Treatment of DVT/PE (VTE) Update 2010 L. Bernardo Menajovsky, MD, MS.

1. Treatment of DVT/PE (VTE)Update 2010L. Bernardo Menajovsky, MD, MS.

2. Case Study

3. Message #1

4. Waiting is NOT Acceptable! “It is inappropriate to wait for symptoms and then rely upon the diagnosis and treatment of established VTE” Chest. 2004 and 2008

5. Consequences of VTE • Recurrent VTE • Post-thrombotic syndrome (PTS)1 • Presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, skin induration, hyperpigmentation, new venous ectasia, redness and pain during calf compression) • Mortality2 1. Prandoni P et al. Haematologica. 1997;82:423-428. 2. Pengo V et al. N Engl J Med. 2004;350:2257-2264.

6. Message #2

7. Abnormal Blood Flow Abnormal Vessel Wall Abnormal Blood The Hypercoagulable State (thrombophilia) Dr. Rudolph Virchow 1821-1902

8. Message #3

9. Facts • 50% clinically significant DVT – Asymptomatic • 60-70% of Fatal PE – Asymptomatic DVT Heit JA, et al. Arch Intern Med. 1999;159:445.

10. Case Study

11. Message #4

12. The Challenge of Assessing Venous Thromboembolism Symptomatic VTE Silent DVT/PE Decieving

13. Message #5

14. Therapeutic Goals and Treatment Options for DVT Goals of Supportive IVC Heparin LMWH Thrombolysis Therapy Care Filter ? Prevent Embolization Prevent Extension Reduce Recurrence Restore Patency ? Prevent Post-thrombotic Syndrome

15. The Heparins

16. ATIII Ternary complex ATIII ATIII ATIII Fixed Variable Pentasaccharide sequence LMWH HEPARIN

17. Factor Xa Inactivation: LMWH/Heparin Xa ATIII Pentasaccharide sequence Xa ATIII

18. Thrombin Inactivation: LMWH&Heparin Heparin/ATIII/IIa Ternary complex accelerates inactivation of IIa by ATIII IIa Pentasaccharide sequence IIa AT AT Pentasaccharide sequence LMW Heparin/ATIII No acceleration of inactivation of IIa by ATIII without ternary complex

19. Authors Leizorovicz et al ‘94 Lensing et al ‘95 Siragusa et al ‘96 Gould et al ‘99 Dolovich et al ’00 van den Belt ‘00 Outcomes More or as effective < Major bleeding < Thrombocytopenia Treatment DVT LMWH Vs UFH Meta-analyses

20. UFH • Therapeutic levels -- First 24 hours. • Otherwise, risk of recurrent VTE -- 15 X Hull, et al. NEJM 1986; 315, 1109-13 Brandjes DPM et al. NEJM 1992; 327, 1485-90

21. Clinical Outcome Trials

22. Advantages of LMWHs • Pharmacokinetics • Reduced protein binding • Predictable dose • Longer plasma half- life • Smaller molecule • Less platelet effect • Clinical Advantage • Better bioavailability • No monitoring • QD or Q12hr dosing • Better SC absorption • Less Thrombocytopenia

23. Concerns With LMWH Use • Obesity • Renal insufficiency • Pregnancy • Adverse effects • osteoporosis • HIT HIT = heparin-induced thrombocytopenia

24. Obese Patients

25. Obese PatientsTreatment of DVT/PE

26. Recommendations: Weight Factor • Actual Body Weight Dose up to 155 kg • Unfractionated Heparin for morbid obesity • Select Target Weight Ceiling • Choose a range but obtain Anti-Xa levels to evaluate dose

27. UFH • Therapeutic levels -- First 24 hours. • Otherwise, risk of recurrent VTE -- 15 X • Caution in obese patients: • aPTT not reliable • Higher risk of bleeding • Heparin resistance Hull, et al. NEJM 1986; 315, 1109-13 Brandjes DPM et al. NEJM 1992; 327, 1485-90 Chest 2004

28. Heparin Resistance 40 K IU total daily dose = mononuclear white cell = acute phase proteins (histidine-rich glycoprotein, vitronectin, and PF-4) = heparin = vascular endothelial cell

29. Dosing Issues • What dose should be administered to patients with renal insufficiency? • Do patients with renal insufficiency have increased risk for bleeding? • How about obese patients?

32. Vitamin K Utilization Reduced Warfarin Mechanism of Action Vitamin K VII IX X II Synthesis of Dysfunctional Coagulation Factors Warfarin

33. Warfarin: Dosing Information • Individualize dose according to patient response(as indicated by INR) • Use of large loading dose not recommended* • May increase hemorrhagic complications • Does not offer more rapid protection • Low initiation doses are recommended for elderly/frail/liver-diseased/malnourished patients • Adequate overlap! *Harrison L, et al. Ann Intern Med 1997;126,133-136.

36. FDA Approves Updated Warfarin (Coumadin) Prescribing InformationAugust 16, 2007 • One-third of patients receiving warfarin metabolize it quite differently than expected. Research has shown that some of the unexpected response to warfarin depends on a patient's variants of the genes CYP2C9 and VKORC1. • "Although genetic testing can currently identify who has these genetic variants, more studies are needed to explore the precise starting dose for these patients,"

39. Duration of Treatment

40. General Aspects • Short-term treatment associated with 15-50% frequency of extension of thrombus or recurrent disease. • Minimum duration 3 months. • Treatment with VKA is the preferred approach for long-term treatment.

41. 6 – 12 months vs. Indefinite 3 months Indefinite Menajovsky L.B. Am J Med in press

42. Bleeding Risk factors • >75 yo. • Previous GI bleeding (especially not reversible cause) • Chronic renal or hepatic disease • Concomitant Anti-platelet therapy • Serious or acute illness • Poor anticoagulation control • Suboptimal anticoagulation monitoring

43. Relative risks of Recurrent VTE

44. Venacaval filters

45. Caval Interruption • Contraindication or complication of Anticoagulation • Recurrent Thromboembolism despite adequate anticoagulation • Massive PE: hemodinamically unstable • Chronic recurrent embolism with pulmonary hypertension • Concurrent pulmonary embolectomy or endarterectomy Sixth ACCP Consensus Conference Chest 2001; 119:176S-193S

46. IVC Filters • ComplicationsReported Rates (%) Death 0.12 • Recurrent PE 0.5–6 • IVC Occlusion 2–30 • Filter Embolization 2–5 • Access Site Thrombosis 0–6 • Migration* 0-18 • IVC Penetration* 0-41 • Filter Fracture 2-10 • * Clinically significant migration/IVC penetration is rare

47. What is the future?

48. New Anticoagulants ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) RivaroxabanApixaban LY517717 YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va AT Xa FondaparinuxIdraparinux II DX-9065a IIa Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007

49. Direct Thrombin inhibition Tissue factor XIIa XIa VIIa IXa Xa II × Factor IIa(thrombin) Dabigatran

50. Direct Factor Xa inhibition XIIa Tissue factor × XIa VIIa IXa Xa Rivaroxaban Apixaban YM150 DU-176b LY517717 Betrixaban TAK 442 Factor II(prothrombin) Fibrinogen Fibrin clot