1

VENOUS THROMBOEMBOLISM TREATMENT

Numan EKİM M.D.

Gazi University Medical SchoolChest Diseases Department

VENOUS THROMBOEMBOLISM TREATMENT

Numan EKİM M.D.

Gazi University Medical SchoolChest Diseases Department

2

The clinician has two worries when decided to treat PE !

The clinician has two worries when decided to treat PE !

Over dosage TREATMENT Low dosage

hemorrhage recurrence

3

Pulmonary embolismPulmonary embolism

not treated !death ratio : % 30

treated !

death ratio : % 8 - 10

4

Should anticoagulant begin in clinically suspected patients during diagnostic procedures ?

Should anticoagulant begin in clinically suspected patients during diagnostic procedures ?

Yes

Because ;

– If acute VTE exsists and not treated ;

progression and reccurence risk of PE is higher than bleeding risk !

5

The main problem of medical treatment ;

The main problem of medical treatment ;

is hemorrhage .

6

Heparin induced bleeding

7

Heparin

Hirsh J, 7th ACCP Guideline on VTE, Chest, 2004

aPTT

(s) (U/kg/sa)

Dose

<35 + 4 Bolus 80U/kg

35-45 + 2 Bolus 40 U/kg

46-70 0 0

71-90 - 2 0

>90 - 3 Hold infusion 1h,

80 U/kg bolus, then 18 U/kg/h

The dose of heparin must be adjusted : aPTT first 24 h; every 6 h, then once a day.

Duration of treatment ; 5 days.

Daily CBC is required

Antithrombin III

Thrombin

Xa-

Advantages• Efficient

• Cheap

• Well researched (Grade A evidence)

Disadvantages

- Hospitalisation

It increases the cost of treatment

- Dose - response relationship can not easily be predicted

- Close laboratory monitoring

8

Is there any relationship between risk of bleeding and dose / response ?

Is there any relationship between risk of bleeding and dose / response ?

YES !

aPTT must be between 45 and 75 s in respect to the efficacy of heparin and bleeding risk . 1

There are not randomized studies which compare different heparin doses for risk of bleeding ! 1

Five major bleedings in 10 patients whose aPTT was prolonged to more than twice, but in only 1 of 40 patients whose aPTT remained therapeutic (relative risk : 20.0) 2

In 5058 patients with acute coronary syndrome ; for every 10-s increase in aPTT, the major bleeding was increased by 7 % (p=0.0004) 3

Studies in patients with ischemic coronary syndromes indicated that a 20 % increase in the IV heparin dose above 1200 U/h increased the risk of intracranial bleeding when combined with thrombolytic therapy. 4

1. Chest 2004 ;126:287s-310s2. The Surg Gynecol Obstet 1977;145:338-423. Ciculation 2003; 107: 2884-884. Circulation 1994; 90: 1631-37

9

Is there any relationship between risk of bleeding and method of administering heparin

Is there any relationship between risk of bleeding and method of administering heparin

METHOD : YES !

There is an increased rate of major bleeding with intermittent IV heparin compared with continuous IV infusion.

( no difference with SC heparin !)

DURATION : NO !

Continuous IV heparin for approximately 10 days and 5 days caused a similar amount of bleeding !

Chest 2004 ;126:287s-310s

10

Is there any relationship between the risk of bleeding and patient risk factors ?

Is there any relationship between the risk of bleeding and patient risk factors ?

YESRecent surgery or trauma, are very important risk factors for heparin-induced bleeding.

This association was demonstrated in the study by Hull and associates in patients with proximal vein thrombosis ;– I. Group ( low-risk patients ) : starting dose of 40.000 U of heparin by

continuous infusion. No clinical risk factors for bleeding (surgery or trauma) . Bleeding occured in 1 of 88 patients ( 1 % )

– II. Group ( high-risk patients ) : starting dose of 30.000 U of heparin by continuous infusion. Well-recognized risk factors for bleeding. Bleeding ocuured in 11 of 111 patients ( 11 % ) 1

Renal failure and patient gender ( female gender ?) have also been implicated as risk factors for heparin –induced bleeding 2

Age >70 years was associated with a clinically important increased risk of major bleeding 3

1. N Engl J Med 1990;322:1260-642. Heparin-induced bleeding.London,UK:Edward Arhold 1989;517-323. Arch Intern Med 1996;156: 857-60

11

Is there any difference in respect to bleeding between UFH and LMWH ? YES !

