUIDELINES: 2008 TO 2012

CHEST GUIDELINES: 2008 TO 2012Danny HillPGY-5, HematologyRecommendationsVTEAcute Management of VTERisk StratificationDuration of AnticoagulationBleeding AssessmentRecurrence AssessmentUpper Extremity ThrombosisSuperficial Vein ThrombosisPost Thrombotic SyndromeIVC FiltersCTEPHSplanchnic Vein Thrombosis

VTE EpidemiologyIncidence in total population ~ 70113 cases/100,000/year

Age exponential increase in VTE with age, particularly after age 40 years2535 years old 30 cases/100,000 persons7079 years old 300500 cases/100,000 persons

Relative incidence of PE vs DVT Absent autopsy diagnosis: 33% PE; 66% DVTWith autopsy: 55% PE, 45% DVTRisk Factor Distribution25% to 50% unprovoked

15% to 25% associated with cancer

20% following surgery

5% to 15%, misc

VTE Presentation

TreatmentIn 1938 Murray and Best described treating surgical patients with DVT/PE with UFH

In 1947, Allen et.al described treating surgical patients with DVT/PE with UFH + Dicoumarol

In 1960, Barritt and Jordan published RCT comparing UFH + nicoumalone vs expectant management

Buller HR, Sohne M, Middeldorp S. J Thromb Haemost 2005; 3: 155460Case Fatality Rates Without ACLandmark RCT by Barritt and Jordan in 1960 conducted for 1 year before study closure~ 25% will have a fatal recurrence (5/19)~ 25% will experience recurrent not fatal PE (5/19)0 fatalities or recurrent events in the AC arm (0/54)

The estimated case-fatality rate of recurrent VTE without anticoagulant therapy is ~ 50%Barritt DW, Jordan SC. Lancet 1960; 1: 130912VTE Recurrence

Time course of rehospitalization for recurrent DVT or PE among patients initially hospitalized for DVT without prior hospitalization for VTE9How good is Coumadin? (@ 1 year for PE)Rate of recurrence ~ 50%Rate of fatal recurrence ~ 25%

Case fatality rate ~ 50%Rate of recurrence ~ 5%Rate of fatal recurrence ~ 1%

Case fatality rate ~ 20%

LoveCoumadin

Suspected VTEAnticoagulation of Presumptive VTE2008For patients with a high clinical suspicion of DVT, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C)2012In patients with a high clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (Grade 2C)2012In patients with an intermediate clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C)2012In patients with a low clinical suspicion of acute VTE, we suggest not treating with parenteral anticoagulants while awaiting the results of diagnostic tests, provided test results are expected within 24 h (Grade 2C)General ConsiderationsManagement of VTEInitial Anticoagulation of Acute VTE2008For patients with objectively confirmed VTE, we recommend short-term treatment with SC LMWH, IV UFH, SC UFH, or SC fondaparinux (Grade 1A) rather than no such acute treatment2012In patients with acute VTE, we recommend initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B)Timing of Initiation of VKA2008In patients with acute VTE, we recommend initiation of VKA together with LMWH, UFH, or fondaparinux on the first treatment day rather than delayed initiation of VKA (Grade 1A)

2012In patients with VTE, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation (Grade 1B)Initiation of VKA and Duration of Parenteral Anticoagulant Therapy2008In patients with acute VTE, we recommend initiation of VKA together with LMWH, UFH, or fondaparinux on the first treatment day rather than delayed initiation of VKA (Grade 1A).

In patients with acute VTE, we recommend initial treatment with LMWH, UFH or fondaparinux for at least 5 days and until the INR is > 2.0 for at least 24 h (Grade 1C)2012In patients with acute VTE, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is > 2.0 for at least 24 h (Grade 1B)Current Choices of Initial Anticoagulant RegimenSix options are available for the initial treatment of VTE:(1) SC LMWH without monitoring(2) IV UFH with monitoring(3) SC UFH given based on weight initially, with monitoring(4) SC UFH given based on weight initially, without monitoring(5) SC fondaparinux given without monitoring

(6) PO RivaroxabanChoice of Initial Anticoagulant Regimen2008In patients with acute VTE, we recommend initial treatment with LMWH, UFH, or fondaparinux for at least 5 days and until the INR is > 2.0 for 24 h (Grade 1C)

2012In patients with acute VTE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is > 2.0 for 24 h (Grade 1B)

20082012In patients with acute VTE treated with LMWH, we suggest once- over twice-daily administration (Grade 2C)Intensity of Anticoagulation2008In patients with VTE, we recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (range, 2.0 to 3.0) for all treatment durations (Grade 1A)2012In patients with VTE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B)2008For patients with unprovoked VTE who have a strong preference for less frequent INR testing to monitor their therapy, after the first 3 months of conventional-intensity anticoagulation (INR range, 2.0 to 3.0), we recommend low-intensity therapy (range, 1.5 to 1.9) with less frequent INR monitoring over stopping treatment (Grade 1A)

We recommend against high-intensity VKA therapy (INR range, 3.1 to 4.0) compared to an INR range of 2.0 to 3.0 (Grade 1A)Novel Anticoagulants for the Long-termTreatment of DVTDabigatran: One completed study has directly compared dabigatran and VKA for the first 6 months of treatment of VTEThis study suggests that treatment with dabigatran or VKA therapy is associated with a similar frequency of recurrent VTE, major bleeding, and death.

