The FDA has approved apixaban for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In a double-blind, multinational trial, the annual rate of stroke or systemic embolism was lower among persons treated with apixaban than among those who received warfarin.

A total of 18,201 patients with nonvalvular atrial fibrillation were enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Of this population, 9,120 patients were randomized to 5 mg or 2.5 mg of apixaban twice daily, and 9,081 patients were randomized to an International Normalized Ratio of 2.0 to 3.0 of warfarin. Treatment continued for a median of 89 weeks. The annual rate of stroke or systemic embolism was 1.27% for patients receiving apixaban, compared with 1.60% for patients receiving warfarin. Apixaban was associated with a statistically significant 21% reduced risk of stroke or systemic embolism, compared with warfarin.

Apixaban’s superiority over warfarin in ARISTOTLE was “primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion, compared to warfarin,” and the rates of “purely ischemic strokes” were similar in patients on warfarin and those on apixaban, according to prescribing information for the drug. The rate of major bleeds was also significantly lower among patients on apixaban (2.13% per year) than in those on warfarin (3.09% per year).

“The randomized clinical trial data for apixaban are quite strong, and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation,” said Deepak Bhatt, MD, Professor of Medicine at Brigham and Women’s Hospital in Boston.

A New Anticoagulant Option
Like apixaban, rivaroxaban (marketed as Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (marketed as Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In addition, rivaroxaban is approved for the treatment of deep vein thrombosis (DVT) and pulmonary embolism. Rivaroxaban also is indicated for reducing the risk of DVT and pulmonary embolism recurrence and for the prophylaxis of DVT, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery.

“Overall, it is good to have therapeutic choices, but it is up to the physician community to optimize the use of these agents,” said Sanjay Kaul, MD, MPH, Director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles.

“With the approval of apixaban, the anticoagulant space has become somewhat crowded,” he added. In the absence of studies directly comparing these drugs, “physicians will have to figure out which patients are best treated with which agent.” Rivaroxaban has the broadest indication and, because of its once-daily recommended dosing, has a potential dose advantage, said Dr. Kaul. Although all of the abovementioned agents reduce hemorrhagic stroke, “dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke, compared with warfarin,” he added.

Apixaban has “the most desirable benefit-risk balance,” because it is associated with reduced stroke and bleeding risk, continued Dr. Kaul. The drug “might be preferable in patients with mild to moderate renal impairment,” given that, of the anticoagulants, it depends the least on renal clearance, he added.

All three anticoagulants have shown a modest reduction in mortality, but the mortality reduction was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of myocardial infarction was reported with dabigatran, but not with rivaroxaban and apixaban, “the clinical relevance of this observation is not clear,” concluded Dr. Kaul.

Prescribing Information
The recommended dose of apixaban is 5 mg twice daily. A dose of 2.5 mg twice daily is recommended for people with at least two of the following features: age 80 or older, body weight of 60 kg or less, and serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when the medicine is administered with strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.

Apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, according to the FDA. Patients with these characteristics were not studied in clinical trials. The agency also noted that “there is no agent that can reverse the anticoagulant effect” of apixaban.

Bristol-Myers Squibb (New York City) and Pfizer (New York City) will market the drug as Eliquis. Apixaban should be available in the United States by the end of January 2013, according to Bristol-Myers Squibb. As part of the Risk Evaluation and Mitigation Strategy required by the FDA, apixaban will be dispensed with a patient medication guide that describes the product’s risks.

—Elizabeth Mechcatie
IMNG Medical News

FDA Approves Apixaban for Nonvalvular Atrial Fibrillation