Authors Major bleeding Minör bleeding LMWH UFH LMWH UFH Prandoni P (%) 1.2 3.5 2.4 7 Hull RD (%) 0.5 5 3.3 3.2 Albada J (%) 10 13 36 28 In general (%)

3 6.7 11.2 10

Relative risk 0.42 1.16 Decrease of risk (%)

58 -

p= 0.01 0.5 AJM 1996;100:269-277

12

Is there any difference in respect to bleeding between UFH and LMWH ?

Is there any difference in respect to bleeding between UFH and LMWH ?

NO !There are some studies. The results of them have been combined in a number of meta - analysis 1

LMWH was associated with less bleeding than UFH in studies published before 1997 ( OR,0.53;95% CI,0.28-0.98 ).

But ;

has been associated with similar frequency of bleeding in more recent studies ( OR,0.97;95% CI, 0.52-1.81 ) 2

1. Chest 2004 ;126:287s-310s 2. Cochrane Review.The Cochrane library,2002, Accessed May 24, 2004

13

Heparin treatment at postoperatively developed VTE

Heparin treatment at postoperatively developed VTE

Heparin can be given in 12-24 h after surgical intervention

İf there is a bleeding in operation site; treatment may be posponed

No UFH bolus dose and lower dose then conventional dose is given

If bleeding risk is very high ; transient VCI filter is inserted

Chest 2004 ;126:287s-310s

14

When heparin treatment should be discontinued before operation ?

When heparin treatment should be discontinued before operation ?

It is enough to discontinue heparin treatment 6 hours before invasive procedures

15

What should be done ,if heparin induced bleeding occurs ?

Stop infusion

Supportive treatment + fresh plasma + blood transfusion

Slow protamin sulphate IV infusion may be considered:

- 1 mg protamin sulphate neutralizes 100 U UFH

- Hypotension and anaphylactic reaction may occur while protamin infusion

Hyers T et al. 6th Consensus Conference, Chest 119; 2001

16

Warfarin ( Vit. K Antagonist ) Induced Bleeding

17

MonitorisationINR (International Normalized Ratio)

Therapeutic range 2.0 – 3.0, ideal ; 2.5

AdministrationFirst day of heparin treatment 5 mg / d

At least 4 - 5 days together with heparin

If INR level is between 2 - 3 two times, heparin is stopped

At the beginning frequently and then weekly INR control

Warfarin ; monitorisation and administration

Warfarin ; monitorisation and administration

18

Recommendations for managing elevated INRs or bleeding in

patients receiving VKAs Recommendations for managing elevated INRs or bleeding in

patients receiving VKAs INR 3.0-5.0

INR 5.0-9.0 ; No significant bleeding

INR 5.0-9.0 ; Bleeding risk exsists

The patient requires urgent surgery

INR >9.0

Severe bleeding or over dose (INR>20.0)

If continuing warfarin therapy is indicated

Lower dose or omit next dose

Omit next or two doses, and resume at lower dose when INR in therapeutic range.

Hold warfarin therapy.Give vitamin K1 (1- 2.5 mg orally)

Give vitamin K1 (2 - 4 mg orally)If INR is high after 24 h

Hold warfarin therapy. Give vitamin K1(3-5 mg orally)Close monitoring of INR

Give vitaminK1 ( 10 mg by slow İV infusion)

Heparin or LMWH can be given until the effects of vit. K1 have been reversed

Lower dose or omit next dose

Omit next or two doses, and resume at lower dose when INR in therapeutic range.