Rivaroxaban: A single study has directly compared rivaroxaban (without initial parenteral anticoagulation) with parenteral anticoagulation and VKA in patients with acute DVTResults suggested that treatment with rivaroxaban and VKA therapy are associated with a similar frequency of recurrent VTE, major bleeding, and death.Choice of Anticoagulant Regimenfor Long-term Therapy: Nonmalignant20082012In patients with VTE and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C).

For patients with VTE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C)Cancer Associated VTE~10-fold higher risk of dying and a threefold higher risk of recurrent VTE and major bleeding during the first 3 or 6 months of treatment

Different mechanisms of thrombosis that may be associated with a poor response to VKA therapyCancer Associated DVT20082012In patients with VTE and active cancer, if the risk of bleeding is not high, we recommend extended anticoagulant therapy over 3 months of therapy (Grade 1B), and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B)Choice of Anticoagulant Regimenfor Long-term Therapy: Malignant2008For patients with VTE and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A)

2012In patients with VTE and cancer, we suggest LMWH over VKA therapy (Grade 2B).

In patients with VTE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B)2008For these patients, we recommend subsequent anticoagulant therapy with VKA or LMWH indefinitely or until the cancer is resolved.2012In patients with VTE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the first 3 months (Grade 2C)Among patients with VTE and cancer, the advantages of LMWH over VKA therapy are expected to be greatest in the following patients:(1) with metastatic disease(2) being treated with aggressive chemotherapy(3) presenting with extensive VTE(4) with liver dysfunction(5) with poor or unstable nutritional status(6) who wish to avoid laboratory monitoring of coagulationAsymptomatic VTE2008In patients who are unexpectedly found to have asymptomatic VTE, we recommend the same initial and long-term anticoagulation as for comparable patients with symptomatic VTE (Grade 1C)2012In patients who are incidentally found to have asymptomatic of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic VTE (Grade 2B)Initial Management of Distal DVTIsolated Distal DVTisolated distal DVT = DVT of the peroneal, posterior tibial, anterior tibial veins without involvement of the popliteal or more proximal veins

If all patients with suspected DVT have ultrasound examination of the calf veins (whole leg ultrasound), isolated distal DVT accounts for ~ 50% of all DVT diagnosed

Natural history studies suggest that when left untreated, 15% of symptomatic distal DVT will extend into the proximal veins if extension does not occur within 2 weeks, it is unlikely to occur subsequently

Treatment of Distal DVTA single controlled trial of 51 patients with symptomatic isolated distal DVT, all of whom were initially treated with heparin, found that 3 months of VKA therapy prevented DVT extension and recurrent VTE (29% vs 0%, P , .01)Isolated Distal DVT2012In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension, we suggest initial AC over serial imaging of the deep veins (Grade 2C)Isolated Distal DVT2012In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial AC (Grade 2C)Risk Factors for Extension+ Ddimer

Thrombosis that is extensive or close to the proximal veins (eg, > 5 cm in length, involves multiple veins, >.7 mm in maximum diameter)

Unprovoked DVT

Active cancer

History of VTE

Inpatient statusTreatment of Distal DVT2008For patients with a first isolated distal DVT that is unprovoked, we suggest that 3 months of anticoagulant therapy is sufficient rather than indefinite therapy2012In patients with acute isolated distal DVT of the leg who are managed with initial anticoagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B) If Expectant Management2012In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no AC if the thrombus does not extend (Grade 1B); we suggest AC if the thrombus extends but remains confined to the distal veins (Grade 2C); we recommend AC if the thrombus extends into the proximal veins (Grade 1B)SummaryInitial Management of Proximal DVTEarly Ambulation of Patients With Acute DVT2008In patients with acute DVT, we recommend early ambulation in preference to initial bed rest when this is feasible (Grade 1A)2012In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C)Inpatient vs Outpatient Management2008In patients with acute DVT, we recommend initial treatment with LMWH once or twice daily, as an outpatient if possible (Grade 1C), or as an inpatient if necessary (Grade 1A), rather than treatment with IV UFH.

2012In patients with acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B)A number of trials have compared LMWH administered at home (without hospital admission or after early discharge) in a substantial proportionof patients, with IV UFH administered in the hospital . This evidence suggests that home treatment is not associated with an increase in mortality,recurrent VTE, or major bleeding and may be associated with improved outcomes.46Catheter-Directed Thrombolysis for Acute DVTPatients with DVT that involves the iliac and common femoral veins are at highest risk for PTS and therefore, are the subset with the greatest potential to benefit from thrombus removal strategies

Thrombus removal strategies are indicated in patients with the very rare complication of impending venous gangrene despite optimal anticoagulant therapy

Patients who are most likely to benefit from CDT have iliofemoral DVT, symptoms for < 14 days, good functional status, life expectancy of >1 year, and a low risk of bleedingThis evidence suggests that CDT may reduce PTS and improve quality of life without being associated with an unacceptable increase in bleeding. However,the quality of evidence is low for mortality, recurrent VTE, and major bleeding because of very serious imprecision, and is low for PTS because of indirectness.

