1. Neue Antikoagulantien bei spontaner und Tumor-assoziierter VTE Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien

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

3. Treatment of VTE acutesubacuteextended up to 2 weeks up to 3 - 6 months> 6 months

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

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

8. EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010 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

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

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

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

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

13. Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies Harry R Büller on behalf of the EINSTEIN Investigators

14. EINSTEIN DVT and EINSTEIN PE studies Randomized, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses  Primary efficacy outcome: first recurrent VTE  Principal safety outcome: first major or non­-major clinically relevant bleeding 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510; 2. The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97 15 mg bid Confirmed DVT without symptomatic PE 1 N=3449 N=8282 Rivaroxaban Day 1Day 21 Enoxaparin bid for at least 5 days + VKA, INR 2.0–3.0 Confirmed PE with or without symptomatic DVT 2 N=4833 Predefined treatment period of 3, 6, or 12 months 20 mg od 30-day post-study treatment period Rivaroxaban R

15. Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) Males, %5554 Age, mean, years ± SD57±17 Weight, n (%) ≤50 kg75(1.8)92(2.2) >50–100 kg3477(84)3432(83) ≥100 kg590(14)605(15) Creatinine clearance, ml/min (%) <3010(0.2)11(0.3) 30–49322(8)311(8) 50–791030(25)992(24) ≥802748(66)2787(67) Index VTE, n (%) DVT1699(41)1690(41) PE1793(43)1804(44) DVT and PE615(15)597(15) Unprovoked VTE, n (%)2003(48)2048(50) Previous VTE, n (%)791(19)819(20) Active cancer, n (%)232(6)198(5) EINSTEIN DVT and EINSTEIN PE pooled analysis: patient characteristics ITT population

16. Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) n %n% First symptomatic recurrent VTE862.1952.3 Fatal PE2<0.11 Death (PE cannot be excluded)100.2110.3 DVT and PE1<0.12 DVT only320.8451.1 PE only411.0360.9 EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Hazard ratio ITT population 1.00 0 Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior 1.75 p=0.41 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided) 0.660.891.19

17. EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Number of patients at risk Rivaroxaban415040183969392436043579328312371163114811021034938 Enoxaparin/VKA413139323876382635233504323612151149110910711019939 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N=4150 Enoxaparin/VKA N=4131 0306090120150180210240270300330360 Time to event (days) Cumulative event rate (%) HR=0.89; p non-inferiority <0.0001 Mean time in therapeutic range = 61.7% ITT population

18. EINSTEIN DVT and EINSTEIN PE pooled analysis: principal safety outcome Number of patients at risk Rivaroxaban413037683671340632703210192810511009936878853453 Enoxaparin/VKA41163738361833303186312517111025981907857823369 Cumulative event rate (%) Rivaroxaban N=4130 Enoxaparin/VKA N=4116 0306090120150180210240270300330360 14 10 12 8 6 4 2 0 Time to event (days) First major or clinically relevant non-major bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 388/4130 (9.4) 412/4116 (10.0) 0.93 (0.81–1.06) p=0.27 Safety population

19. EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding Number of patients at risk Rivaroxaban4130392138623611347934332074113510951025969947499 Enoxaparin/VKA411638683784352533943348183511091065990950916409 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N=4130 Enoxaparin/VKA N=4116 0306090120150180210240270300330360 Time to event (days) Cumulative event rate (%) First major bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 40/4130 (1.0) 72/4116 (1.7) 0.54 (0.37–0.79) p=0.002 Safety population

20. Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n%n% Major bleeding*401.0721.7 0.54 (0.37–0.79) p=0.002 Fatal3<0.180.2 Retroperitoneal001<0.1 Intracranial2<0.14 Gastrointestinal/thorax1<0.13 In a critical site100.2290.7 Retroperitoneal1<0.180.2 Intracranial3<0.1100.2 Intraocular3<0.13 Pericardial002<0.1 Intra-articular004<0.1 Adrenal/pulmonary/abdominal3<0.12 Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units 270.7370.9 EINSTEIN DVT and EINSTEIN PE pooled analysis: types of major bleeding *Some patients had >1 event

