Title Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation Clinical Trial Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with.

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.

CitationPatel 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

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.

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.

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.

Trial Design

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.

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.

Exclusion CriteriaCardiac-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…

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.

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)

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

Primary 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

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

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.

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

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

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

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.

LIMITATIONS

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

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.

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?

1. Patel MR, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011; 365:883-891.

2. 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.

3. Xarelto® (rivaroxaban) Product Package Insert. 2011; July. Janssen Pharmaceuticals, Inc. Titusville, NJ.