47Catheter-Directed Thrombolysis for Acute DVT2008In selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, symptoms for 1 year) who have a low risk of bleeding, we suggest that CDT may be used to reduce acute symptoms and postthrombotic morbidity (Grade 2B)2012In patients with acute proximal DVT of the leg, we suggest AC therapy alone over catheter-directed thrombolysis (Grade 2C)Systemic Thrombolytic Therapy forAcute DVT2008In selected patients with extensive proximal DVT (eg, symptoms for < 14 days, good functional status, life expectancy of > 1 year) who have a low risk of bleeding, we suggest that systemic thrombolytic therapy may be used to reduce acute symptoms and postthrombotic morbidity (Grade 2C)2012In patients with acute proximal DVT of the leg, we suggest AC therapy alone over systemic thrombolysis (Grade 2C)A meta-analysis 138 summarized the findings of trials that assessed mortality, recurrent VTE, major bleeding, and PTS. This evidence suggests that systemic thrombolysis has the potential to reduce PTS at the expense of an increase in major bleeding. However, the overall quality of this evidence is low because of imprecision and risk of bias.We believe that systemic thrombolysis should be considered only in patients who meet all of the following criteria: iliofemoral DVT, symptomsfor 14 days, good functional status, life expectancy of 1 year, and low risk of bleeding49Operative Venous Thrombectomy forAcute DVT2008In selected patients with acute iliofemoral DVT (eg, symptoms for < 7 days, good functional status, and life expectancy of > 1 year), we suggest that operative venous thrombectomy may be used to reduce acute symptoms and postthrombotic morbidity (Grade 2C)2012In patients with acute proximal DVT of the leg, we suggest AC therapy alone over operative venous thrombectomy (Grade 2C)A single small randomized trial with extended follow-up compared iliofemoral venous thrombectomy with a temporary arteriovenous fistula plus anticoagulation with anticoagulation alone. Results at 6 months, 5 years, and 10 years suggested improved iliac vein patency, less leg swelling, and fewer leg ulcers with thrombectomy.We believe that operative venous thrombectomy should be considered only if all of the following criteria are met: iliofemoral DVT, symptomsfor >7 days (criterion used in the single randomized trial), good functional status, life expectancy of >1 year, and both resources and expertiseare available.50Initial Management of PEMortalityOf patients who are diagnosed with PE and start treatment, 5% die of the initial PE or another PE within the next 7 days

Risk of dying of PE is ~ 70% if cardiopulmonary arrest occurs (1% of patients), 30% if there is shock requiring inotropic support (5% of patients), and 2% in patients who are not hypotensive.Risk Stratification20082012In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg, after first 5 days of treatment) (Grade 2B)Risk StratificationSeveral clinical prediction rules exist to identify patients with acute PE who have a low risk of serious complications and may be suitable for treatment at home.EKGBNP & TropsTTECTPAClinical Risk ScoresThe PE Severity Index (PESI) is best validated

Simplified PESI

Jimenez, D. et al. Arch Intern Med 2010;170:1383-1389Simplified PESI1) age > 802) cancer3) Cardiopul disease4) tachy5) hypotension6) hypoxiaPatients with a score of 0 (ie, no variables present) are categorized as low risk; those with a score of > 1 (any variable present) are high risk.30 Day Mortality

Jimenez, D. et al. Arch Intern Med 2010;170:1383-1389OriginalSimplifiedSensitivity88.5 (81.4-95.5)96.1 (91.9-100.0)Specificity38.4 (35.2-41.532.9 (29.9-36.0)LR +1.44 (1.31-1.581.43 (1.35-1.53)LR -0.30 (0.16-0.560.12 (0.04-0.36)

Jimenez, D. et al. Arch Intern Med 2010;170:1383-1389ACCP Risk StratificationPatients with acute PE who meet the following criteria appear to be suitable for treatment out of the hospital:

(1) Clinically stable with good cardiopulmonary reserve (eg, PESI score of , 65 yPrevious bleedingCancerRenal failureLiver failureThrombocytopeniaPrevious strokeDiabetesAnemiaAntiplatelet therapyPoor anticoagulant controlComorbidity and reduced functional capacityRecent surgeryFrequent fallsAlcohol abuseACCP Bleeding Risk ModelLow (0 RF)Int (1 RF)High (>1 RF)3 months AC(%)Baseline Risk0.61.24.8Risk Increase1.02.08.0Total1.63.212.8> 3 months AC(%/y)

