PARIS, France—Apixaban, an oral direct factor Xa inhibitor, is the latest novel anticoagulant to prove superior to warfarin for preventing stroke or systemic embolism in patients with atrial fibrillation in a large randomized trial. Moreover, the newer agent reduces major bleeding and mortality compared with the older anticoagulant.

Results of the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) trial were presented August 28, 2011, at the European Society of Cardiology Congress by Christopher B. Granger, of the Duke University Medical Center (Durham, NC) and simultaneously published in the New England Journal of Medicine.

For the study, 18,201 patients with atrial fibrillation and at least 1 additional risk factor for stroke were randomized to apixaban (n = 9,120; 5 mg twice daily, or 2.5 mg twice daily in selected patients) or warfarin (n = 9,081) titrated to a target INR range of 2.0-3.0. 

The 2 groups were well balanced for baseline characteristics. The median age was 70 years; slightly over one-third were women, and the mean CHADS2 score (an index of stroke risk) was 2.1. For warfarin, patients spent a median of 66% of the study time in the therapeutic range.

Major Reduction in Hemorrhagic Stroke

After a median follow-up of 1.8 years, apixaban was not only noninferior but, in a subsequent analysis, superior to warfarin for the primary outcome of stroke or systemic embolism, yielding a 21% reduction in relative risk. Hemorrhagic stroke was almost halved, while no difference was seen in ischemic stroke or stroke of unknown etiology. The newer anticoagulant also reduced all-cause death by 11% compared with warfarin (table 1).

Table 1. Efficacy Outcomes

^a P for noninferiority; P = 0.01 for superiority.

In terms of safety, apixaban produced a 31% relative risk reduction in major bleeding defined by International Society on Thrombosis and Hemostasis (ISTH) criteria (the primary safety outcome) as well as major or clinically relevant minor bleeding, or any bleeding (table 2).

 Table 2. Bleeding Outcomes

 
The reduction in the primary outcomes were consistent across all major subgroups; the only baseline characteristics for which interaction was significant were diabetes status and renal function, with a greater reduction in bleeding among patients without diabetes (P = 0.003) and those with moderate or severe renal impairment P = 0.03).

“There is an enormous unmet need for treatment of patients at risk for stroke associated with atrial fibrillation,” Dr. Granger noted. “Only about half of patients who should be treated are being treated,” he added, in part because of warfarin’s drawbacks, such as variable response and interactions with other drugs and foods, which require frequent monitoring for dosage adjustment. In addition, warfarin carries a significant risk of intracranial hemorrhage.

A ‘Sweet Spot’ Between Efficacy and Safety

“The most exciting aspect of apixaban in the ARISTOTLE trial is that we think we have hit the ‘sweet spot’ in terms of the dose [that balances efficacy and safety],” Dr. Granger said in a press conference. “That’s really good news.”

He was reluctant to compare apixaban with the other new warfarin rivals such as dabigatran and rivaroxaban, although he did single out apixaban’s “impressive safety profile,” especially with regard to overall bleeding, and the fact that it has been shown to be as tolerable as aspirin. Dr. Granger stressed, though, that the various new warfarin alternatives stand to benefit many patients.

In an editorial accompanying the NEJM study, Jessica L. Mega, MD, of Brigham and Women’s Hospital (Boston, MA), heralds a “new era” in protection for A-fib patients and highlights some common themes emerging from recent trials not only of apixaban but also of dabigatran and rivoraxaban. All of the new agents:

• Dramatically reduce hemorrhagic stroke
• Have favorable bleeding profiles
• Reduce mortality

Commenting after the presentation, Michael D. Ezekowitz, MBChB, of the Lankenau Institute for Medical Research (Wynnewood, PA), agreed that stroke prophylaxis has moved beyond warfarin, adding that it is very reassuring that dabigatran (a direct thrombin inhibitor) and apixaban have now both been shown in large, blinded trials to be safer and more effective than warfarin despite having different mechanisms of action. The main challenge now will be translating clinical trial findings into practice to minimize discontinuation of therapy.

Drs. Ezekowitz and Mega both observed that differences in trial design preclude direct comparison among the new agents.

Apixaban Superiority Holds Up Across Range of Warfarin INR Control

In a substudy bolstering the main findings, Lars C. Wallentin, MD, PhD, of the Uppsala Clinical Research Center (Uppsala, Sweden), reported on an analysis of the effects of apixaban relative to the actual time that warfarin patients were within therapeutic range. This varies widely and could potentially have a significant impact on the comparison with apixaban, he noted.

The ARISTOTLE investigators stratified the 1,034 participating sites in 39 countries into quartiles of time in therapeutic range, testing for interactions with treatment effects, after correcting for differences in baseline characteristics and medications.

They found that the superiority of apixaban over warfarin for the primary efficacy and safety endpoints as well as most others were consistent across the wide range of warfarin management (table 3).

Table 3. Outcomes According to Time in Therapeutic Range (TTR)

A key question is whether a patient with good INR control would benefit from switching to apixaban, said Jean-Philippe Collet, MD, PhD, of Hôpital de la Pitié-Salpêtrière (Paris, France), commenting on the presentation. Making the answer less clear, he noted, is the fact that although time in therapeutic range is a known marker of patients’ baseline risk, it may not be a valid marker of drug effectiveness and thus not a basis on which to compare different agents.

1. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;Epub ahead of print.
2. Mega JL. A new era for anticoagulation in atrial fibrillation. N Engl J Med. 2011;Epub ahead of print.
3. Wallentin LC. ARISTOTLE: Efficacy and safety of apixaban compared to warfarin at different levels of INR control for stroke prevention in 18,202 patients with atrial fibrillation in the ARITOTLE trial. Presented at: ESC Congress; August 28, 2011; Paris, France.

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