Oral Rivaroxaban for Symptomatic Venous Thromboembolism

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 • 1⁰ 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 2⁰ 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 • 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)

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? OutcomesAssessor 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