Baseline Risk0.3 0.6 >2.5Risk Increase0.51.0 >4.0Total0.81.6>6.5

Estimated Absolute Difference in Recurrent VTE and Major Bleeding EventsOutcomes After 5 y of TreatmentRisk of BleedingLowIntermediateHighFirst VTE provoked by surgeryRecurrent VTE reduction per 1,000 26 (19-27) (1 fatal) 26 (19-27) (1 fatal) 26 (19-27) (1 fatal)Major bleeding increase per 1,000 24 (2-73) (3 fatal) 49 (1-173) (5 fatal) 98 (1-346) (11 fatal)Estimated Absolute Difference in Recurrent VTE and Major Bleeding EventsOutcomes After 5 y of TreatmentRisk of BleedingLowIntermediateHighFirst VTE provoked by a nonsurgical factorRecurrent VTE reduction per 1,000 132 (93-137) (5 fatal) 132 (93-137) (5 fatal) 132 (93-137) (5 fatal)Major bleeding increase per 1,000 24 (2-73) (3 fatal) 49 (1-173) (5 fatal) 98 (1-346) (11 fatal)Estimated Absolute Difference in Recurrent VTE and Major Bleeding EventsOutcomes After 5 y of TreatmentRisk of BleedingLowIntermediateHighFirst unprovoked VTERecurrent VTE reduction per 1,000 264 (186-273) (10 fatal) 264 (186-273) (10 fatal) 264(186-273) (10 fatal)Major bleeding increase per 1,000 24 (2-73) (3 fatal) 49 (1-173) (5 fatal) 98 (1-346) (11 fatal)Estimated Absolute Difference in Recurrent VTE and Major Bleeding EventsOutcomes After 5 y of TreatmentRisk of BleedingLowIntermediateHighSecond unprovoked VTERecurrent VTE reduction per 1,000 396 (279-409) (14 fatal) 396 (279-409) (14 fatal) 396 (279-409) (14 fatal)Major bleeding increase per 1,000 24 (2-73) (3 fatal) 49 (1-173) (5 fatal) 98 (1-346) (11 fatal)Provoked(Surgical & Nonsurgical) Distal DVT2012In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor, we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time limited period (eg, 6 or 12 months) (Grade 1B) or extended therapyProvoked Surgical Proximal DVT & PE2008For patients with DVT secondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A)2012In patients with a proximal DVT of the leg or PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over: (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B)Provoked Nonsurgical DVT & PE2012In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with AC for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time limited period (eg, 6 or 12 months) (Grade 1B), and (iii) extended therapy1st Unprovoked Distal DVT2008For patients with a first isolated distal DVT that is unprovoked, we suggest that 3 months of anticoagulant therapy is sufficient rather than indefinite therapy (Grade 2B)2012In patients with a first VTE that is an unprovoked isolated distal DVT of the leg, we suggest 3 months of anticoagulant therapy over extended therapy in those with a low bleeding risk (Grade 2B), and recommend 3 months of anticoagulant treatment in those with a moderate or high bleeding risk1st Unprovoked Proximal DVT & PE2008For patients with unprovoked DVT or PE, we recommend treatment with a VKA for at least 3 months (Grade 1A).

We recommend that after 3 months of anticoagulant therapy, all patients with unprovoked DVT or PE should be evaluated for the risk-benefit ratio of long-term therapy (Grade 1C)2012In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B).

After 3 months of treatment, patients with unprovoked DVT of the leg or PE should be evaluated for the risk-benefit ratio of extended therapy.1st Unprovoked Proximal DVT or PE & Low Risk Bleeding2008For patients with a first unprovoked VTE that is a proximal DVT or PE, and in whom risk factors for bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment (Grade 1A)2012In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)1st Unprovoked Proximal DVT or PE & High Risk Bleeding20082012In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B)2nd Unprovoked VTE & Low Risk Bleeding2008For patients with a second episode of unprovoked VTE, we recommend long-term treatment (Grade 1A)2012In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B), and we suggest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B)2nd Unprovoked VTE & High Risk Bleeding20082012In patients with a second unprovoked VTE who have a high bleeding risk, we suggest 3 months of anticoagulant therapy over extended therapy (Grade 2B)Upper Extremity DVT (UEDVT)About 5% to 10% of VTE involve the upper extremities.

UEDVT involves the subclavian, axillary, or brachial veins and may include extension to the brachiocephalic vein, superior vena cava, or the internal jugular vein

UEDVT may lead to complications, including symptomatic PE (5% of patients), recurrent UEDVT (8% at 5 years), and PTS of the arm (20% of patients)UEDVT includes two etiologic groups:

Primary (unprovoked with or without thrombophilia, effort-related and thoracic outlet syndrome) Paget-Schroetter Syndrome

Secondary (provoked by central venous catheters, pacemakers, or cancer) Secondary UEDVT accounts for 75% of cases.No randomized controlled studies have evaluated acute anticoagulation for initial treatment of UEDVT.

Several small prospective cohort studies have reported low rates of recurrent DVT, PE, and major bleeding when UEDVT was treated similarly to leg DVT

Upper Extremity DVT (UEDVT)2008For patients with acute upper-extremity DVT (UEDVT), we recommend initial treatment with therapeutic doses of LMWH, UFH, or fondaparinux (Grade 1C)2012In patients with acute UEDVT that involves the axillary or more proximal veins, we recommend acute treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such acute treatment (Grade 1B)20082012In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B)Thrombolysis2008For most patients with acute UEDVT, we recommend against the routine use of systemic or catheter-directed thrombolytic therapy (Grade 1C)2012In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis (Grade 2C)Patients who (i) are most likely to benefit from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv)attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagulation alone.1082008In selected patients with acute UEDVT (eg, in those with a low risk of bleeding and severe symptoms of recent onset), we suggest that CDT may be used for initial treatment if appropriate expertise and resources are available (Grade 2C)20082012In patients with UEDVT who undergo thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombolysis (Grade 1B)Duration of Therapy20082012In patients with UEDVT that involves the axillary or more proximal veins, we suggest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B)20082012In patients who have UEDVT that is not associated with a central venous catheter or with cancer, we recommend 3 months of anticoagulation over a longer duration of therapy (Grade 1B)Catheter Associated Venous Thrombosis20082012In most patients with UEDVT that is associated with a central venous catheter, we suggest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C)20082012In patients who have UEDVT that is associated with a central venous catheter that is not removed, we recommend that anticoagulation is continued as long as the central venous catheter remains over stopping after 3 months of treatment (Grade 1C)20082012In patients who have UEDVT that is associated with a central venous catheter that is removed, we recommend 3 months of anticoagulation over a longer duration of therapy (Grade 1B)Superficial Vein Thrombosis (SVT)Superficial Vein Thrombosis (SVT)It usually affects the lower limbs; often involves a varicose vein; is associated with chronic venous insufficiency, malignancy, thrombophilia, pregnancy or estrogen therapy, obesity, sclerotherapy, long-distance travel, and a history of VTE; or may be unprovoked.

