The clinician has two worries when decided to treat PE !

1. VENOUS THROMBOEMBOLISM TREATMENTNuman EKİM M.D.Gazi University Medical SchoolChest Diseases Department

2. The clinician has two worries when decided to treat PE ! Over dosage TREATMENT Low dosage hemorrhage recurrence

3. Pulmonary embolism not treated ! death ratio : % 30 treated ! death ratio : % 8 - 10

4. 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 ; ishemorrhage .

6. Heparin induced bleeding

7. Heparin • Advantages • Efficient • Cheap • Well researched (Grade A evidence) Thrombin Xa Antithrombin III - 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 Disadvantages - Hospitalisation It increases the cost of treatment - Dose - response relationship can not easily be predicted - Close laboratory monitoring Hirsh J, 7th ACCP Guideline on VTE, Chest, 2004

8. 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-310s 2. The Surg Gynecol Obstet 1977;145:338-42 3. Ciculation 2003; 107: 2884-88 4. Circulation 1994; 90: 1631-37

9. 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 ? YES • Recent 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;322:1260-64 2. Heparin-induced bleeding.London,UK:Edward Arhold 1989;517-32 3. Arch Intern Med 1996;156: 857-60

12. 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 - analysis1 • 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 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 ? • 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. Warfarin ; monitorisation and administration Monitorisation • INR (International Normalized Ratio) Therapeutic range 2.0 – 3.0, ideal ; 2.5 Administration • First 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

18. 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 Recommendations for managing elevated INRs or bleeding in patients receiving VKAs

19. 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 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 > 3.01 • 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 characteristics • Age • Risk for major bleeding ( especiallyintracranial ! ) 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 bleeding • Alcoholism or liver disease Chest 2004 ;126:287s-310s

22. 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 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=0.01Lancet 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 • 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 • 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 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) • 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 > LMWH • Surgical >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 • At least every other day platelet count monitoring until day 14 or until UFH is stopped

30. 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 months • An 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 ? No

32. HIT Treatment • Treatment of proved or strongly suspected HIT • Lepirudin • Argatroban • Bivaluridin • Danaparoid • Ximelagatran

33. Heparin Resistance

34. 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 fault Rapid heparin clearance ( massive PTE) Heparin inhibition ( AT III inadequacy) Heparin notralization (Antibody) withiv nitro-glycerine Increased FVIII level Heparin Resistance

35. Low Molecular Weight Heparins (LMWH) and VTE Treatment

36. 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 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 UFH Nurmohomed MT et al. Lancet 1992 ; 340: 152-156 Hirsch J et al. Chest 2001 ; 119(1). Suppl 643-945

39. Therapeutic Dosages for pulmonary embolism of LMWH Uresandi F. et al.(SEPAR Recomm.) Arch Bronchoneumol 2004;40(12) :580-94

40. New 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 - 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. 3 - 6 months ≥ 6 months 12 ay - lifelong First attack :reversible risk factors surgery trauma immobilisation ostrogen usage İdiopatic PE, first attack Cancer Anticardiolipin antibodies. Antithrombin deficiency first attack İdiyopatic or thrombophilia recurrent attack The duration of maintenance treatment of PE 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 Pulmonary embolism Absolute contraindication to anticoagulant therapy Vena cava filter 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