ROCKET AF Published: Rivaroxaban Matches Warfarin in Treating A-Fib Patients

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Rivaroxaban, an oral factor Xa inhibitor, is a reasonable alternative to warfarin in preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation (A-fib), with less fatal bleeding, according to a large randomized controlled trial. Findings were published online August 10, 2011, ahead of print in the New England Journal of Medicine.

Data from the ROCKET AF trial were previously presented in November 2010 at the annual American Heart Association Scientific Sessions in Chicago, IL.

This July, the US Food and Drug Administration (FDA) approved rivaroxaban (Xarelto; Johnson & Johnson, New Brunswick, NJ; Bayer HealthCare, Leverkusen, Germany) for the prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery. An FDA advisory meeting to discuss the drug’s potential in A-fib patients is set for September 8.

Similar Efficacy, Signs of Superior Safety

For the double-blind 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) study, Manesh R. Patel, MD, of the Duke Clinical Research Institute (Durham, NC), and colleagues enrolled 14,264 patients with electrocardiographically documented nonvalvular A-fib and moderate-to-high stroke risk. Subjects were randomized to receive fixed-dose rivaroxaban (20 mg daily, or 15 mg daily in those with creatinine clearance 30-49 mL/min) or dose-adjusted warfarin (target international normalized ratio [INR] 2.0-3.0). Among patients given warfarin, INR values were within the therapeutic range a mean of 55% of the time.

Overall, patients were a median of 73 years old and had substantial comorbidities including hypertension (90.5%), heart failure (62.5%), diabetes (40.0%), and previous stroke, systemic embolism, or transient ischemic attack (54.8%).

In the main efficacy analysis of the per-protocol population, rivaroxaban was found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. An intention-to-treat analysis also found that the drugs were equivalent. Yet a safety analysis that examined the as-treated population—patients who received at least 1 dose of a study drug and were followed for events during treatment—showed a significant advantage for rivaroxaban (table 1).

Table 1. Annual Risk of Stroke or Systemic Embolism

 

Rivaroxaban

Warfarin

HR (95% CI)

P Value

Per Protocol

1.7%

2.2%

0.79 (0.66-0.96)

< 0.001a

Intention to Treat

2.1%

2.4%

0.88 (0.75-1.03)

0.12

Safety

1.7%

2.2%

0.79 (0.65-0.95)

0.02

a P for noninferiority.

Although the risk of major and nonmajor clinically relevant bleeding, the primary safety endpoint, was similar in both treatment groups, rivaroxaban decreased both intracranial and fatal bleeding. In contrast, rivaroxaban increased the need for transfusion and the likelihood that hemoglobin would drop at least 2 g/dL (table 2).

Table 2. Annual Risk of Bleeding Outcomes

 

Rivaroxaban
(n = 7,111)

Warfarin
(n = 7,125)

HR (95% CI)

P Value

Major + Nonmajor Clinically Relevant Bleeding

14.9%

14.5%

1.03 (0.96-1.11)

0.44

Fatal Bleeding

0.2%

0.5%

0.50 (0.31-0.79)

0.003

Intracranial Hemorrhage

0.5%

0.7%

0.67 (0.47-0.93)

0.02

Decrease in Hemoglobin ≥ 2 g/dL

2.8%

2.3%

1.22 (1.03-1.44)

0.02

Transfusion

1.6%

1.3%

1.25 (1.01-1.55)

0.04


According to the study authors, the trial design prespecified that data would be “analyzed in a variety of ways because we anticipated that some patients would discontinue the study treatment and we wished to evaluate both noninferiority and superiority.”

An editorial by Gregory J. del Zoppo, MD, of the University of Washington School of Medicine (Seattle, WA), and Misha Eliasziw, PhD, of the University of Calgary (Calgary, Canada), however, takes issue with this aspect of ROCKET AF. “[T]he multiple analyses have muddied the waters regarding rivaroxaban’s efficacy and effectiveness over warfarin,” they write.

The Contenders: Rivaroxaban vs. Dabigatran

The editorial draws comparisons between ROCKET AF and RE-LY, the pivotal trial backing dabigatran (Pradaxa, Boehringer-Ingelhiem, Ridgefield, CT), a direct thrombin inhibitor that is currently the only FDA-approved alternative to warfarin for stroke prevention in nonvalvular A-fib.

When interpreting the 2 trials, they say, it is important to weigh how well warfarin was managed. Not only are different methods used to produce the ‘dummy INR’ results for patients receiving placebo, but RE-LY’s warfarin cohort maintained INR values within the therapeutic range 64% of the time, whereas ROCKET AF achieved this goal 55% of the time. “So the interpretation of noninferiority in a given trial may also depend on both the homogeneity and treatment accuracy of the warfarin cohort and on the dummy INR algorithm that is used,” they explain.

Interestingly, both RE-LY and ROCKET AF found that the new oral antithrombotic medications reduced intracranial hemorrhage compared with warfarin, Drs. del Zoppo and Eliasziw point out.

One explanation may be that dabigatran and rivaroxaban have single targets in the hemostatic system, while warfarin’s mechanism involves multiple targets. “More intriguing,” they say, “is the possibility that cerebral vascular beds have protective features that are more apparent at the doses of either of the new agents tested [and] could modulate vascular hemostatic activity within brain vessels.”

In an e-mail communication, Dr. Patel told TCTMD that he hoped the ROCKET AF findings along with other trial results might provide valuable alternatives to warfarin for stroke prevention in A-fib patients. “Importantly, we have had 50 years without anything to treat patients with [A-fib] outside of warfarin,” he said. “The ROCKET AF study found that in patients at moderate-high risk for stroke with [A-fib], rivaroxaban is a very reasonable alternative to warfarin.”

With no direct comparison among the slate of warfarin alternatives—dabigatran and rivaroxaban as well as the promising factor Xa inhibitor apixaban—it is hard to judge why physicians should choose 1 agent over another, Dr. Patel noted. “What I feel we can do is look at the patients enrolled in [trials] and compare them to the patients clinicians are considering prescribing the medicine,” he said. “So, ROCKET AF enrolled older patients with higher risk than some of the other studies, and that would be where we feel there is evidence of effect.”

Downsides to the novel drugs include a lack of understanding about how to use them in clinical practice and possibly higher cost, Dr. Patel commented. The editorial adds another concern: “The absence of antidotes to rapidly reverse the anticoagulant effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery.”

That being said, Drs. del Zoppo and Eliasziw appear encouraged by recent trial results. “For the management of atrial fibrillation, oral alternatives to warfarin have arrived,” they conclude. “Their simplicity of use is attractive, and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin.”

 


Sources:
1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;Epub ahead of print.

2. del Zoppo GJ, Eliasziw M. New options in anticoagulation for atrial fibrillation. N Engl J Med. 2011;Epub ahead of print.

 

 

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Disclosures
  • Dr. Patel reports receiving consulting fees from Bayer HealthCare and Ortho McNeil Janssen and serving on an advisory board for Genzyme.
  • Drs. del Zoppo and Eliasziw report no relevant conflicts of interest.

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