The long saphenous vein is involved in ~ 2/3 of lower-limb SVTAlthough traditionally considered a benign disease, a number of studies indicate that the consequences of SVT may be more serious. Proximal DVT & PE

A prospective study of 844 patients with acute SVT of 5 cm found that at initial presentation, 4% of patients had symptomatic PE, and routine ultrasound detected proximal DVT in 10% and distal DVT in an additional 13% of patients.CALISTO Trial

proximal DVT + PE @ 47d = 1.3 vs 0.2%The primary efficacy outcome was a composite of death from any cause, symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis119Provoked SVT2008For patients with symptomatic infusion thrombophlebitis as a complication of IV infusion, we suggest oral diclofenac or another NSAID (Grade 2B), topical diclofenac gel (Grade 2B), or heparin gel (Grade 2B) until resolution of symptoms or for up to 2 weeks.

We recommend against the use of systemic anticoagulationAnticoagulant therapy generally is not used to treat SVT that occurs in association with an IV infusion (ie, infusion thrombophlebitis).120Unprovoked SVT2008For patients with SVT, we suggest prophylactic or intermediate doses of LMWH (Grade 2B) or intermediate doses of UFH (Grade 2B) for at least 4 weeks.

We suggest that as an alternative to 4 weeks of LMWH or UFH, VKA (target INR, 2.5; range, 2.0 to 3.0) can be overlapped with 5 days of UFH and LMWH and continued for 4 weeks (Grade 2C)2012In patients SVT of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B)

Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTEare likely to decline anticoagulation.12120082012In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C)Post Thrombotic SyndromePTS of the LegPTS is a cluster of leg symptoms and signs attributable to previous DVT.

The most prominent symptoms are chronic dependent swelling and pain, discomfort on walking, and skin discoloration; the most severe manifestation is a venous ulcer of the lower leg.

PTS occurs in ~ one-third of patients after acute DVT and up to two-thirds who have had an iliofemoral DVT

Prevention of Lower Extremity PTS2008For a patient who has had a symptomatic proximal DVT, we recommend the use of an elastic compression stocking with an ankle pressure gradient of 30 to 40 mm Hg if feasible (Grade 1A)2012In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B)Compression stockings should be worn for 2 years, and we suggest beyond that if patients have developed PTS and fi nd the stockings helpful.1252008Compression therapy should be started as soon as feasible after starting anticoagulant therapy and should be continued for a minimum of 2 years, and longer if patients have symptoms of PTSTreatment of Lower Extremity PTS2008For patients with mild edema of the leg due to PTS, we suggest the use of elastic compression stockings (Grade 2C)

For patients with severe edema of the leg due to PTS, we suggest a course of intermittent pneumatic compression (Grade 2B)2012In patients with PTS of the leg, we suggest a trial of compression stockings (Grade 2C)

In patients with severe PTS of the leg that is not adequately relieved by compression stockings, we suggest a trial of an intermittent compression device (Grade 2B)

2008In patients with persistent venous ulcers, we suggest that rutosides, or sulodexide be added to local care and compression (Grade 2B)2012In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defibrotide, and hidrosmin) not be used (Grade 2C)UEDVT PTS Prevention2008For patients at risk for PTS after UEDVT, we do not suggest routine use of elastic compression or venoactive medications (Grade 2C)2012In patients with acute symptomatic UEDVT, we suggest against the use of compression sleeves or venoactive medications (Grade 2C)Treatment of UEDVT PTS2008In patients with UEDVT who have persistent edema and pain, we suggest elastic bandages or elastic compression sleeves to reduce symptoms of PTS of the upper extremity (Grade 2C)2012In patients who have PTS of the arm, we suggest a trial of compression bandages or sleeves to reduce symptoms (Grade 2C)20082012In patients with PTS of the arm, we suggest against treatment with venoactive medications (Grade 2C)IVC FiltersNo randomized trial or prospective observational study has evaluated IVC filters as sole therapy (ie, without concurrent anticoagulation) in patients with DVT

IVC filters can be used instead of initial anticoagulant therapy in patients with acute PE if there is an unacceptable risk of bleeding or as an adjunct to anticoagulation

The PREPIC study, which evaluated IVC filters as an adjunct to anticoagulation in 400 high-risk patients with proximal DVT, showed that filters reduced PE, increased DVT, and did not change overall frequency of VTE (DVT and PE combined) or mortalityVena Caval Filters for the InitialTreatment of VTE2008For patients with proximal DVT or PE, we recommend against the routine use of a IVC filter in addition to anticoagulants (Grade 1A)2012In patients with acute DVT of the leg or PE, we recommend against the use of an IVC filter in addition to anticoagulants (Grade 1B)

