1. Oral Rivaroxaban for Symptomatic Venous Thrombroenbolism Group 9 611 - 10/06/11

2. Background of The Study Sponsor: Bayer Schering Pharma & Ortho McNeil Objectives: To compare efficacy and safety for treatment of DVT o In acute setting  Rivaroxaban (a factor Xa inhibitor)  Standard treatment: enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) o In long-term treatment  Rivaroxaban  Placebo

3. Background (continued) Pathophysiological background o Vitamin K antagonist: prevents the formation of factors II, VII, IX, and X in the coagulation cascade o Factor Xa inhibitor: inhibits the conversion of prothrombin to thrombin Current standard therapy requires initial parenteral administration of heparin then extensive lab monitoring and dose adjustment for vitamin K antagonists Goal: to develop an oral anticoagulant that is effective as a single agent and does not require lab monitoring

4. Method Study design o Acute DVT study: randomized, open-labeled  Non-inferiority study o Continued Treatment study: randomized, double-blinded  Superiority study Population o Eligibility  Acute DVT study: participants diagnosed with acute, symptomatic DVT without symptomatic PE  Continued treatment study: participants currently on treatment for symptomatic DVT or PE for 6-12months o Exclusion criteria: patients with liver disease, renal failure (CrCl 180/110)

5. Outcomes Primary outcome: o Efficacy: recurrent VTE o Safety: major bleeding Secondary outcomes: all-cause mortality, vascular events, and net clinical benefit

6. Numerical tables were used to compare the clinical characteristics of both groups in each study. This representation makes it easier to detect the difference in terms of efficacy and safety Acute DVT Study: less # of people in rivaroxaban group experienced recurrent VTE; same first bleeding events in both groups Continued Treated Study: 5x more cases of recurrent VTE in placebo group; there is an acceptable risk of bleeding. Results/Analysis

7. Results/Analysis Time course for % of recurrent VTE is depicted graphically for both studies, allowing reader to visually see the difference in efficacy of two groups. From the plots we see that less people suffered from recurrent events in Rivaroxaban group vs. Enoxaparin group Placebo group has even higher rates of recurrent VTE. Safety Outcome profile is also plotted from Acute DVT data. Rivaroxaban is shown to have slightly lower % of bleeding events.

8. Conclusion Conclusion: oral rivaroxaban provides an effective and safe, single drug approach in treatment and management of DVT without requiring lab monitoring

9. Analysis The use of Cox proportional hazard model was well suited in evaluation of drugs' efficacy and safety Efficacy analyses was based on intention-to-treat to ensure randomization

10. Strengths Participants were randomly assigned to groups, so selection bias is unlikely Eligibility and exclusion criteria were stated clearly Efficacy analyses was based on intention-to- treat to ensure randomization Article includes useful charts and graphs Sample size is large

11. Limitations Cancer status may interfere with the results: About 7% in both groups with active cancer were enrolled Some possible confounding factors such as ethnicity and family history were not included in analysis

12. Clinical Relevance No lab monitoring Fast acting oral dosage form, good oral bioavailability Therefore, no need for bridge therapy Offer additional anticoagulation treatment options

13. Recommendations Future studies can be conducted to compare the efficacy and safety profile between Rivaroxaban and Dabigatran Need more information on the long term effects of the drug before making conclusive decisions about safety and efficacy

14. Reference Bauersachs R, et al. "Oral rivaroxaban for symptomatic venous thromboembolism." N Engl J Med. 2010;363:2499-510.