Advanced Practice of Pharmacy Experience: Journal Club Mai Nguyen Mercer University COPHS Doctor of Pharmacy Candidate 2012 Preceptor: Dr. Ali Rahimi October 20, 2011

General Overview Title Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation Clinical Trial Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) Authors Patel MR, Mahaffey KW, et al. Citation Patel MR, Mahaffey KW, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365:883-891. Funding Johnson & Johnson Pharmaceutical Research and Development Bayer Healthcare

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. which makes it difficult for many patients to use in clinical practice.

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.

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.

Design and Setting Trial Design Setting Prospective, multicenter, double-blind, randomized event-driven trial 14,264 participants underwent randomization from December 18, 2006, through June 17, 2009. The study was terminated on May 28, 2010. Setting Study was conducted at 1,178 sites in 45 countries.

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. They must have at least one elevated risk factor

Study Population Exclusion Criteria Cardiac-Related Conditions: Mitral valve stenosis, prosthetic heart valve, active endocarditis, etc… Hemorrhage Risk-Related Criteria: Active internal bleeding, planned invasive procedure with potential for uncontrolled bleeding, including major surgery, platelet count <90,000/μL, sustained uncontrolled hypertension, etc… Concomitant Conditions and Therapies: Severe, disabling stroke within 3 months or any stroke within 14 days before randomization, treatment with ASA >100mg daily, pregnant or breast-feeding, CrCl <30ml/min at screening, etc… Study Participation and Follow-Up Related Criteria: Serious concomitant illness associated with life expectancy of less than 2 years, drug addiction or alcohol abuse within 3 years, have received experimental drug within 30 days, inability or unwillingness to comply with study-related procedures, etc… They have an extensive list of exclusion criteria. They are broken into 4 categories.

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.

Interventions 14,264 patients were randomly assigned to receive: Fixed-dose rivaroxaban 20 mg daily or 15 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) Each patient in each group received the placebo in order to maintain the blinding.

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 TIA = transient ischemic attack MI = myocardial infarction = heart-attack

Outcome Measures Primary Endpoint Secondary Endpoints Safety Endpoint Composite of stroke (ischemic or hemorrhagic) and systemic embolism Secondary Endpoints Composite of stroke, systemic embolism, or death from cardiovascular causes Composite of stroke, systemic embolism, death from cardiovascular causes, or myocardial infarction Individual components of the composite endpoints. Safety Endpoint Composite of major and non-major clinically relevant bleeding events

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 They determined that a minimum of 363 events would provide a power of 95% to calculate a noninferiority margin with a one sided significance level of 0.025. But they actually used 405 events to ensure good statistical results.

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.

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

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 decreased the 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 So we want to see Hazard Ratios less than 1 in this study.

Results – Primary Endpoint In the per-protocol population (patients in the primary endpoint analysis), stroke or systemic embolism occurred in 188/6958 patients in the rivaroxaban group (1.7% per year) and 241/7004 patients in the warfarin group (2.2% per year) with hazard ratio of 0.79 in the rivaroxaban group and p-value of <0.001 for noninferiority In the as treated safety population, primary events occurred in 189/7061 patients in the rivaroxaban group (1.7% per year) and 243/7082 patients in the warfarin group (2.2% per year) with HR of 0.79 and P = 0.02 for superiority In the intention-to-treat population, primary events occurred in 269/7081 patients in the rivaroxaban group (2.1% per year) and 306/7090 patients in the warfarin group (2.4% per year) with hazard ratio 0.88; P<0.001 for noninferiority; P = 0.12 for superiority

Results – Secondary Endpoints

Results – Safety Endpoint Major and clinically relevant nonmajor bleeding occurred in 1475 patients in the rivaroxaban group and in 1449 patients in the warfarin group (14.9% and 14.5% per year, respectively; hazard ratio in the rivaroxaban group, 1.03; P = 0.44) Rates of major bleeding were similar in the rivaroxaban and warfarin groups (3.6% and 3.4%, respectively; P = 0.58) Major bleeding that decreases hemoglobin level of 2g/dL or more and require transfusion were more common in rivaroxaban group, but critical bleeding, fatal bleeding, and intracranial hemorrhage occurred less frequently in the rivaroxaban group. In Supplementary Appendix not shown here, GI bleeding was more common in the rivaroxaban group with 224 bleeding events (3.2%), as compared with 154 events in the warfarin group (2.2%, P<0.001)

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

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.

Evaluations limitations Strengths 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 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. The primary endpoint of stroke was a composite of ischemic and hemorrhagic strokes. BUT Warfarin only used in ischemic stroke treatment and should be stopped in hemorrhagic strokes (increase bleeding) No inclusion of data for increased GI bleeding in actual article only mentioned in Supplementary Appendix Treatment groups appeared similar at baseline Included almost 40% females which we rarely see in these kinds of studies. Usually they are made entirely of males.

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? But there are some things that we still need to think about: Cost: Rivaroxaban ($560/month) vs warfarin ($4/month) Antidote: no antidote right now. One thing to keep in mind is that due to the high plasma protein binding of this drug, it is not expected to be removed via dialysis like Pradaxa. We still need monitoring parameters BUT then again Plavix doesn’t have any monitoring parameters but we use it all the time. If we decide to switch a patient from warfarin to rivaroxaban, how do we do that? Do we need to bridge the 2 treatments? Since it’s a new drug, we don’t know about the risk for bleeding years from now, beyond the follow up period used in this study.

Level of Evidence: IA

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.