Neue Konzepte der Therapie venöser Thromboembolien

1. Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien

2. Therapie der VTE – verschiedene Möglichkeiten • Thrombolyse • hämodynamisch instabile PE, 4-Etagen tVT (?) • UFH • Niereninsuffizienz, hohes Blutungsrisiko • Cave: HIT II (~ 2 %) • Fondaparinux • NMH

3. Therapie der VTE mit NMH/VKA • gewichtsadaptiert („therapeutische Dosis“) • 1 x oder 2 x tgl. s.c. • mindestens 5 Tage • bis INR mindestens 24 Stunden > 2 • VKA ab Tag 1, mindestens 3 Monate (INR 2-3)

4. Treatment of VTE: past, present and future Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban

5. Treatment of VTE: past, present and future Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban

6. Treatment of VTE acute subacute extended up to 2 weeks up to 3 - 6 months > 6 months

7. Idraparinux vs. Heparin/VKA – van Gogh-PE The van Gogh Investigators. N Engl J Med 2007;357:1094-1104

9. LMWH/Dabigatran vs. LMWH/VKA for acute VTE RE-COVER Single-dummy period Double-dummy period Warfarin placebo Dabigatran Warfarin placebo Dabigatran placebo Warfarin Warfarin (INR 2.0–3.0) Initial parenteral therapy 6 months End of treatment Until INR  2.0 E R E= enrolment R= randomization Schulman, N Engl J Med 2009

10. RE-COVER - Dabigatran for acute/subacute VTE Recurrent VTE and related death Non-inferiority p<0.001 Schulman, N Engl J Med 2009

11. RE-COVER - Dabigatran for acute/subacute VTE Bleeding Schulman, N Engl J Med 2009

13. EINSTEIN: Rivaroxaban for acute VTE Randomized, open-label, event-driven, non-inferioritystudy EINSTEIN DVT/PE Treatment period of 3, 6 or 12 months Objectively confirmed DVT without symptomatic PE Rivaroxaban Rivaroxaban N=~2,900 15 mg bid 20 mg od 30-day observation period R Objectively confirmed PE with or without symptomatic DVT Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start ≤48 hours, target INR 2.5 (INR range 2–3) N=~3,300 Day 1 Day 21

14. EINSTEIN-DVT - Rivaroxaban for acute DVT Recurrent VTE and related death HR=0.68 (95% CI: 0.44–1.04) p<0.001 for non-inferiority p=0.08 for superiority EINSTEIN Investigators, N Engl J Med 2010

15. EINSTEIN-DVT - Rivaroxaban for acute DVT Clinically significant bleeding EINSTEIN Investigators, N Engl J Med 2010

17. EINSTEIN-PE Büller et a., NEJM 2012

18. EINSTEIN-PE Büller et a., NEJM 2012

19. EINSTEIN-PE Büller et a., NEJM 2012

20. Treatment of VTE acute subacute extended up to 2 weeks > 6 months up to 3 - 6 months NOACS as safe and effective NOACS as effective, but safer

21. Transient risk factors Iorio, Arch Intern Med 2012 (systematic review of 15 studies)

22. Risk of recurrence after unprovoked VTE Kyrle, Rosendaal & Eichinger, Lancet 2010

23. distal DVT p < 0,001 proximal DVT RR (95% CI): distal 1 proximal 2,5 (1,6 – 3,9) PE 2,4 (1,5 – 3,7) symptomatic PE +/- DVT Cumulative Probability of Recurrence (%) n = 347 n = 333 n = 151 Years after Discontinuation of Anticoagulation

24. Rezidivrisiko der VTE • Antikoagulation • VKA • NOAK • Aspirin • Therapie nach Risikostratifitierung

25. Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE program Treatment period of 6 or 12 months ~53% Rivaroxaban 20 mg od N=1,197 R 30-day observational period Placebo Day 1 Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~47% EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE Study design EINSTEIN Investigators, NEJM 2011

26. EINSTEIN-DVT - Rivaroxaban for acute DVT Continued treatment EINSTEIN Investigators, N Engl J Med 2010

27. no major bleeds 4 major bleeds EINSTEIN-DVT - Rivaroxaban for acute DVT Continued treatment EINSTEIN Investigators, N Engl J Med 2010

29. AMPLIFY - Extended Agnelli, NEJM 2012

30. AMPLIFY - Extended Agnelli, NEJM 2012

32. RE-MEDY™ study design Screening/ baseline Follow up 30 days Treatment period Dabigatran etexilate 150 mg bid Warfarin placebo Anticoagulant therapy 3–12 months* Warfarin (INR 2.0–3.0) Dabigatran placebo and “increased risk of recurrence” 0–7 days untilINR ≤2.3 ConfirmedVTE Up to 36 months* End of treatment S R *Original protocol, 3–6 months of pre-treatment, then 18 months on study drug; amendment allowed 3–12 months of pre-treatment, then up to 36 months on study drug. S, screening; R, randomization.

33. Time to first VTE or VTE-related death

34. Risk of first onset of any bleeding

35. Major bleeding HR 0.52 (95% CI: 0.27–1.02) Percentage p = 0.058 48% RRR 1.8% 0.9% 13/1430 25/1426 On treatment RRR, relative risk reduction.

36. RESONATE

37. RESONATE

38. Rezidivrisiko der VTE • Antikoagulation • VKA • NOAK • Aspirin • Therapie nach Risikostratifitierung

40. WARFASA

41. WARFASA

43. ASPIRE

44. ASPIRE

45. ASPIRE

46. WARFASA + ASPIRE

47. Rezidivrisiko der VTE • Antikoagulation • VKA • NOAK • Aspirin • Therapie nach Risikostratifitierung

48. Prediction rules for recurrent VTE • Men continue and HER DOO2 • Vienna Prediction Model • DASH Score • Ottawa Score (cancer patients only)

49. Preselection of risk factors Vienna Prediction Model • 929 patients with first unprovoked VTE • impact on the recurrence risk independently confirmed • simple assessment, reproducibility • clinical variables: age at venous thrombosis, sex, location, BMI • laboratory variables: FV Leiden, prothrombin mutation, D-Dimer Eichinger, Circulation 2010

50. RFs after forward selection Vienna Prediction Model • sex • location (distal vs. proximal vs. PE) • D-Dimer 3 weeks after cessation of anticoagulation Eichinger, Circulation 2010