Hold warfarin therapy.Give vitamin K1 (1- 2.5 mg orally)

Give vitamin K1 (2 - 4 mg orally)If INR is high after 24 h

Hold warfarin therapy. Give vitamin K1(3-5 mg orally)Close monitoring of INR

Give vitaminK1 ( 10 mg by slow İV infusion)

Heparin or LMWH can be given until the effects of vit. K1 have been reversed

19

The major determinants of oral vitamin K

antagonist-induced bleeding The major determinants of oral vitamin K

antagonist-induced bleeding

Intensity of anticoagulant effect

Patient characteristics

The concomitant use of drugs that interfere with hemostasis

Length of therapy

20

Intensity of anticoagulant effectIntensity of anticoagulant effect

There is strong relationship between the intensity of anticoagulant therapy and the risk of bleeding

For various indications, the frequency of major bleeding in patients ;

- At a targeted INR of approximately 2.0 - 3.0 has been less than half the frequency in patients randomly assigned to warfarin therapy at a targeted INR > 3.0 1

– The intensity of anticoagulant effect is probably the most important risk factor for intracranial hemorrhage . The risk increases dramatically with an INR > 4.0-5.0 . 2

– In a case-control study, the risk of intraserebral hemorrhage doubled for each increase of approximately 1 in the INR. 3

1. Lancet 1988;1:1242-45 2. N Engl J Med 1990;322:428-32 3. Ann Intern Med 1994;120:897-902

21

Patient characteristicsPatient characteristics

Age– Risk for major bleeding ( especially intracranial ! ) may be

increased among older patients, especially those >75 years old when the INR is above therapeutic levels. The mechanism of how aging causes anticoagulant-related bleeding is not known. Arch Intern Med 1996;156:409-16

A history of bleeding has been reported as a risk factor for subsequent bleeding . Am J Med 1998;105:91-99

Comorbid diseases– Cerebrovascular disease – Ischemic stroke– Serious heart disease– Renal insufficiency– Malignancy

Women and bleedingAlcoholism or liver disease

Chest 2004 ;126:287s-310s

22

Low dose warfarin therapy Low dose warfarin therapy

Old patients ( >80 years)

Liver insufficiency (chronic alcoholism)

Malnutrition

bleeding risk is high

Daily dose must be less than 5 mg (eg; 2mg per day)

23

Concomitant drugsConcomitant drugs

Aspirin has been associated with a higher frequency of bleeding, even in patients treated with warfarin therapy with a mean INR of 1.5

– In patients with a history of MI ;• I. Group: 3 mg/d warfarin ( INR< 2.0 ) + 80 mg/d aspirin• II. Group : 160 mg/d aspirin The frequency of spontaneous major hemorrhage during the first

year of therapy : I. Group: % 1.4, II. Group: % 0.7, p=0.01 Lancet 1997;350:389-96

NSAİDs, (together with warfarin ) ;– prolongs INR ! ( case reports ! ) Pharmacotherapy 2000;20:234-39

– does not prolong INR ! . Br J Clin pharmacol 1999;47:1-4

No randomized trial has been done ! The quality of evidence supporting any relationship between NSAID use

and bleeding on warfarin is weak

24

Relationship between bleeding risk and duration of

treatment Relationship between bleeding risk and duration of

treatment

Higher frequencies of bleeding early in the course of therapy

Major bleeding in warfarin therapy (outpatient) :

– first month : 3.0 % / mo– during the rest of the first year of therapy : 0.8 % / mo– and thereafter : 0.3 % / mo

Am J Med 1989; 87 : 153-59 Chest 2004 ;126:287s-310s

25

Checklist of information to review with patients when prescribing a coumarin

Checklist of information to review with patients when prescribing a coumarin

Your blood thinner (...........) can cause bleeding and bruising.If you develop execessive bruising or any bleeding (eg, pink urine or a black bowel movement.)

The amount of vitamin K in your diet should be consistent. Bingeing on foods that are rich in vitamin K (eg, green leafy vegetables) counteracts the effect of your blood thineer.

Because alcohol interacts with your blood thinner and can cause stomach ulsers, you should consume alcohol only in moderation ( ie, no more than two drinks per day)

Your blood thinner must be monitored every few weeks by a blood test called INR.

If you miss one dose, take it as soon as possible. If you miss more than one dose , call your doctor for instructions

Many drugs interact with blood thinner. When starting any new medication , including aspirin chech with your doctor or pharmacist to find out whether it is safe for you take.

Women taking blood thinner pills must avoid pregnancy ; if you intend to become pregnant , a blood thinner shot is safer for your baby.

