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PARIS -- The investigational direct factor Xa inhibitor apixaban was better than warfarin at preventing stroke in patients with atrial fibrillation, the large, randomized ARISTOTLE trial showed.

Through a median of 1.8 years, the annual rate of stroke or systemic embolism was 1.27% with apixaban and 1.60% with warfarin (HR 0.79, 95% CI 0.66 to 0.95), according to Christopher Granger, MD, of the Duke Clinical Research Institute in Durham, N.C.

The difference met criteria for both noninferiority (P<0.001) and for superiority (P=0.01), he reported at the European Society of Cardiology meeting here. The findings were reported simultaneously online in the New England Journal of Medicine.

Apixaban also topped warfarin for major bleeding (2.13% versus 3.09%; HR 0.69, P<0.001) and for all-cause death (3.52% versus 3.94%; HR 0.89, P=0.047).

Thus, for every 1,000 patients treated for 1.8 years, apixaban would prevent six strokes, 15 major bleeds, and eight deaths, Granger and colleagues wrote in their paper.

The main mechanism of stroke prevention with apixaban was a reduction in hemorrhagic stroke, particularly intracranial hemorrhage, which is an important advantage over warfarin, according to Granger. There was not a significant reduction in a composite of ischemic strokes or strokes of an uncertain type.

Apixaban joins the approved direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitor rivaroxaban -- which has not been approved for stroke prevention -- as agents shown to be at least as good as warfarin at preventing strokes in patients with atrial fibrillation.

"After all this time, a new era of anticoagulation in patients with atrial fibrillation appears to be emerging for patients with atrial fibrillation," Jessica Mega, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, wrote in an editorial in NEJM.

She said, however, that even though some of the newer agents appear to be better than warfarin, it might not be necessary to switch patients who have been well controlled on warfarin to one of the newer anticoagulants.

"The problem with that argument is the data really don't support it," Granger said in an interview, noting that the benefits of apixaban were seen both in patients who had and who had not previously taken warfarin.

Not only can patients who are well controlled on warfarin be switched to apixaban (assuming FDA approval), but they should be, Granger argued.

"One of the important messages from the ARISTOTLE trial is we should no longer be satisfied with warfarin -- even with reasonably good INR control -- as an optimal therapy," he said.

The researchers enrolled 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke at 1,034 centers in 39 countries. The median age of the patients was 70, and 35.3% were female. The average CHADS₂ score was 2.1.

About half of the patients received apixaban 5 mg twice daily and half received warfarin with a target INR of 2.0 to 3.0. During the trial, patients in the warfarin group had an INR in the therapeutic range for a median of 66% of the time, which Granger called "reasonable."

Through a median duration of 1.8 years, the primary outcome and major secondary outcomes all favored apixaban. All types of bleeding were reduced with apixaban, although the difference was not statistically significant for gastrointestinal bleeding.

The results were consistent across subgroups, and a separate subanalysis looking at the level of INR control achieved at various centers found that outcomes did not differ based on the quality of the warfarin therapy.

The reduction in stroke was largely attributed to a lower rate of hemorrhagic stroke (0.24% versus 0.47% per year; HR 0.51, 95% CI 0.35 to 0.75). Previous trials of dabigatran and rivaroxaban versus warfarin have also shown a reduction in this endpoint.

Apixaban was well tolerated compared with warfarin, and fewer patients on apixaban discontinued before the end of the study (25.3% versus 27.5%). There were similar rates of adverse events (81.5% versus 83.1%) and serious adverse events (35% versus 36.5%) in the two groups.

Stuart Connolly, MD, of McMaster University in Hamilton, Ontario, called the ARISTOTLE findings "truly a spectacular result." He said the trial "is really good news for patients. [Apixaban's] obviously going to be very effective in the clinic."

Granger cited cost as the only potential limitation of apixaban and the other newer anticoagulants, although he noted that having up to four competing drugs -- dabigatran and the investigational agents apixaban, rivaroxaban, and edoxaban (another direct factor Xa inhibitor) -- might force prices down.

Connolly, who was involved in the AVERROES trial pitting apixaban against aspirin for stroke prevention in patients with atrial fibrillation who were not candidates for vitamin K antagonist therapy, said that the twice-daily dosing of apixaban is also a disadvantage because it makes it harder to remain compliant.

"But I don't think we can assume that that's a true limitation," he added. "That's a limitation of all chronic therapies and something that we have to work on with all of these drugs."

When it comes to deciding which of the newer anticoagulants is best, Connolly said it might depend on what a physician's priority is. He noted that dabigatran had a large effect on ischemic stroke, whereas most of the benefit of apixaban came from preventing hemorrhagic stroke and other bleeding.

"Physicians are probably not going to want to stick just to one drug, but they're going to want to have the full armamentarium eventually of probably four different drugs," he said.

In comments following Granger's presentation, Michael Ezekowitz, MBChB, DPhil, of Thomas Jefferson University Medical School, said that the consistent results of RE-LY -- which showed that dabigatran was superior to warfarin -- and ARISTOTLE "assure us that these are real findings with respect to these novel agents.

"It's clear to me, that on the basis of these trials, millions of patients worldwide with atrial fibrillation will benefit very significantly from stroke reduction," said Ezekowitz, who was the co-principal investigator of RE-LY.

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