FDA panel recommends approval for rivaroxaban

Issue: October 2011

The FDA's Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, to approve the use of rivaroxaban for the reduction of stroke and non-CNS systemic embolism in patients with non-valvular atrial fibrillation, according to a press release.

The vote follows a review issued by the FDA which suggests withholding from approval due to a noninferior result of rivaroxaban vs. warfarin and insufficient information on rivaroxaban's safety profile.

The panel based its decision on the results of the ROCKET-AF trial. The study involved 14,264 patients across 1,178 sites in 45 countries. Patients were diagnosed with persistent or paroxysmal AF with additional risk factors for stroke, and were randomly assigned to warfarin (Coumadin, Bristol-Meyers Squibb) or rivaroxaban (Xarelto, Johnson & Johnson). Patients who were assigned to rivaroxaban received a 20mg dose once daily, and warfarin was titrated to a target range of two to three.

Overall, a decreased rate of stroke and non-CNS embolism events were associated with rivaroxaban during treatments vs. warfarin (P=.015). In the intention-to-treat analysis, rivaroxaban was noninferior to warfarin (P=.117). The rate of bleeding and adverse events was similar between the rivaroxaban and warfarin arms, but rivaroxaban was associated with less intercraniall hemorrhage and fatal bleeding.

"No one, I believe, doubts that rivaroxaban is effective in preventing stroke in patients with AF," Norman Stockbridge, MD, director of the division of cardiovascular and renal drug products at FDA , said in the opening remarks of the meeting. "Nor are there safety issues that would cause one to question that the stroke reduction benefit was on the whole worthwhile … By at least one analysis, rivaroxaban was superior to warfarin in the ROCKET AF study. Nevertheless, the clinical reviewers question whether the study can be interpreted as showing that rivaroxaban is even as good as warfarin."

When asked if rivaroxaban merits a superior claim to warfarin, 1 out of 12 voted yes and 9 voted no; a claim as an effective alternative to warfarin, 4 voted yes and 5 voted no; a claim as effective, 7 voted yes and 3 voted no; and a claim for patients failing other anticoagulant therapy, 7 voted yes and 2 voted no.

"What constitutes failure," Sanjay Kaul, MD, director of cardiovascular diseases fellowship training program at the Cedars-Sinai Heart Institute, said, "[is] if patients are, for some reason, not well anticoagulated on warfarin, if they don't want to be on warfarin because of the diet or the medications they are on, or if patients simply refuse to take warfarin because they don't want to be bothered with monitoring anticoagulation. Those will be the types of patients where, I think, rivaroxaban would be an effective alternative to warfarin and other anticoagulants that are approved. So, third line option."

Overall, 4 out of 12 committee members thought it would be beneficial to resolve issues for rivaroxaban pre-market vs. post-market.

"I would really like to see this drug tested in this AF population twice daily because it makes a lot more sense from a pharmacodynamic point of view," Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, said. "And, you know, maybe this drug will have more point estimates and confidence intervals and look more like dabigatran if it's studied in a more optimal dosage regimen."

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. - by Casey Murphy

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