2008For patients with acute proximal DVT or PE, if anticoagulant therapy is not possible because of the risk of bleeding, we recommend placement of an IVC filter (Grade 1C)2012In patients with acute proximal DVT of the leg or PE and contraindication to anticoagulation, we recommend the use of an IVC filter (Grade 1B)2008For patients with acute DVT who have an IVC filter inserted as an alternative to anticoagulation, we recommend that they should subsequently receive a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 1C)2012In patients with acute proximal DVT of the leg or PE and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B)We do not consider that a permanent IVC filter, of itself, is an indication for extended anticoagulation136CTEPHChronic ThromboembolicPulmonary Hypertension (CTPH)20082012In patients with CTPH, we recommend extended anticoagulation over stopping therapy (Grade 1B)20082012In selected patients with CTPH, such as those with central disease under the care of an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C)Splanchnic Vein ThrombosisSplanchnic Vein Thrombosis20082012In patients with symptomatic splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we recommend anticoagulation over no anticoagulation (Grade 1B)20082012In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation (Grade 2C)20082012In patients with symptomatic hepatic vein thrombosis, we suggest anticoagulation over no anticoagulation (Grade 2C)20082012In patients with incidentally detected hepatic vein thrombosis, we suggest no anticoagulation over anticoagulation (Grade 2C)The EndFondaparinux vs Placebo for Acute SVTOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With No FondaparinuxRisk Difference With Fondaparinux (95% CI)Mortality3,002 (1 study), 3 moModerated-g due to imprecision RR 1.99 (0.18-21.87)4 per 1,000h4 more per 1,000 (from 3 fewer to 83 more)VTE3,002 (1 study), 3 moHighdRR 0.18 (0.06-0.53)33 per 1,000h27 fewer per 1,000 (from 16 fewer to 31 fewer)SVT recurrence3,002 (1 study), 3 moHighdRR 0.31 (0.14-0.68)19 per 1,000h13 fewer per 1,000 (from 6 fewer to 16 fewer)Major bleeding2,987(1 study), 47 dModerated,e,i due to imprecision RR 0.99 (0.06-15.86)e1 per 1,0000 fewer per 1,000 (from 1 fewer to 10 more)Risk Factors for BleedingAge > 65 y17-25Age > 75 y17-21,23,25-34Previous bleeding18,24,25,30,33-36Cancer20,24,30,37Metastatic cancer36.38,Renal failure18,24,25,28,30,33Liver failure19,21,27,28Thrombocytopenia27,36Previous stroke18,25,27,39Diabetes18,19,28,32,34Anemia18,21,27,30,34Antiplatelet therapy19,27,28,34,40Poor anticoagulant control22,28,35Comorbidity and reduced functional capacity24,28,36Recent surgery21,41,bFrequent falls27Alcohol abuse24Estimated Absolute Risk of Major BleedingEstimated Absolute Risk of Major Bleeding, %Categorization of Risk of BleedingcLow Riskd (0 Risk Factors) Moderate Riskd (1 Risk Factor) High Riskd ( 2 Risk Factors) Anticoagulation 0-3 moeBaseline risk (%)0.61.24.8Increased risk (%)1.02.08.0Total risk (%)1.6e3.212.8fAnticoagulation after first 3 mogBaseline risk (%/y)0.3h0.6 2.5Increased risk (%/y)0.51.0 4.0Total risk (%/y)0.8i1.6i 6.5Anticoagulation vs No Parenteral Anticoagulation in Acute VTEaOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated absolute effectsRisk With No Parenteral AnticoagulationRisk Difference With Parenteral Anticoagulation (95% CI)Mortality120 (1 study), 6 moModerateb,c due to imprecision RR 0.5 (0.05-5.37)33 per 1,00016 fewer per 1,000 (from 31 fewer to 144 more)VTE symptomatic extension or recurrence120 (1 study), 6 moModerateb,d due to imprecision RR 0.33 (0.11-0.98)200 per 1,000134 fewer per 1,000 (from 4 fewer to 178 fewer)Major bleeding120 (1 study), 6 moModerateb,c due to imprecision RR 0.67 (0.12-3.85)50 per 1,00016 fewer per 1,000 (from 44 fewer to 142 more)CDT vs No CDT for Extensive Acute DVT of the LegOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With No CDTRisk Difference With CDT (95% CI)Mortality153 (2 studies), 3 moLowc,d due to imprecision RR 0.14 (0.01-2.71)39 per 1,000e34 fewer per 1,000 (from 39 fewer to 67 more)Nonfatal recurrent VTE153 (1 study), 3 moLowc,d due to imprecision RR 0.35 (0-8.09)48 per 1,000f31 fewer per 1,000 (from 48 fewer to 340 more)Nonfatal major bleeding153 (2 studies), 7 dLowc,d due to imprecision RR 2.00 (0.19-19.46)29 per 1,0006,729 more per 1,000 (from 