ADELPHI, Md. -- A U.S. Food and Drug Administration advisory committee has voted 9-2, with one abstention, to recommend that the FDA approve the direct oral factor Xa inhibitor rivaroxaban (Xarelto) to prevent stroke in patients with a heart condition known as nonvalvular atrial fibrillation.
The overwhelmingly positive endorsement by the FDA's Cardiovascular and Renal Drugs Advisory Committee came just two days after the release of briefing documents prepared by an FDA reviewer -- documents that assailed the efficacy and safety of the drug.
Johnson & Johnson, which partnered with Bayer to develop rivaroxaban, had already secured marketing approval for the direct oral factor Xa inhibitor to prevent deep vein thrombosis in patients undergoing joint replacement surgery. In the application reviewed by the panel Thursday the company sought to extend marketing approval to include the stroke prevention indication.
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The advisory committee spent most of the day reviewing J&J's ROCKET-AF study of more than 14,000 patients with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. The study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.
If the FDA approves rivaroxaban, J&J would like to claim that their drug does work better than warfarin because ROCKET-AF showed the drug worked better than warfarin in patients when success was measured two days after the patients stopped taking rivaroxaban.
However, there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin.
"Clearly it is not superior to warfarin," said panelist Dr. Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles.
Warfarin, an inexpensive drug, is a mainstay in stroke prevention. But it's notoriously tricky to dose and requires INR testing to get it right as well as dietary restrictions to keep it right, which makes warfarin unpopular with many patients -- and many physicians.
The rivaroxaban, on the other hand, is one 20 mg pill a day, and neither INR monitoring nor dietary restrictions are required.
Panelists voiced concerns about a spike in adverse events seen when patients stopped taking rivaroxaban and were transitioned to warfarin at the end of the study.
Panelist Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic and one of the two panel members who voted against recommending approval for rivaroxaban, said it's very common to interrupt anticoagulant treatment.
"Although warfarin is a drug we love to hate, its treatment effects are slow and it's forgiving," he said. By comparison "the first few days you stop rivaroxaban, pretty bad things happen. We haven't studied that. And it makes me concerned."
Most panelists favored requiring J&J to perform a postmarketing study to examine what is the safest way to transition patients off rivaroxaban onto a new drug. Several panelists wanted that study done before the FDA approved the drug.