1. Oral Rivaroxaban for Symptomatic Venous Thromboembolism

2. Background  Tx ↓ risk of recurrence from 25% to 3% during first 6-12 months of therapy  Risk after tx ends: 5-10% during first year  Standard: Parenteral heparin initially + Vit K antagonist  Annual risk of major bleeding after first year 1-2%

3. Background  Monitoring challenging for outpatients  Solution: oral anticoagulant without monitoring  Rivaroxaban: Direct factor Xa inhibitor

4. Methods: Acute DVT  Design: Randomized, open label, event driven, non-inferiority study  P: Pts with acute, symptomatic DVT  I: Rivaroxaban  C: Enoxaparin + Vit K antagonist  O: Symptomatic, recurrent VT

5. Acute DVT: Inclusion Criteria  Legal age for consent  Acute, symptomatic objectively confirmed proximal DVT, without symptomatic PE

6. Acute DVT: Exclusion Criteria  If therapeutic doses of LMWH, fondaparinux or UFH received for >48 hours or >1 dose of a VKA before randomization  Treated with thrombectomy, vena cava filter or a fibrinolytic agent for the current episode of thrombosis  Any CIs

7. Methods: Acute DVT  Duration of tx: determined by the treating physician  15 mg BID X 3 wks  20 mg OD for 3,6 or 12 months  Standard: SC enoxaparin ( 1mg/kg BID)  Warfarin or acenocoumarol started within 48 hrs of randomization

8. Methods: Continued Tx Study  Design: Randomized, double-blind (subject, caregiver,investigator, outcomes assessor), event-driven superiority study  P: Pts with DVT or PE treated x 6-12 months with a Vit K antagonist or rivaroxaban  I: Rivaroxaban 20 mg OD  C: Placebo  O: Symptomatic, Recurrent VT

9. Continued Tx Study: Inclusion Criteria  Objectively confirmed symptomatic DVT or PE  Treated X 6-12 months with acenocoumarol or warfarin or rivaroxaban  If there was equipoise with respect to the need for continued anticoagulation

10. Exclusion criteria for both studies  Another indication for Vit K antagonist  CrCl< 30ml/min  Clinically significant liver disease (acute hepatitis, chronic active hepatitis, or cirrhosis) or an ALT>3 ULN  Bacterial endocarditis  Active bleeding or a high risk of bleeding

11. Exclusion Criteria for both studies  CI anticoagulant treatment  SBP >180 mm Hg or DBP>110 mm Hg  Childbearing potential without proper contraception measures  Pregnancy or breast feeding  Concomitant use of strong P-450 3A4 inhibitors or inducers  Participation in another experimental pharmacotherapeutic program within 30 days before screening  Life expectancy <3 months

12. Methods  Continued Tx: Rivaroxaban 20 mg OD or matching placebo for 6 or 12 months  Both studies: NSAID & antiplatelet use discouraged  If indicated ASA (up to 100 mg), clopidogrel (75 mg) or both allowed

13. Outcome assessments  1 ⁰ efficacy outcome: Symptomatic, recurrent VT  Acute DVT Study: Principal safety outcome: Clinically relevant bleeding = composite of major or clinically relevant nonmajor bleeding  Continued Treatment Study: Major bleeding

14. Outcome assessments  Predefined 2 ⁰ outcome: All-cause mortality Vascular events (ACS, ischemic stroke, TIA or SE) Net clinical benefit (composite of primary efficacy outcome +major bleeding)

15. Statistical Analysis: Acute DVT  Event driven, Non-inferiority Study  Assumption: equal efficacy in 2 study groups A total of 88 events would provide a power of 90% to demonstrate that rivaroxaban is non inferior to standard therapy  Margin = 2.0, corresponds to maintenance of at least 50% of the proven efficacy of standard tx

16. Statistical Analysis: Continued Tx  Event driven, superiority study  Assumption: 70% RR with rivaroxaban 30 events, power of 90%

17. Results: Acute DVT Efficacy Rivaroxaban (1731 ) Enoxaparin- VKA (1718) HR (95% CI)P value Recurrent VTE 36(2.1)51(3.0)0.68(0.44- 1.04) <0.001 Net clinical benefit 51(2.9)73(4.2)0.67(0.47- 0.95) 0.03 Principal safety outcome: 8.1% in each group No difference in safety outcomes and total deaths

18. Results: Continued Treatment  Nonfatal major bleed 0.7% in rivaroxaban group vs. none (P=0.11) EfficacyRivaroxaban (602) Placebo (594) HR (95% CI)P value Recurrent VTE 8(1.3)42(7.1)0.18(0.09- 0.39) <0.00 1 Net clinical benefit 12(2.0)42(7.1) 0.28 (0.15- 0.53) <0.0 01

19. CASP SR Checklist  Did the study ask a clearly focused question? Yes  Was this a randomized controlled trial (RCT) and was it appropriately so? The first study is open label but the second one is RCT. Yes  Were participants appropriately allocated to intervention and control groups? Yes  Were participants, staff and study personnel ‘blind’ to participants’ study group? Outcomes Assessor blinded  Were all of the participants who entered the trial accounted for at its conclusion? Yes

20. CASP SR Checklist  Were the participants in all groups followed up and data collected in the same way? Yes  Did the study have enough participants to minimize the play of chance? Yes  How are the results presented and what is the main result?  How precise are these results?  Were all important outcomes considered so the results can be applied?

21. Limitations  Blinding: no protection from bias  Suspected cases higher in rivaroxaban group  Margin of 2.0 = at least 50% of proven efficacy of standard therapy. Acceptable?  On-treatment & per-protocol analyses similar to ITT but data not shown

22. Limitations  Safety: Bleeding events included in the analyses if occurred during tx or within 2 days after d/c  Compliance  Serious events not defined  Results of non-inferiority trial not as credible as a superiority trial

23. Implications to practice  Dose needs to be studied more  Single-drug approach to short-term & continued tx of VT Option in patients not willing to do INR monitoring  Reversal of bleeding: no specific antidote, general hemostatic measures Activated charcoal within 2 hours of dose  Highly protein bound not dialyzable