No FDA Approval Yet of Apixaban for Stroke Prevention in AF

Susan Jeffrey

June 25, 2012

June 25, 2012 — For now, the US Food and Drug Administration (FDA) has declined approval of apixaban (Elquis, Pfizer/Bristol-Myers Squibb) as a third warfarin alternative in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF).

The companies issued a joint release saying the agency issued a complete response letter requesting additional information on data management and verification from the ARISTOTLE trial.

"The FDA has not requested that the companies complete any new studies," the statement notes. "FDA and the companies are committed to working expeditiously to address the outstanding questions and move the application forward."

Two other alternatives are already approved for this indication: dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer). Apixaban is not approved for any other indication in the United States but is approved in the European Union for the prevention of venous thromboembolism in adults undergoing hip or knee replacement surgery.

The FDA's decision comes ahead of the projected decision date of June 28, 3 months later than the initial action date of March 28. Apixaban was designated for priority review in this indication in November 2011 when the New Drug Application was accepted. However, the date was extended, the companies noted because data submitted to the FDA at that time was seen as a major amendment to the application, and would require additional time for review. No advisory panel meeting was held on apixaban.

The application was based on apixaban's performance in the ARISTOTLE and AVERROES trials, both published in the New England Journal of Medicine. In ARISTOTLE, apixaban was superior to warfarin in preventing stroke or systemic embolism, with less bleeding and lower mortality, which was seen as giving apixaban an edge over dabigatran and rivaroxaban. In AVERROES, apixaban reduced the risk for stroke and systemic embolism vs aspirin alone, without increasing major or intracranial bleeding in patients with AF not considered candidates for warfarin therapy.

Asked for comment on this development, Ralph Sacco, MD, chairman of neurology, Jackson Memorial Miller School of Medicine at the University of Miami, Florida, and immediate past president of the American Heart Association, pointed out that AF is the most frequent cardiac rhythm disturbance and a significant cause of many strokes.

"Despite the evidence-based recommendations regarding warfarin to prevent strokes among patients with AF, there are still too many patients not adequately protected," Dr. Sacco told Medscape Medical News. "We need more effective options to prevention stroke in these patients. Based on the published trial data, apixaban looks destined to be a third new option — as long as the FDA is content with all aspects of the data."

"We believe that the 2 large trials called ARISTOTLE and AVERROES have established the therapeutic profile for ELIQUIS and demonstrated a meaningful advance over the standard of care," said Elliott Sigal, MD, PhD, executive vice president and chief scientific officer, Bristol-Myers Squibb, in the company statement. The companies also plan to pursue approval for apixaban for stroke prevention in AF outside of the United States, the statement notes, as well as continue their ongoing clinical development program for the drug in multiple indications.

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