Sept. 8, 2011 -- An FDA advisory panel has voted to recommend approval of a new blood thinner to prevent strokes and dangerous blood clots in patients with the heart rhythm disorder atrial fibrillation.
In a vote of nine to two, with one member abstaining, the panel said Xarelto (rivaroxaban) was at least as safe and effective as the older drug warfarin.
The vote puts the panel at odds with the FDA's own reviewers, who recommended against approval in a 388-page report released in advance of the meeting.
The FDA is not required to follow the panel's recommendation, but often does.
"Having treated thousands of patients with atrial fibrillation and dealt with the tremendous problems of using warfarin and patients having issues with warfarin, I think there's a tremendous unmet medical need for new therapies," says panel member Philip Sager, MD, in explaining his vote for approval. Sager is a pharmaceutical consultant and chair of the scientific programs committee of the Cardiac Safety Research Consortium in San Francisco.
Others said they felt "fatal flaws" in the way the drug was studied and lingering questions about the safest way to give it were reasons to vote no.
"When you deal with a morbid, mortal complication like [stroke], we owe patients the best therapy we can get," says panel member Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic. "It makes me concerned that this may be a step back, rather than a step forward."
The vote was a boost for the drug's developers, Johnson & Johnson and partner Bayer Healthcare. The drugmakers see Xarelto as a potential blockbuster treatment for atrial fibrillation, a condition that's becoming more common in an aging population.
Xarelto was approved in July to prevent blood clots in people having hip and knee replacement surgery.
As many as 2.2 million Americans have atrial fibrillation, a condition that causes the heart to beat in an irregular and uncoordinated way. When that happens, blood may pool and clot in the heart's upper chambers. Those blood clots can then break free and travel to the brain, causing strokes and other dangerous complications.
Studies have shown that people with atrial fibrillation have an increased risk of having a stroke compared to people without the condition.
Questions About Study Design
The panel's discussion centered on the findings of the company-sponsored ROCKET-AF study. The results of that study were published last month in The New England Journal of Medicine.
Panel members say they were particularly concerned that many of the patients in the study who were taking warfarin didn't seem to have been getting optimal doses of that drug.
As a result, FDA reviewers said, Xarelto may have looked more effective in the study than it actually was.
Nearly 40% of the 14,000 patients in the trial were in countries in Eastern Europe, where doctors had the most trouble managing patients on warfarin.
"The ROCKET study enrolled the majority of their patients in countries that don't use warfarin well," says Martin Rose, MD, JD, who reviewed the clinical data on Xarelto for the FDA, in his presentation to the panel.
Rose also points out that among six other recent trials of blood-thinning drugs, ROCKET-AF had the fewest number of patients on warfarin who were maintained at an optimal dosage that would prevent strokes.
Other trials had kept as many as 68% of patients on an optimal warfarin dose. Only 55% of patients in the ROCKET trial were kept within a so-called optimal therapeutic range.
Other concerns cited by the panel included a high rate of adverse events in patients soon after they discontinued Xarelto, an issue they said warranted further study.
Investigators who led the ROCKET trial defended the quality of the study.
"We gave warfarin not only in an acceptable way, we gave it in a commendable way during this trial considering the complexity of the trial design that we had," says Robert M. Califf, MD, vice chancellor of clinical research at Duke University.
Califf points out that warfarin is known to be a drug that's difficult for doctors and patients to use.
Patients enrolled in the trial, Califf pointed out, had many other medical conditions and were taking an average of nine other medications in addition to their blood thinner.
Though he acknowledges that those other health conditions likely made the trial trickier to execute, Califf points out that those were the kind of patients most doctors were likely to be seeing in their practices.
That means, he says, that doctors could have confidence in the study's results.