General Overview

1. Advanced Practice of Pharmacy Experience: Journal ClubMai NguyenMercer University COPHSDoctor of Pharmacy Candidate 2012Preceptor: Dr. Ali Rahimi October 20, 2011

2. General Overview

3. Background • Atrial fibrillation is associated with an increase in the risk of ischemic stroke by a factor of 4 to 5 and accounts for up to 15% of strokes in persons of all ages and 30% in persons over the age of 80.1 • Current guidelines for preventing stroke in patients with atrial fibrillation recommend using warfarin, a vitamin K antagonist, with a target INR of 2-3, as the standard care of therapy. • However, warfarin has many food and drug interactions, and requires frequent monitoring and dose adjustments.

4. Background • Rivaroxaban (Xarelto®):3 • First oral, selective inhibitor of Factor Xa approved by the FDA on July 1, 2011. • FDA indicated for prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery. • Convenient once daily, oral dosing • No need for routine monitoring of INR or other coagulation parameters.

5. Objective • To compare once daily oral rivaroxaban with dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation who were at moderate to high risk for stroke. • Primary hypothesis: rivaroxaban is noninferior to warfarin for the prevention of stroke or systemic embolism.

6. Design and Setting

7. Study Population • Inclusion Criteria: • Men or women aged ≥ 18 years with nonvalvular atrial fibrillation (ECG evidence), who were at moderate-to-high risk for stroke. • Elevated risk factors: history of stroke, transient ischemic attack, or systemic embolism OR • At least 2 of the following risk factors: heart failure or left ventricular ejection fraction of ≤ 35%, hypertension, age ≥ 75 years, or DM • Female subjects must be postmenopausal, surgically sterile, or abstinent. • If sexually active, must use effective method of birth control before entry and throughout the study. • Must have a negative pregnancy test at screening.

8. Study Population

9. Study Population • Baseline Demographics: • Median age was 73 years • 39.7% women; 60.3% male • 90.5% of patients had hypertension • 54.8% of patients had previous stroke or systemic embolism • 62.4% of patients had previous use of warfarin • Baseline characteristics did not differ significantly between the two treatment groups.

10. Interventions • 14,264 patients were randomly assigned to receive: • Fixed-dose rivaroxaban 20 mg daily or15 mg daily in patients with CrCl 30-49 mL/min AND placebo (n = 7,131) • Dose-adjusted warfarin (target INR 2.0-3.0) AND placebo (n = 7,133)

11. Interventions • Patients were seen at weeks 1, 2, and 4, then monthly for duration of study to measure INR, primary endpoint events, TIA, MI, medical/surgical procedures, adverse events and vital stats • Median duration of treatment: 590 days • Median follow-up period: 707 days

12. Outcome Measures

13. Statistical Analysis • Primary Analysis: • Performed in the per-protocol population • Included all patients who received at least one dose of a study drug, did not have major protocol violation, and were followed for events while receiving drug or within 2 days after discontinuation. • Power of 95% • 363 events needed; study used 405 events • One-sided significance level of 0.025

14. Statistical Analysis • If noninferiority was achieved in the primary analysis, • Primary Superiority Analysis: • Performed in the as-treated safety population • Included patients who received at least one dose of a study drug and were followed for events, regardless of adherence to the protocol, while they were receiving the assigned study drug or within 2 days after discontinuation. • Two-sided significance level of 0.05 • Key secondary endpoints were also tested for superiority in the as-treated safety population.

15. Statistical Analysis • Testing for noninferiority and superiority was also performed in the intention-to-treat population • Included all patients who underwent randomization and were followed for events during treatment or after premature discontinuation • Hazard ratios, confidence intervals, and P values were calculated using Cox proportional-hazards models • Warfarin group: • Rosendaal method - calculate overall time that INR values fell within therapeutic range

16. Statistical Analysis • Hazard Ratio (AKA Relative Risk or Risk Ratio): • The ratio of risk of an outcome event occurring in the experimental group compared to the risk of the same outcome event occurring in the control group. • HR < 1.0 indicates the therapy decreasedthe risk of developing the adverse outcome • HR = 1.0 indicates no difference between treatments • HR > 1.0 indicates the therapy increased the risk of developing the adverse outcome

17. Results – Primary Endpoint

18. Results – Secondary Endpoints

19. Results – Safety Endpoint

20. Results – Calculations • NNT (primary endpoint – stroke and systemic embolism): • ARR = 241/7,004 – 188/6,958 = 0.0074 • NNT = 1/0.0074 = 135 • NNH (safety endpoint – major and nonmajor bleeding): • ARI = 1,475/7,111 – 1,449/7,125 = 0.004 • NNH = 1/0.004 = 250

21. Author’s Conclusion • In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. • There was no significant difference in the risk of major bleeding between groups, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

22. Evaluations limitations Strengths Randomized, double-blind, multi-center study with a large sample size Treatment groups appeared similar at baseline Included almost 40% females Duke Clinical Research Institute coordinated the trial, managed database, and performed primary analyses independently of the sponsors. • In warfarin group, INR values were within therapeutic range only 55% of the time. • Switching from per-protocol population to as-treated safety population to achieve superiority. • The primary endpoint of stroke was a composite of ischemic and hemorrhagic strokes. • No inclusion of data for increased GI bleeding

23. Conclusion and Application • Rivaroxaban is a potential alternative to warfarin, especially for patients with compliance issues. • Things to consider: • Cost • No Antidote • Monitoring for coagulation parameters needed • How to bridge patients when switching from warfarin to rivaroxaban? • Long-term effects?

24. Level of Evidence: IA

25. References • Patel MR, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011; 365:883-891. • Supplement to: Patel MR, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011; 365:883-891. DOI: 10.1056/NEJMoa1009638. • Xarelto® (rivaroxaban) Product Package Insert. 2011; July. Janssen Pharmaceuticals, Inc. Titusville, NJ.