21. Outcome RivaroxabanEnoxaparin/VKA HR (95% CI) n/N% % Recurrent VTE Fragile21/7912.730/7823.8 0.68 (0.39–1.18) Non-fragile65/33591.965/33491.9 0.98 (0.70–1.38) Major bleeding Fragile10/7881.335/7794.5 0.27 (0.13–0.54) Non-fragile30/33420.937/33371.1 0.80 (0.49–1.29) EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in fragile patients* *Age >75 years or CrCl <50 ml/min or body weight ≤50 kg

22. RivaroxabanEnoxaparin/VKA n/N% % Limited (≤25% of vasculature of a single lobe, popliteal vein only) 11/8141.419/8262.3 Intermediate47/19412.450/19422.6 Extensive (multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein) 28/12182.325/11902.1 EINSTEIN DVT and EINSTEIN PE pooled analysis: clot size and recurrent VTE

23. EINSTEIN DVT and EINSTEIN PE pooled analysis: conclusions  In patients with acute symptomatic DVT and/or PE, rivaroxaban showed:  Non-inferiority versus enoxaparin/VKA for efficacy  Similar incidence rates to enoxaparin/VKA for the principal safety outcome  Superiority for major bleeding  Consistent efficacy and safety results irrespective of age, body weight, gender, renal function, cancer, and severity of DVT/PE  Single-drug approach: no LMWH needed

24. Treatment of VTE - conclusion acutesubacuteextended up to 2 weeks up to 3 - 6 months > 6 months NOACS as safe and effective NOACS as effective, but safer

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

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

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

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

30. AMPLIFY - Extended Agnelli, NEJM 2012

31. AMPLIFY - Extended Agnelli, NEJM 2012

33. RESONATE

35. Time to first VTE or VTE-related death

36. Risk of first onset of any bleeding

37. 13/1430 Major bleeding 0.9% 1.8% HR 0.52 (95% CI: 0.27–1.02) 25/1426 Percentage p = 0.058 On treatment 48% RRR RRR, relative risk reduction.

38. VKA in cancer patients Prandoni, Blood 2002

39. VKA in cancer patients

40. CLOT (Lee, NEJM 2003) Major bleeding: Dalteparin 19/338 (6%) VKA 12/335 (4%) p = 0.3

41. VTE and cancer  ACCP 2012 LMWH over VKA (2B) VKA over NOACs (2C) Dalteparin –once daily 200 IU/kg body weight s.c. –dose reduction to 75 - 85% of therapeutic dose after 4 weeks

42. EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in patients with cancer Outcome RivaroxabanEnoxaparin/VKA HR (95% CI) n/N% % Recurrent VTE Cancer6/2322.68/1984.0 0.62 (0.22–1.80) No cancer 80/39182.087/39332.2 0.91 (0.67–1.24) Major bleeding Cancer 6/2322.68/1964.1 0.61 (0.21–1.77) No cancer34/38980.964/39201.6 0.53 (0.35–0.80)

43. RE-COVER Dabigatran in VTE cancer patients D W

44. Advantages of NOACs in cancer patients with VTE oral route  better quality of life/adherence short half-life  better flexibility at least as effective and safe as VKA

45. Caveats für using NOACs in cancer patients with VTE Small patient numbers in clinical trials Generalizability of trial data (low-risk pts) Oral route in pts with nausea, vomiting and diarrhea Interaction with chemotherapy No on-going trials, neither with LMWH nor with NOACs

46. Summary as effective as LMWH/VKA less (major) bleeding single drug approach (rivaroxaban, apixaban) effective in VTE long-term prevention (up to 1 year) suitable for selected cancer patients NOACs for treatment of VTE