ROCKET AF

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Patel MR, et al. "Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation". The New England Journal of Medicine. 2011. 365(10):883-891.
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Clinical Question

Among patients with nonvalvular atrial fibrillation, is rivaroxaban noninferior to warfarin in preventing stroke and systemic thromboembolism?

Bottom Line

Among patients with nonvalvular atrial fibrillation, rivaroxaban is noninferior to warfarin in preventing stroke and systemic thromboembolism.

Major Points

Rivaroxaban is an oral factor Xa inhibitor of great appeal because of its long half-life, once-daily dosing, and reliable anticoagulation, obviating the need for laboratory monitoring. Several studies have evaluated the noninferiority of rivaroxaban compared to warfarin in various conditions, and ROCKET AF is among those comparing the two in atrial fibrillation.

ROCKET AF randomized 14,264 patients with nonvalvular atrial fibrillation and at least a moderate risk of stroke (mean CHADS2 score 3.5) to rivaroxaban or warfarin. At a mean follow-up of 2 years, rivaroxaban was noninferior to warfarin for the composite endpoint of stroke or systemic embolism, without increasing the bleeding rates.

The statistical methods employed by the investigators drew some criticism,[1] but are actually common in noninferiority trials. In particular, such trials use both per-protocol and intention-to-treat analyses, and if the noninferiority margin is reached in both approaches, then noninferiority is established.[2] ROCKET AF reached the noninferiority margin in both per-protocol and intention-to-treat analyses, which made it possible to assert rivaroxaban's noninferiority to warfarin. Rivaroxaban was not superior to warfarin in the intention-to-treat analysis.

As such, rivaroxaban joins dabigatran (RE-LY; 2009), apixaban (ARISTOTLE; 2011), and edoxaban (ENGAGE AF-TIMI 48; 2013)[3] as the new generation of anticoagulants.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[4]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)

Design

  • Multicenter, double-blind, comparative, randomized controlled trial
  • N=14,264
    • Rivaroxaban (n=7,131)
    • Warfarin (n=7,133)
  • Setting: 1,178 centers in 45 countries
  • Enrollment: 2006-2009
  • Median follow-up: ~2 years
  • Analysis: Intention-to-treat and per-protocol
  • Primary outcome: Composite of CVA or systemic embolism

Population

Inclusion Criteria

  • Age ≥18 years
  • Nonvalvular atrial fibrillation
  • CHADS2 score ≥2

Exclusion Criteria

  • Hemodynamically significant mitral valve stenosis, prosthetic heart valve, atrial myxoma, LV thrombus
  • Reversible atrial fibrillation cause or planned cardioversion
  • Current endocarditis
  • Current internal bleeding, history of increased bleeding risk, or planned procedure with risk of uncontrolled bleeding
  • Platelets <90k, hemoglobin <10 g/dL
  • Uncontrolled HTN
  • CVA in prior 14 days, CVA with modified Rankin score of 4-5 in prior 3 months, TIA in prior 3 days
  • Other indication for anticoagulation
  • Contraindication to warfarin or hypersensitivity or allergy to study interventions
  • Treatment with aspirin >100 mg/day, aspirin/thienopyridine in prior 5 days, IV antiplatelet medication in prior 5 days, or fibrinolytics in prior 10 days
  • Need for chronic NSAIDS, CYP450 3A4 strong inhibitor or inducer
  • Known HIV, CrCl <30 mL/min, liver disease or ALT >3x ULN
  • Life expectancy <2 years
  • Drug addiction or alcohol abuse in prior 3 years
  • Experimental drug or device in prior 30 days or previous study with rivaroxaban on trial
  • Pregnancy, ability to become pregnant, or breast feeding

Baseline Characteristics

From the rivaroxaban group.

  • Demographics: Age 73 years, female 39.7%
  • Health data: BMI 28.1 kg/m2, BP 130/80 mmHg
  • Type of afib
    • Persistent: 81.1%
    • Paroxysmal: 17.5%
    • New diagnosis: 1.4%
  • Previous medications: ASA 36.3%, vitamin K antagonist 62.3%
  • Current medications: Beta-blocker 65.1%, diuretic 60.32%, ACE inhibitors 55.1%, statin 43.0%, digitalis 38.8%, aspirin 38.3%
  • CHADS2:
    • Mean: 3.48
    • 2: 13.0%
    • 3: 42.9%
    • 4: 29.3%
    • 5: 13.1%
    • 6: 1.7%
  • Prior CVA/embolism/TIA 54.9%, HF 62.6%, HTN 90.3%, DM 40.4%, MI 16.6%, PVD 5.6%, COPD 10.6%
  • Mean CrCl 67 mL/min

Interventions

  • Randomization to one of two groups:
    • Rivaroxaban 20mg daily (CrCl ≥50 mL/min) or 15 mg daily (CrCl 30-49 mL/min)
    • Warfarin targeted to an INR of 2-3 with sham values provided for those on rivaroxaban
  • Discontinuation per clinical direction

Outcomes

Comparisons are rivaroxaban vs. warfarin.

Primary Outcome

Stroke or systemic embolism
Intention-to-treat: 2.1 vs. 2.4 events per 100 patient-years (HR 0.88; 95% CI 0.75-1.03; P<0.001 for noninferiority; P=0.12 for superiority)
Per-protocol: 1.7 vs. 2.2 events per 100 patient-years (HR 0.79; 95% CI 0.66-0.96; P<0.001 for noninferiority)

Secondary Outcomes

Intervention cessation before trial end
23.7% vs. 22.2% (statistics not given)
MI
0.9 vs. 1.1 events per 100 patient-years (HR 0.81; 95% CI 0.63-1.06; P=0.12)
All-cause mortality
1.9 vs. 2.2 events per 100 patient-years

Adverse Events

Major and non-major clinically-relevant bleeding
20.7% vs. 20.3% (P=NS)
Major bleeding
5.6% vs. 5.4% (P=NS)

Subgroup Analysis

There was no significant difference in the primary outcome for age, sex, race, weight, BMI, renal function, CHADS2 risk score, history of CVA/TIA/systemic thromboembolism, HF, HTN, DM, type of a fib, region, previous MI, or prior use of ASA, vitamin K inhibitors, or PPI.

Criticisms

  • Unclear if the differences between the as-treated and intention-to-treat groups represents a significant underlying effect of the intervention[5]
  • The warfarin group had therapeutic INR only 55% of the time (the RE-LY trial achieved 64%) and may not represent a standard-of-care comparison[5]
  • No standardized reversal protocol[5]

Funding

Johnson & Johnson Pharmaceutical Research and Development and Bayer HealthCare

Further Reading

  1. del Zoppo GJ, et al. "New Options in Anticoagulation for Atrial Fibrillation." N Engl J Med. 2011;365:952-953.
  2. Snapinn SM. "Noninferiority trials." Curr Control Trials Cardiovasc Med. 2000;1(1):19-21.
  3. Giugliano RP, et al. "Edoxaban versus warfarin in patients with atrial fibrillation." The New England Journal of Medicine. 2013;369(22):2093-2104.
  4. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.
  5. 5.0 5.1 5.2 "Correspondence: Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation." N Engl J Med. 2011;365:2333-2335