FDA Approves Rivaroxaban for Stroke Prevention in AF Patients

November 04, 2011

November 4, 2011 (Rockville, Maryland) — Another oral anticoagulant will soon be available to US physicians treating patients with atrial fibrillation. Today, the US Food and Drug Administration approved rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, the agency has announced [1].

"Xarelto has a boxed warning to make clear that people using the drug should not discontinue it before talking with their healthcare professional. Discontinuing the drug can increase the risk of stroke," the FDA said in its statement.

The approval is based largely on the results of Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).

First presented at the American Heart Association 2010 Scientific Sessions and later published in the New England Journal of Medicine [2], ROCKET-AF showed that the new anticoagulant, a factor Xa inhibitor, met its primary end point, with rivaroxaban noninferior to warfarin in terms of reducing the risk of stroke and non-central-nervous-system (CNS) embolism.

In September, as reported by heartwire, the Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2, with one abstention, in favor of recommending approval. One of the biggest hurdles rivaroxaban faced with the FDA advisory committee was in its comparison to warfarin, and more specifically, the amount of time the warfarin-treated patients spent at the optimal international normalized ratio (INR). In ROCKET-AF, the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), which was lower than in other trials with warfarin, including the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial with dabigatran etexilate (Pradaxa, Boehringer Ingelheim).

For some panelists, the TTR issue introduced some uncertainty about the efficacy of rivaroxaban, while others raised concerns about the dose tested and the risk of adverse clinical events when patients are transitioned off rivaroxaban. In the 28-day period after rivaroxaban was stopped in ROCKET-AF and patients were transitioned to another anticoagulant, there was a significantly increased risk of stroke in the rivaroxaban arm, a finding that investigators attributed to the drug's short half-life (and the lack of dual anticoagulation during the overlap period).

Overwhelmingly, however, many panelists felt it was at least an effective alternative to warfarin. One panel member felt the drug should be used as a third-line agent only, an option for patients who failed other anticoagulant therapies. Advisors for the European Medicines Agency (EMA), the Committee for Medicinal Products for Human Use (CHMP), also issued a positive opinion for rivaroxaban in the prevention of stroke and systemic embolism in nonvalvular AF. They recommended the new indication for rivaroxaban based on data from the ROCKET-AF trial.

Just last month, the US consumer group Public Citizen urged the FDA not to approve rivaroxaban, citing some of the concerns raised during the FDA advisory panel meeting. The group noted that while several committee members voted for approval, they also expressed "serious reservations, stating were still unanswered questions that will require postmarketing studies to resolve.

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