Summary

• The ROCKET AF trial was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, noninferiority study that evaluated the efficacy and safety of XARELTO and warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) at moderate-to-high risk for stroke.¹
• In ROCKET AF, XARELTO demonstrated noninferiority to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or noncentral nervous system systemic embolism. Superiority to warfarin was not demonstrated.¹

CLINICAL STUDY - ROCKET AF

The ROCKET AF (Rivaroxaban, Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, noninferiority study to evaluate the efficacy and safety of oral fixed-dose XARELTO 20 mg once daily (15 mg for patients with creatinine clearance [CrCl] 30-49 mL/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular AF at moderate-to-high risk for stroke.^1,2

Inclusion Criteria

• Patients ≥18 years of age with documented nonvalvular AF who were at moderate to high risk of stroke were included in the study.^1,3
• Elevated risk was indicated by history of prior stroke, transient ischemic attack (TIA), or systemic embolism, or had ≥2 of the following risk factors¹:
  • Heart failure or left ventricular ejection fraction ≤35%; hypertension; age ≥75 years; diabetes mellitus (ie, CHADS₂ score ≥2).
• The percentage of patients who did not have a previous stroke, TIA, or systemic embolism and had ≤2 risk factors was limited to 10%; the remainder of the patients were required to have either previous thromboembolism or ≥3 risk factors.¹

Exclusion Criteria

• Patients were excluded if they had any of the following³:
  • hemodynamically significant mitral stenosis; any valve prosthesis; transient AF due to reversible disorders; planned cardioversion; active endocarditis; atrial myxoma or left ventricular thrombus; active internal bleeding; any prior or current condition associated with an increased risk of bleeding; platelet count <90,000/µL; severe, disabling stroke within 3 months or any stroke within 14 days of randomization; TIA within 3 days before randomization; required anticoagulation for conditions other than AF; anemia; pregnancy or lactation; contraindication to warfarin; human immunodeficiency virus infection; CrCl <30 mL/min; significant hepatic impairment or alanine aminotransferase >3x the upper limit of normal.
• The following treatments resulted in study exclusion³:
  • aspirin >100 mg per day; aspirin in combination with thienopyridines or use of intravenous antiplatelets within 5 days before randomization; fibrinolytics within 10 days before randomization; long-term nonsteroidal anti-inflammatory drug use; strong CYP450 3A4 inhibitors or inducers within four days before randomization or during the study.
  • The use of aspirin (≤100 mg) monotherapy and thienopyridine monotherapy was allowed.

Study Design

• The study consisted of a screening period, a double-blind treatment period, and an approximate ~30 day post-treatment observation period.²
• At the end of the double-blind treatment visit (or earlier if study drugs were prematurely discontinued), patients were transitioned from study drug to an open-label vitamin K antagonist or other appropriate regimen (See Figure: Study Design for ROCKET AF).²
• Patient visits were scheduled on weeks 1, 2, and 4 and every month thereafter for follow-up after randomization. A standardized questionnaire and examination were used to screen for stroke symptoms and potential clinical events during follow-up.²

Treatment Populations

• The primary analysis of the study was prespecified to demonstrate the noninferiority of XARELTO to that of dose-adjusted warfarin (INR, 2.0 to 3.0) in the per-protocol (PP) population during treatment (PP, as-treated population).¹
• The PP population included all patients who received at least one dose of study drug, did not have a major protocol violation, and were followed for events while receiving study drug or within 2 days of discontinuation.¹
• If noninferiority was achieved, the primary superiority analysis was conducted in the safety population during treatment (safety, as-treated population), which included patients who received at least one dose of a study drug and were followed for events while they were receiving study drug or within 2 days after discontinuation, regardless of adherence to study protocol.^1,3
• Testing  for noninferiority and superiority was performed in the intention-to-treat (ITT) population, which included all patients who underwent randomization and were followed for events during treatment or after premature discontinuation. The ITT population was a sensitivity test in the ROCKET AF trial and not prespecified for the main superiority testing.¹
  • In the ITT population, the patients who discontinued early were transitioned to open-label warfarin or other appropriate therapy (e.g., aspirin or no therapy) at the discretion of the treating physician.⁴
  • Of patients ending treatment before the end of the prescribed period (premature permanent discontinuation), 51.2% in the XARELTO arm and 48.8% in the warfarin arm subsequently received (open-label) warfarin.³
  • In addition, a post hoc analysis was performed of events in the ITT population and events occurring during the end-of-study transition to open-label treatment with conventional anticoagulant agents.¹

Noninferiority Margins

• To provide a power of 95% to calculate a noninferiority margin of 1.46 with a one-sided alpha level of 0.025 in the primary analysis, a minimum of 363 events were required; however the prespecified target was 405 events to ensure a robust result. ¹
• Approximately 14,000 patients were needed for randomization, based on a projected event rate of 2.3% per 100 pt-years in the warfarin group and projected 14% rate of annual attrition.¹

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 May 2024.