New Oral Anticoagulants Top Warfarin in A-fib Stroke Prevention

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A recent wave of oral anticoagulants is paving the way toward better stroke prevention in patients with atrial fibrillation (A-fib), according to a meta-analysis published online April 27, 2012, ahead of print in the American Journal of Cardiology. Apixaban, dabigatran, and rivaroxaban decrease the likelihood of intracranial bleeding and appear to be promising alternatives to warfarin.

Researchers led by Corey S. Miller, BA, of McGill University (Montreal, Canada), pooled the results of 3 randomized trials that included a total of 44,563 patients:

  • ARISTOTLE: apixaban (n = 9,120; 5 mg twice daily, or 2.5 mg twice daily) vs. warfarin (n = 9,081)
  • RE-LY: dabigatran (n = 6,076; 110 mg or 150 mg twice daily) vs. warfarin (n = 6,022)
  • ROCKET AF: rivaroxaban (n = 7,131; 20 mg/day) vs. warfarin (n = 7,133)

Less Stroke, Intracranial Bleeding

Each new drug was found to be at least noninferior to warfarin for the composite endpoint of stroke (including hemorrhagic stroke) and systemic embolism. ARISTOTLE and RE-LY further demonstrated the superiority of apixaban and dabigatran, respectively, to warfarin with respect to this endpoint (table 1).

Table 1. All Stroke and Systemic Embolism: Individual Drugs vs. Warfarin


New Drug


HR (95% CI)

ARISTOTLE (apixaban)



0.79 (0.66-0.95)

RE-LY (dabigatran)



0.65 (0.52-0.81)

ROCKET AF (rivaroxaban)



0.88 (0.75-1.03)

Overall, patients randomized to a new oral anticoagulant fared better than those on warfarin, though the risk of MI was similar. Data from ARISTOTLE were excluded from the vascular mortality analysis because only event rates, not individual events, were reported (table 2).

Table 2. Secondary Outcomes: Novel Oral Anticoagulants Overall vs. Warfarin


RR (95% CI)

All-Cause Stroke and Systemic Embolism

0.78 (0.67-0.92)

Ischemic and Unidentified Stroke

0.87 (0.77-0.99)

Hemorrhagic Stroke

0.45 (0.31-0.68)

All-Cause Mortality

0.88 (0.82-0.95)

Vascular Mortality

0.87 (0.77-0.98)


0.96 (0.73-1.26)

The novel drugs saw a reduced risk of intracranial bleeding compared with warfarin (RR 0.49; 95% CI 0.36-0.66). However, data on major bleeding (RR 0.88; 95% CI 0.71-1.09) and gastrointestinal bleeding (RR 1.25; 95% CI 0.91-1.72) were “inconclusive,” suggesting effect but not demonstrating statistical significance.

‘Very Attractive’ Options

“Overall, our results support the use of the new oral anticoagulants as alternatives to warfarin for long-term anticoagulation therapy in patients with [A-fib],” the authors write. “Given the recent approval of dabigatran and rivaroxaban for stroke prevention in patients with [A-fib] by the United States Food and Drug Administration, it is essential that evidence comparing the novel treatment alternatives to warfarin be available to inform clinical decisions.”

In a telephone interview with TCTMD, Mr. Miller said he was “happy” that the meta-analysis found conclusive evidence not seen in the individual trials that the latest drugs outperform warfarin in some of the secondary outcomes.

“One advantage to these new oral anticoagulants . . . is that they don’t require monitoring,” he said, adding that the new drugs represent “potential new options [that] are very attractive” for the growing population of A-fib patients.

Lead investigator of ROCKET AF Manesh R. Patel, MD, of Duke Clinical Research Institute (Durham, NC), told TCTMD in a telephone interview that “most in the field would agree that novel anticoagulants in general represent a step forward in the management of patients with atrial fibrillation.” The new meta-analysis contributes by showing that “there are some general themes” to outcomes with the new drugs, he added.

“I hope what this means for these patients with atrial fibrillation is that there are more conversations with their doctors, and patients recognize that there are alternatives. In a perfect world, people understand all the possibilities before they start a new therapy,” he said, adding that warfarin still has a role in treating those who are difficult to manage or may not have all the indications for some of the new anticoagulants.

Since A-fib is “in many ways . . . a disease of the elderly,” the market for these drugs will continue to grow, Dr. Patel said. “Clearly the pharmaceutical companies recognize that this is a large group of patients with a large unmet need if you consider how warfarin is currently used.”

Unanswered Questions

Going forward, Mr. Miller said that the 3 drugs being considered plus the next agent in the pipeline, edoxaban, all show promise. Yet he urged further research given the inconclusive results for bleeding in the current analysis.

Dr. Patel also noted that 30 to 50% of A-fib patients do not take anticoagulants; rather they are on aspirin alone. “First we need to make sure that all patients with atrial fibrillation at risk for stroke are having the conversation about being on an anticoagulant,” he said. “Second, they should have discussions about which one to be on.”

Cost is a concern, however, Dr. Patel stressed. The issue for the health care system will be to understand how these drugs, which likely save money when considering the entire system, can ultimately lower health care costs.

Study Details

Median length of follow-up ranged from 657 to 730 days, and the average age ranged from 70 to 73 years. Women constituted 35% to 40% of the patients studied.


Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;Epub ahead of print.



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New Oral Anticoagulants Top Warfarin in A-fib Stroke Prevention

A recent wave of oral anticoagulants is paving the way toward better stroke prevention in patients with atrial fibrillation (A-fib), according to a meta-analysis published online April 27, 2012, ahead of print in the American Journal of Cardiology.
  • Mr. Miller is supported by the Ivan Racheff and Clarke McLeod Scholarships funded through the McGill University Research Bursary Program.
  • Dr. Patel reports receiving research support from Johnson & Johnson.