Sept. 9, 2011 -- 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.
But physicians who work for J&J said the adverse events observed in the study wouldn't be mirrored in the real world because patients generally don't just stop taking a blood thinner cold-turkey as they did in the study. In the "real world," patients are transitioned more seamlessly onto a different anticoagulant, the company said.
An FDA reviewer and panelists were also concerned that warfarin wasn't administered ideally in the trial, causing rivaroxaban to appear more effective than it may have been had warfarin been dosed properly. Just 56 percent of patients who received warfarin in the ROCKET-AF were in the ideal INF range of 2 to 3 during the study, which the panel criticized as being way too low.
"INR control in ROCKET was worse than in other recent trials, which might have biased the overall results in favor of rivaroxaban," said FDA reviewer Dr. Martin Rose, who authored a highly critical review of rivaroxaban that was released several days before Thursday's meeting.
One of those recent trials is the RE-LY trial, which found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin.
But panel chairman Dr. Michael Lincoff, another cardiologist from the Cleveland Clinic, said the spotty warfarin dosing in ROCKET-AF was acceptable because it was similar to how warfarin is used outside of clinical trials.
Dabigatran was a constant topic of conversation at the meeting, with panelists and the FDA making comparisons between rivaroxaban and dabigatran, despite the fact that no trial has yet been conducted pitting the two anticoagulants head-to-head.
"Any current expert will say it's important to do head-to-head clinical trials," said Dr. Robert Califf, director of Duke University's Translational Medicine Institute and a principal investigator in the ROCKET-AF trial.
Some panelists questioned the need for another blood thinner that was shown to be noninferior to warfarin, when dabigatran was shown to be superior to warfarin.
But others at the meeting -- including a patient representative -- said more oral anticoagulants are needed because warfarin is not always well-tolerated and dabigatran can cause gastrointestinal side effects.
"All afib patients are aware of the three drugs we need to take," said patient representative Debra McCall of California. "A drug to regulate rhythm, a drug to regulate rate, and a blood thinner. We have options for rate and rhythm, but we don't have many options for blood thinners."
Following the committee vote the American Heart Association released a statement noting it will review its guidelines for anticoagulation therapy in patients with nonvalvular atrial fibrillation if the FDA does decide to approve the drug for stroke prevention in that population.
"For the millions of patients with atrial fibrillation, stroke is a real health threat, and the emerging studies of new anticoagulant drugs like rivaroxaban have been very encouraging," said Dr. Gordon Tomaselli, president of the American Heart Association.
The FDA is expected to make an approval decision on rivaroxaban by Nov. 4. The agency isn't required to follow the advice of its advisory committees, but it often does.