Yusen RD. Clin Chest Med 24(2003) 49-61

26

Bleeding Risk IndexWells PS. Et al. Arch Intern Med 2003;163:917-20

Bleeding Risk IndexWells PS. Et al. Arch Intern Med 2003;163:917-20

Points

Age > 65 1

History of digestive hemorrhage 1

History of stroke 1

1 or more of the following signs 1

Hematocrit < 30 %

Creatinin > 1.5 mg/dL

Diabetes mellitus

Recent acute myocardial infarction

Low risk: 0 points, intermediate risk :1 or 2 points, high risk 3 or > 3 points

27

Heparin - Induced Thrombocytopenia (HIT)

28

Heparin - Induced Thrombocytopenia (HIT)Heparin - Induced Thrombocytopenia (HIT)

Benign ( Simple) HIT– It occurs in early period of heparin therapy and by nonimmun

mechanism. It is reversibl

Immun HIT ( 01-02 % )– Paradoxically, it is associated with venous and arterial

thrombosis.– There are IgG antibodies against platelet factor 4 + heparin .– The platelet count begins to fall 5 to 10 days after starting heparin

(eg, >30-50 % fall or to < 100.000/mm3 ).– When heparin therapy stopped, platelet count returns to normal

levels in 10 days.– HIT is seen more frequently with UFH therapy than LMWH

therapy.Cattle UFH > Pig UFH > LMWHSurgical >Medical > Pregnancy

Wood AJJ. N Engl J Med 1996; 335(24):1816-28 Task Force Report. Eur Heart J 2000; 21: 1301-36 Warkentin T. Chest 2004;126:311-337s

29

Platelet count monitoring in patients receiving

therapeutic- dose UFH Platelet count monitoring in patients receiving

therapeutic- dose UFH

At least every other day platelet count

monitoring until day 14 or until UFH is stopped

30

Why treatment of HIT is necessary ?Why treatment of HIT is necessary ?

It is a protrombotic condition that is evidenced by the precence of elevated levels of thrombin- antithrombin complexes

It can be considered an acquired , hypercoagulability syndrome.

Unlike other acquired hypercoagulability syndromes (eg, antiphospholipid antibody syndrome, malignancy-associated thrombosis) ;– HIT is transient, with recovery of platelet count to normal levels

within days or weeks and,– disappearance of the pathogenic HIT atibodies within weeks or a few

monthsAn optimum antithrombotic therapy should be done. With this type of therapy ;

• Decompensated DIC,• The risk for progression of DVT to venous limb gangrene, can be prevented

Chest 2004;126:311-337s

31

Can warfarin and LMWH be used in HIT treatment ?Can warfarin and LMWH be used in HIT treatment ?

No

32

HIT TreatmentHIT Treatment

Treatment of proved or strongly suspected HIT

– Lepirudin– Argatroban – Bivaluridin– Danaparoid– Ximelagatran

33

Heparin Resistance

34

Heparin Resistance Heparin Resistance

Clinical resistance : (<5 %)While aPTT is in the therapeutic

level, occurence of reccurent PE

Malignancy ( Adeno Ca )

Lupus anticoagulants

Invitro resistance : (20 %)If aPPT is subtherapeutic

although heparin dose ( >35000 U ) is adequate

Administration faultRapid heparin clearance

( massive PTE )

Heparin inhibition ( AT III inadequacy)

Heparin notralization (Antibody)

with iv nitro-glycerineIncreased FVIII level

35

Low Molecular Weight Heparins (LMWH)

and VTE Treatment

36

LMWH and VTE treatment LMWH and VTE treatment

- Nadroparin is effective and safe for submassive PE treatment ( in 101 patients )

Circulation 1992;85:1380

- LMWH is effective and safe for acute PE treatment ( in 612 patients ) N Engl J Med 1997;337:663

- In acute PE ( 13 meta –analysis studies ) ; - to prevent PE reccurence,

- to diminish mortality LMWH is effective like UFH The major bleeding ratio of LMWH is less than UFH Am J Med 1996;100:269

- LMWH is effective and safe for acute PE treatment ( in 54patients ) Oğuzülgen K, Ekim N. et al. Toraks Dergisi 2001;2: 31-34

37

The advantages of LMWHsThe advantages of LMWHs

LMWHs have reduced anti-factor IIa activity relative to anti-factor Xa activity ( Anti Xa / Anti II a : 2 - 4 / 1 )

Long plasma half-life. Single dose or twice a day

Excreted via kidneys, do not cross plasenta

The administration route is subcutaneously

Length of hospitalisation is short

Outpatient treatment is possible in patients with DVT and PE

No monitorisation

The risk of osteoporosis of LMWHs is less than UFH for long term treatment

They cause HIT less than UFHNurmohomed MT et al. Lancet 1992 ; 340: 152-156Hirsch J et al. Chest 2001 ; 119(1). Suppl 643-945

38

Is there any difference for VTE recurrence between LMWH and UFH ?