23 fewer to 535 more)PTS (complete lysis on venography [Elsharawy et al73]; patency on ultrasound and air plethysmography [Enden et al74]) 138 (2 studies), 2 yModeratec,g due to indirectness RR 0.46 (0-0.79)588 per 1,000h318 fewer per 1,000 (from 123 fewer to 588 fewer)iRisk Factors for Bleeding With and Contraindications to Use of Thrombolytic Therapy Major contraindicationsaStructural intracranial diseasePrevious intracranial hemorrhageIschemic stroke within 3 moActive bleedingRecent brain or spinal surgeryRecent head trauma with fracture or brain injuryBleeding diathesisRelative contraindicationsbSystolic BP > 180 mm HgDiastolic BP > 110 mm HgRecent bleeding (nonintracranial)Recent surgeryRecent invasive procedureIschemic stroke more that 3 mo previouslyAnticoagulation (eg, VKA therapy)Traumatic cardiopulmonary resuscitationPericarditis or pericardial fluidDiabetic retinopathyPregnancyAge > 75 yLow body weight (eg, < 60 kg)Female sexBlack raceSystemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the LegOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With No Systemic LysisRisk Difference With Systemic Lysis (95% CI)Mortality688 (5 studies), 3 moaLowb-e due to imprecision RR 0.86 (0.27-2.68)21 per 1,0003 fewer per 1,000 (from 16 fewer to 36 more)Nonfatal recurrent VTE687 (3 studies), 3 mofLowd,e,g due to imprecision RR 1.28 (0.25-6.68)48 per 1,000h13 more per 1,000 (from 36 fewer to 273 more)Nonfatal major bleeding688 (10 studies), 3 mofModeratec,d,i due to imprecision RR 1.84 (0.94-3.59)29 per 1,000h,j24 more per 1,000 (from 2 fewer to 75 more)PTS678 (2 studies), 2 ykLowd,e,l,m due to risk of bias and imprecision RR 0.71 (0.49-1.04)588 per 1,000n171 fewer per 1,000 (from 300 fewer to 24 more)Vena Cava Filter vs No Vena Cava Filter for Acute Proximal DVT of the Leg Treated With AnticoagulationaOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With No vena cava FiltersRisk Difference With Vena cava Filters (95% CI)Mortality400 (1 study), 8 yModeratec,d due to imprecision RR 0.95 (0.78-1.16)e515 per 1,00026 fewer per 1,000 (from 113 fewer to 82 more)Symptomatic PE304 (1 study), 8 yModeratec,f due to imprecision RR 0.41 (0.2-0.86)g151 per 1,00089 fewer per 1,000 (from 21 fewer to 121 fewer)Recurrent DVT310 (1 study), 8 yModeratec,f due to imprecision RR 1.3 (0.93-1.82)h273 per 1,00082 more per 1,000 (from 19 fewer to 224 more)Major bleeding337 (1 study), 8 yModeratec,d due to imprecision RR 0.83 (0.52-1.34)i185 per 1,00031 fewer per 1,000 (from 89 fewer to 63 more)PTS308 (1 study), 8 yLowd,j due to risk of bias and imprecision RR 0.87 (0.66-1.13)699 per 1,00091 fewer per 1,000 (from 238 fewer to 91 more)Four or Six Weeks vs Three or Six Months as Minimum Duration of Anticoagulation for VTEOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With ControlRisk Difference With 4 or 6 wk vs 3 or 6 mo Months of Anticoagulation (95% CI)Recurrent VTE2,185 (5 studiesc), 1-2 ydHighe-gRR 1.83 (1.39-2.42)64 per 1,00053 more per 1,000 (from 25 more to 91 more)Major bleeding2,185 (5 studies), 1-2 yHighfRR 0.54 (0.22-1.32)12 per 1,0005 fewer per 1,000 (from 9 fewer to 4 more)Mortality2,098 (5 studies), 1-2 yHighe,f,hRR 0.97 (0.68-1.38)55 per 1,0002 fewer per 1,000 (from 18 fewer to 21 more)Six or Twelve Months vs Three Months as Minimum Duration of Anticoagulation for VTEOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With 3 moRisk Difference With 6 or 12 mo (95% CI)Recurrent VTE2,061 (6 studies), 1-3 yModeratec-e due to imprecision RR 0.89 (0.69-1.14)115 per 1,00013 fewer per 1,000 (from 36 fewer to 16 more)Major bleeding2,061 (6 studies), 1-3 yHighfRR 2.49 (1.2-5.16)9 per 1,00013 more per 1,000 (from 2 more to 37 more)Mortalityg1,331 (5 studies), 1-3 yModerated due to imprecision RR 1.3 (0.81-2.08)44 per 1,00013 more per 1,000 (from 8 fewer to 47 more)Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients with VTEOutcomesNo. of Participants (Studies), Follow-upQuality of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute EffectsRisk With No Extended Duration Oral AnticoagulationRisk Difference With Extended Duration Oral Anticoagulation (95% CI)Mortality1,184 (4 studies), 10-36 moModeratec-e due to imprecision RR 0.57 (0.31-1.03)63 per 1,00027 fewer per 1,000 (from 44 fewer to 2 more)Recurrent VTE at 1 y1,184 (4 studies), 10-36 moHighRR 0.12 (0.09-0.38)First VTE provoked