Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation - ROCKET AF

Aug 16, 2016
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Johnson & Johnson, Bayer HealthCare
Date Presented:
11/15/2010
Date Published:
08/15/2016
Date Updated:
08/16/2016
Original Posted Date:
08/10/2011
References

Description:

The goal of the trial was to evaluate treatment with the oral direct factor Xa inhibitor rivaroxaban compared with warfarin among patients with nonvalvular atrial fibrillation (AF).

Contribution to the Literature: The ROCKET AF trial showed that among patients with nonvalvular AF, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism.

Study Design

  • Blinded
  • Parallel
  • Randomized

Patient Populations:

  • Patients with nonvalvular AF and history of stroke, transient ischemic attack (TIA), or systemic embolism
  • Patients without stroke, TIA, or systemic embolism were eligible if they had at least two additional risk factors, defined as congestive heart failure or left ventricular ejection fraction ≤35%, hypertension, age ≥75 years, or diabetes

    Number of enrollees: 14,264
    Duration of follow-up: Median 1.9 years
    Mean patient age: 73 years
    Percentage female: 40%

Exclusions:

  • Severe valve disease, prosthetic heart valve
  • Planned cardioversion
  • Atrial fibrillation due to reversible cause (thyrotoxicosis, pulmonary embolus, surgery, myocardial infarction, etc.)
  • Atrial myxoma or left ventricular thrombus
  • Active endocarditis
  • Active internal bleeding, or increased bleeding risk
  • Planned invasive procedure
  • Anemia or thrombocyotopenia
  • Uncontrolled hypertension
  • Severe disabling stroke within the previous 14 days
  • TIA within the previous 3 days
  • Alternative indication for anticoagulation therapy
  • Treatment with aspirin >100 mg, recent fibrinolytic therapy, or combined low-dose aspirin plus an ADP receptor blocker
  • Need for chronic non-steroidal anti-inflammatory drug
  • Use of a cytochrome P450 inhibitor
  • Pregnancy or breast-feeding
  • Contraindication to warfarin
  • Known HIV infection
  • Creatinine clearance <30 ml/min
  • Significant liver disease
  • Limited life expectancy
  • Drug or alcohol addiction
  • Receipt of another experimental drug
  • Allergy to any component of the study medication

Primary Endpoints:

  • Stroke or non‒central nervous system systemic embolism (noninferiority)

Secondary Endpoints:

  • Major or nonmajor clinically relevant bleeding
  • Stroke, systemic embolism, or cardiovascular death
  • Stroke, systemic embolism, cardiovascular death, or myocardial infarction

Drug/Procedures Used:

Patients with AF at increased risk for stroke were randomized to rivaroxaban 20 mg oral daily (n = 7,131) versus dose-adjusted warfarin with target international normalized ratio (INR) 2-3 (n = 7,133). Patients with a creatinine clearance of 30-49 ml/min received rivaroxaban 15 mg daily.

Principal Findings:

Overall, 14,264 patients were randomized. In the rivaroxaban group, the median age was 73 years, 40% were women, mean CHADS2 score was 3.5, 40% had diabetes, mean blood pressure was 130/80 mm Hg, and 55% had prior stroke, TIA, or systemic embolism. In the warfarin group, the mean time in the target INR range was 55%.

The primary outcome per 100 patient-years, stroke, or non‒central nervous system systemic embolism occurred in 1.7 of the rivaroxaban group versus 2.2 of the warfarin group (p for noninferiority < 0.001, p for superiority by intention to treat = 0.12). By on-treatment analysis, rivaroxaban was superior to warfarin (p = 0.015).

By on-treatment analysis, vascular death, stroke, or embolism per 100 patient-years occurred in 3.1 versus 3.6 (p = 0.034), stroke occurred in 1.7 versus 2.0 (p = 0.092), non‒central nervous system embolism occurred in 0.04 versus 0.2 (p = 0.003), myocardial infarction occurred in 0.9 versus 1.1 (p = 0.12), and all-cause mortality occurred in 1.9 versus 2.2 (p = 0.07), respectively, for rivaroxaban versus warfarin. Among those with worsening renal function and randomized to rivaroxaban, stroke or systemic embolism was 1.54 events per 100 patient-years compared with 3.25 events per 100 patient-years among those randomized to warfarin, which was not seen among those with normal renal function (p for interaction = 0.050).