Authors 1-90 days LMWH UFH Simonneau G (%) 0 3 Prandoni P (%) 4.7 8.2 Hull RD (%) 2.8 6.8 In general (%) 2.7 6.4 Relative risk 0.39 Decrease of risk (%) 61 p= 0.006

AJM 1996;100:269-277

39

Drug Dosage

Enoxaparin Na 1 mg / kg / 12 h or 1.5 mg / kg / 24 h

Dalteparin Na 100 U / kg / 12 h or 200 U/ kg / 24h

Nadroparin Ca 85.5 U/ kg /12 h or 171 U / kg / 24 h

Tinzaparin Na 175 U kg / 24 h

Therapeutic Dosages for pulmonary embolism

of LMWH

Uresandi F. et al.(SEPAR Recomm.) Arch Bronchoneumol 2004;40(12) :580-94

40

New anticoagulants - 1New anticoagulants - 1

Fondaparinux– In plasma, fondaparinux binds to antitrombin

– With excellent bioavailability after sc injection and a plasma half-life of about 17 h, it can be administered subcutaneously once daily

– Thu drug is excreted unchanged in the urine. Dose adjustments are necessary in patients with renal insufficiency

– Because it does not induce the formation of heparin / PF4 complexes, HIT is unlikely occur with fondaparinux

– It has been used for thromboprophylaxis in patients undergoing major orthpedic surgery, and in general medical and surgical patients (single dose - 2.5 mg per day)

– No monitorization

– Treatment of VTE: MATISSE study (2.213 patients, randomized to receive either fondaparinux or UFH ). Fondaparinux appears to be at least as effective and safe as LMWH or UFH for the initial treatment of VTE

41

New anticoagulants - 2New anticoagulants - 2

Ximelagatran– It is absorbedfrom the small intestine– Plasma half-life is 3 or 4 h and is administered orally twice daily. No foods or

drugs have been documented to influence its absorbtion,– Melagatran, the active agent, is eliminated via kidneys. Dose adjustments may

be needed inthe elderly and in patients with renal insuffiency– Venous thromboprophylaxis ; EXPRESS study * (2764 major orthopedic

surgery patients randomized to receive either melagatran/ximelagatran or enoxaparin.

Ximelagatran therapy reduces the incidence of proximal DVT and PE by 63 % compared with enoxaparin therapy

- Treatment of venous thrombosis : a phase III, placebo –controlled,blinden trial ** ; 2489 patients,comparing ximelagatran with enoxaparin. The primary end point ; recurrent VTE :2.1% and 2.0%,major bleeding :1.3% and 2.2% respectively.

Therapy oral ximelagatran is as effective and safe as cLMWH * Blood 2002;100:299** J thromb Haemost 2003;1(suppl):OC003

42

The duration of maintenance treatment of PEThe duration of maintenance treatment of PE

3 - 6 months

≥ 6 months

12 ay - lifelong

First attack :reversible risk factors – surgery– trauma– immobilisation– ostrogen usage

İdiopatic PE, first attack

CancerAnticardiolipin antibodies.Antithrombin deficiency first attackİdiyopatic or thrombophilia recurrent attack

Hyers TM et al. Chest 2001: 119 :176S -193S

43

Guidelines for the diagnosis, treatment, and follow up of pulmonary embolismUresandi F. et al.(SEPAR Recomm.) Arch Bronchoneumol 2004;40(12) :580-94

Guidelines for the diagnosis, treatment, and follow up of pulmonary embolismUresandi F. et al.(SEPAR Recomm.) Arch Bronchoneumol 2004;40(12) :580-94

Pulmonary embolism

Absolute contraindication to anticoagulant therapy

Vena cavafilter Yes No Stable Unstable 1-2 doses / daily Thrombolytic agents LMWH followed by LMWH or UFH (minimum 5 days)

Serious hemorrhage Vena cava filter

Warfarin or LMWH