Expert Insight Into: ROCKET AF—A Comparison of Factor Xa Inhibition Versus Vitamin K Inhibition for the Prevention of Stroke or Systemic Embolism in Patients with Atrial Fibrillation or Systemic Embolism (Part 5 of Series)

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Clinical Insights

Rivaroxaban, an oral factor Xa inhibitor, was recently shown to be noninferior to adjusted-dose warfarin in the large ROCKET AF trial, with significantly fewer intracranial and fatal hemorrhages.
Rivaroxaban is one of several new generation oral anticoagulants and is the first factor Xa inhibitor to be FDA approved for prevention of stroke in patients with atrial fibrillation.
Clinicians now have three options for anticoagulation of atrial fibrillation patients: warfarin, dabigatran, or rivaroxaban, with additional agents likely to become available soon. We are entering an era of debate on the comparative efficacy and safety of these anticoagulants that is unlikely to be resolved soon.

PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.

Rivaroxaban is a new oral factor Xa inhibitor, which was recently evaluated for its efficacy for prevention of stroke and embolism in patients with atrial fibrillation. 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 double-blind randomized noninferiority trial that compared rivaroxaban (20 mg/day) to dose-adjusted warfarin in patients with nonvalvular atrial fibrillation at moderate to high risk for stroke.¹

To be eligible, patients were required to have nonvalvular atrial fibrillation and be at moderate to high risk for stroke. To be considered at elevated risk, patients must have had a history of stroke, transient ischemic attack, or systemic embolism. If these criteria were not present, they were required to have at least 2 of the following risk factors: heart failure or a left ventricular ejection fraction ≤35%, hypertension, age ≥75 years, or the presence of diabetes mellitus. The study protocol restricted the number of patients with 2 risk factors to ≤10%. Notably, these criteria resulted in inclusion of atrial fibrillation patients with higher estimated risk for stroke than were included in other recent randomized trials.

Eligible patients were randomized to receive rivaroxaban (20 mg/day or 15 mg/day in patients with a creatinine clearance of 30-49 mL per minute) or adjusted-dose warfarin (target international normalized ratio [INR] of 2.0 to 3.0). The primary efficacy outcome was stroke or systemic embolism. The primary safety endpoint was the composite of major and nonmajor clinically relevant bleeding events.

A total of 14,264 patients were randomized. The median age was 78 years, and 39.7% of patients were women. The mean CHADS2 score was 3.5, and 54.8% of patients had previously had a stroke, TIA, or systemic embolism. INR values were in the therapeutic range for a mean of 55% of the time in the warfarin group.

At a median follow-up of 707 days, the annual rate of stroke or systemic embolism was 1.7% in the rivaroxaban arm compared to 2.2% in the warfarin arm in the per-protocol population (Hazard Ratio [HR] 0.79; P <.001 for noninferiority). (Table 1) In the intent-to-treat population, the rate of primary events was 2.1% in the rivaroxaban group versus 2.4% in the warfarin group (HR 0.88; P <.001 for noninferiority; P = .12 for superiority). Annual rates of myocardial infarction were similar between arms (0.9% for rivaroxaban vs 1.1% for warfarin; HR 0.81; P = .12). The annual rate of death was also similar between arms in the intent-to-treat population (4.5% for rivaroxaban vs 4.9% for warfarin; HR 0.92; P = .15).

Table 1. ROCKET AF Trial: Key Efficacy Results¹

Event (% per Year)	Warfarin INR 2.0–3.0	Rivaroxaban 20 mg/day	Hazard Ratio^* (95% CI)	P Value
Stroke or Systemic Embolism^†	2.2%	1.7%	0.79 (0.66-0.96)	<.001 (noninferiority)
Stroke or Systemic Embolism^§	2.4%	2.1%	0.88 (0.74-1.03)	<.001 (noninferiority) .12 (superiority)
Myocardial Infarction	1.1%	0.9%	0.81 (0.63-1.06)	.12
Death^§	4.9%	4.5%	0.92 (0.82-1.03)	.15

^*Compared with warfarin.
^†Per-protocol analysis.
^§Intent-to-treat analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio.