by surgeryf-j10 per 1,00010 fewer per 1,000 (from 6 fewer to 9 fewer)First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j50 per 1,00044 fewer per 1,000 (from 31 fewer to 45 fewer)First unprovoked VTEf-j100 per 1,00088 fewer per 1,000 (from 62 fewer to 91 fewer)Second unprovoked VTEf-j150 per 1,000132 fewer per 1,000 (from 93 fewer to 137 fewer)Major bleeding at 1 y1,184 (4 studies), 10-36 moModerate due to imprecisionRR 2.63 (1.02-6.76)Lowk,l (see Table 2) 3 per 1,0005 more per 1,000 (from 0 more to 15 more)Moderatek,l (see Table 2) 6 per 1,00010 more per 1,000 (from 1 more to 29 more)Highk,l (see Table 2) 25 per 1,00040 more per 1,000 (from 3 more to 122 more)Recurrent VTE at 5 y1,184 (4 studies), 10-36 moHighRR 0.12 (0.09-0.38)First VTE provoked by surgeryf-j30 per 1,00026 fewer per 1,000 (from 19 fewer to 27 fewer)First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j150 per 1,000132 fewer per 1,000 (from 93 fewer to 137 fewer)First unprovoked VTEf-j300 per 1,000264 fewer per 1,000 (from 186 fewer to 273 fewer)Second unprovoked VTEf-j450 per 1,000396 fewer per 1,000 (from 279 fewer to 409 fewer)Major bleeding at 5 y1,184 (4 studies), 10-36 moModerate due to imprecisionRR 2.63 (1.02-6.76)Lowk,l (see Table 2) 15 per 1,00024 more per 1,000 (from 2 more to 73 more)Moderatek,l (see Table 2) 30 per 1,00048 more per 1,000 (from 4 more to 146 more)Highk,l (see Table 2) 125 per 1,000199 more per 1,000 (from 17 more to 609 more)Burden of anticoagulation not reportedWarfarin: daily medication, dietary and activity restrictions, frequent blood testing/monitoring, increased hospital/ clinic visitsmExtended Anticoagulation for Different Groups of Patients with VTEOutcomesNo. of Participants (Studies), Follow-upRelative Effect (95% CI)Anticipated Absolute EffectsRisk With No Extended Duration Oral AnticoagulationRisk Difference With Extended Duration Oral Anticoagulation (95% CI)Mortality1,184 (4 studies), 10-36 moRR 0.57 (0.31-1.03)63 per 1,00027 fewer per 1,000 (from 44 fewer to 2 more)Recurrent VTE at 1 y1,184 (4 studies), 10-36 moRR 0.12 (0.09-0.38)First VTE provoked by surgeryf-j10 per 1,00010 fewer per 1,000 (from 6 fewer to 9 fewer)First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j50 per 1,00044 fewer per 1,000 (from 31 fewer to 45 fewer)First unprovoked VTEf-j100 per 1,00088 fewer per 1,000 (from 62 fewer to 91 fewer)Second unprovoked VTEf-j150 per 1,000132 fewer per 1,000 (from 93 fewer to 137 fewer)Extended Anticoagulation for Different Groups of Patients with VTEOutcomesNo. of Participants (Studies), Follow-upRelative Effect (95% CI)Anticipated Absolute EffectsRisk With No Extended Duration Oral AnticoagulationRisk Difference With Extended Duration Oral Anticoagulation (95% CI)Major bleeding at 1 y1,184 (4 studies), 10-36 moRR 2.63 (1.02-6.76)Lowk,l (see Table 2) 3 per 1,0005 more per 1,000 (from 0 more to 15 more)Moderatek,l (see Table 2) 6 per 1,00010 more per 1,000 (from 1 more to 29 more)Highk,l (see Table 2) 25 per 1,00040 more per 1,000 (from 3 more to 122 more)Extended Anticoagulation for Different Groups of Patients with VTEOutcomesNo. of Participants (Studies), Follow-upRelative Effect (95% CI)Anticipated Absolute EffectsRisk With No Extended Duration Oral AnticoagulationRisk Difference With Extended Duration Oral Anticoagulation (95% CI)Recurrent VTE at 5 y1,184 (4 studies), 10-36 moRR 0.12 (0.09-0.38)First VTE provoked by surgeryf-j30 per 1,00026 fewer per 1,000 (from 19 fewer to 27 fewer)First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j150 per 1,000132 fewer per 1,000 (from 93 fewer to 137 fewer)First unprovoked VTEf-j300 per 1,000264 fewer per 1,000 (from 186 fewer to 273 fewer)Second unprovoked VTEf-j450 per 1,000396 fewer per 1,000 (from 279 fewer to 409 fewer)Extended Anticoagulation for Different Groups of Patients with VTEOutcomesNo. of Participants (Studies), Follow-upRelative Effect (95% CI)Anticipated Absolute EffectsRisk With No Extended Duration Oral AnticoagulationRisk Difference With Extended Duration Oral Anticoagulation (95% CI)Major bleeding at 5 y1,184 (4 studies), 10-36 moRR 2.63 (1.02-6.76)Lowk,l (see Table 2) 15 per 1,00024 more per 1,000 (from 2 more to 73 more)Moderatek,l (see Table 2) 30 per 1,00048 more per 1,000 (from 4 more to 146 more)Highk,l (see Table 2) 125 per 1,000199 more per 1,000 (from 17 more to 609 more)