Among those with valvular heart disease, the efficacy of rivaroxaban versus warfarin was similar compared with those without valvular heart disease; however, bleeding was increased with rivaroxaban among those with mitral regurgitation or aortic regurgitation (hazard ratio 1.6, 95% confidence interval 1.2-2.3).

Bleeding:

  • Major and nonmajor clinically relevant bleeding (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44) , respectively for rivaroxaban vs. placebo
  • Intracranial hemorrhage (per 100 patient-years): 0.5 vs. 0.7 (p = 0.019), respectively for rivaroxaban vs. placebo
  • Fatal bleeding (per 100 patient-years): 0.2% vs. 0.5% (p = 0.003), respectively for rivaroxaban vs. placebo
  • Gastrointestinal (GI) site major bleeding (per 100 patient-years) occurred in 3.2% vs. 2.2% (p < 0.001), respectively for rivaroxaban vs. placebo. Fatal GI bleeds were similar between treatment groups.
  • Study drug discontinuation: 16% vs. 15%, respectively for rivaroxaban vs. placebo
  • Any serious adverse event: 37% vs. 38%, respectively for rivaroxaban vs. placebo

During follow-up, 1.1% of patients underwent percutaneous coronary intervention (PCI). The study drug was continued in 81%. The use of dual antiplatelet therapy (DAPT) was variable; DAPT ≥30 days in 37%, monotherapy with clopidogrel in 18%, monotherapy with aspirin in 16%, and no antiplatelet therapy after PCI in 15%.

Interpretation:

Among patients with AF and increased risk for stroke, the use of the direct Xa inhibitor rivaroxaban was noninferior to warfarin. Although intention-to-treat analysis is the standard for assessing superiority, rivaroxaban (on-treatment analysis) was associated with reduced incidence of the primary outcome without an excess of major bleeding or serious adverse events. Regarding types of bleeding events, intracranial and fatal bleeds occurred less frequently with rivaroxaban, whereas major GI bleeding occurred more frequently.

In addition to rivaroxaban, an alternative to warfarin for AF patients includes the direct thrombin inhibitor dabigatran studied in the RE-LY trial. Both agents appear to have a similar safety profile (less intracranial hemorrhage/more GI bleeding vs. warfarin). The signal for increased myocardial infarction observed with dabigatran versus warfarin was not seen with rivaroxaban versus warfarin.

References:

Sherwood MW, Cyr DD, Jones WS, et al. Use of Dual Antiplatelet Therapy and Patient Outcomes in Those Undergoing Percutaneous Coronary Intervention: The ROCKET AF Trial. JACC Cardiovasc Interv 2016;9:1694-1702.

Breithardt G, Baumgartner H, Berkowitz SD, et al, on behalf of the ROCKET AF Steering Committee & Investigators. Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban. Heart 2016;102:1036-43.

Fordyce CB, Hellkamp AS, Lokhnygina Y, et al., on behalf of the ROCKET AF Steering Committee and Investigators. On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF. Circulation 2016;134:37-47.

Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial. J Am Coll Cardiol 2015;66:2271-81.

Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;Aug 28:[Epub ahead of print].

Patel MR, Mahaffey KW, Garg J, et al., on behalf of the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:833-91.

Presented by Dr. Kenneth Mahaffey at the American Heart Association Scientific Sessions, Chicago, IL, November 15, 2010.

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Morpholines, Thiophenes, Warfarin, Blood Pressure, Creatinine, International Normalized Ratio, Intracranial Hemorrhages, beta-Alanine, Benzimidazoles, Intention to Treat Analysis, Atrial Fibrillation, Embolism, Factor Xa, Diabetes Mellitus, Gastrointestinal Hemorrhage, Heart Valve Diseases, Renal Insufficiency


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