The annual rate of major and nonmajor bleeding was similar between arms (14.9% with rivaroxaban vs 14.5% with warfarin; HR 1.03; P = 0.44). (Table 2) Rivaroxaban was associated with significantly lower rates of intracranial hemorrhage (0.5% vs 0.7%; P = .02) than warfarin. Although the absolute difference was small, this reduction may be clinically relevant as intracranial bleeding causes most fatal and disabling warfarin-associated hemorrhages.² Rivaroxaban was associated with significantly less fatal bleeding (0.2% vs 0.5%, P = .003) compared with warfarin. Major gastrointestinal bleeding rates were higher in the rivaroxaban arm compared with warfarin (3.2% vs 2.2%; P <.001).

Table 2. ROCKET AF Trial: Key Safety Results¹

Event (% per Year)	Warfarin INR 2.0 to 3.0	Rivaroxaban 20 mg/day	Hazard Ratio^* (95% CI)	P Value
Major and Nonmajor Bleeding	14.5%	14.9%	1.03 (0.96–1.11)	.44
Intracranial Hemorrhage	0.7%	0.5%	0.67 (0.47–0.93)	.02
Fatal Bleeding	0.5%	0.2%	0.50 (0.31–0.79)	.003
Major Gastrointestinal Bleeding	2.2%	3.2%	NR	<.001

^*Compared with warfarin
Abbreviations: CI, confidence interval; HR, hazard ratio; NR, not reported.

The efficacy and safety of rivaroxaban compared with warfarin was similar across patient subgroups. In addition, no difference was seen for the effect of rivaroxaban when compared across quartiles of patients in the warfarin arm based on INR time within therapeutic range (P = .74 for interaction).

The double-blind design of ROCKET AF is a strength. However, the relatively low average INR in the warfarin arm and complicated reporting of results in subgroup populations have engendered criticism.^3,4 In addition, noninferiority within a variably defined margin is a difficult concept.

Based on the results of the ROCKET AF trial, rivaroxaban was approved in the United States for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation. This addition further expands the treatment options for these patients, who now have the option of warfarin, dabigatran, or rivaroxaban.

References

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120:700-705.

Fleming TR, Emerson SS. Evaluating rivaroxaban for nonvalvular atrial fibrillation—regulatory considerations. N Engl J Med. 2011;365:1557-1559.

del Zoppo GJ, Eliasziw M. New options in anticoagulation in atrial fibrillation. N Engl J Med. 2011;365:952-953.

Privacy Policy

Expert Insight Into:
ROCKET AF—A Comparison of Factor Xa Inhibition Versus Vitamin K Inhibition for the Prevention of Stroke or Systemic Embolism in Patients with Atrial Fibrillation or Systemic Embolism (Part 5 of Series)

Based on the Article:

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation.

Expert Faculty: Robert G. Hart, MD
Medical Writer: Susan R. Peck, PhD

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Privacy Policy

Expert Insight Into: ROCKET AF—A Comparison of Factor Xa Inhibition Versus Vitamin K Inhibition for the Prevention of Stroke or Systemic Embolism in Patients with Atrial Fibrillation or Systemic Embolism (Part 5 of Series)

Based on the Article: Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation.

Expert Faculty: Robert G. Hart, MD Medical Writer: Susan R. Peck, PhD

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Expert Insight Into:
ROCKET AF—A Comparison of Factor Xa Inhibition Versus Vitamin K Inhibition for the Prevention of Stroke or Systemic Embolism in Patients with Atrial Fibrillation or Systemic Embolism (Part 5 of Series)

Based on the Article:

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation.

Expert Faculty: Robert G. Hart, MD
Medical Writer: Susan R. Peck, PhD