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LOS ANGELES -- Patients starting dabigatran (Pradaxa) did not have an excess risk of bleeding compared with new users of warfarin, according to a postmarketing data review by the FDA. The finding may provide some reassurance to clinicians trying to prevent strokes in patients with atrial fibrillation.
Following a spate of reports of serious bleeding events with dabigatran within a year after it was approved in October 2010, the agency initiated a safety review last December. It announced the verdict yesterday after comparing rates of gastrointestinal bleeding and intracranial hemorrhage between the newer drug and warfarin using insurance claims and administrative data.
"The results of this ... assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin," consistent with the results of the RE-LY trial, the FDA announced.
The safety review of the drug -- which accounted for about 3.7 million dispensed prescriptions through August -- is ongoing, but the agency said that recommendations for using dabigatran have not changed.
"Healthcare professionals who prescribe Pradaxa should carefully follow the dosing recommendations in the drug label, especially for patients with renal impairment ... to reduce the risk of bleeding," according to the advisory.
In an interview here at the American Heart Association meeting, program chair Elliott Antman, MD, of Harvard Medical School in Boston, said he was reassured by the review, which provided the appropriate context to compare the bleeding risks with dabigatran and warfarin.
"I believe that if physicians adhere to the recommendations for adjusting the dose if there is diminished kidney function, patients who receive a drug like dabigatran will be treated optimally," he said.
David Callans, MD, associate director of electrophysiology at the University of Pennsylvania Health System in Philadelphia, said that he hadn't been overly concerned with the reports of excess bleeding because it was not a problem detected in RE-LY.
The FDA's announcement, however, "is nice in response to the rather tiresome lawyer ads about Pradaxa on television," he told ѻý.
An important issue, Callans said, is making sure that the drug is being used appropriately.
"A lot of the excess bleeding that was seen and the early furor over that was from people who were getting the drug but shouldn't have gotten it," he said.
The intricacies of patient selection are not always well known among all practitioners in the early days after a drug's approval, he said, resulting in some clinicians prescribing the drug when they're not completely familiar with it.
In its announcement, the FDA noted that assessments of renal function should be performed before prescribing dabigatran, which is excreted by the kidneys, so the appropriate dose can be selected. Patients with severe renal impairment -- a creatinine clearance of 15 to 30 mL/min -- can still receive the drug, but they should receive the lower 75-mg dose instead of the 150-mg dose.
"If you don't understand the drug, you shouldn't prescribe it, whether it's new or old," Callans said.
Although the FDA review discounted an excess bleeding risk with dabigatran, it did not address another potential concern -- the ability to reverse the anticoagulant effect acutely in cases of emergency.
Antman acknowledged that there is no specific, approved antidote for dabigatran or any of the novel anticoagulants, although it is an area of active investigation and the topic of several studies that will be presented at the AHA meeting in the coming days.
He said it's not true, however, that clinicians don't have any options. Intravenous administration of blood coagulation factors -- prothrombin complex concentrates that are available in every hospital -- can help to reverse the effect, though not completely.
In comparison, the effects of warfarin can be reversed with the administration of vitamin K. Antman noted. But that that doesn't always work either, and patients can die because of it, he added.
Both Antman and Callans said that the focus on the reports of bleeding events with dabigatran and the cases in which patients bleed out because of the inability to reverse the anticoagulation effect overshadow the more important issue -- that dabigatran significantly reduces the risk of stroke in patients with atrial fibrillation.
"Prevention of an embolic stroke in the setting of atrial fibrillation is one of the most important things we can do for a patient's life over the time horizon of decades, rather than just the next few days," Antman said, adding that everything in medicine carries some risk that needs to weighed against the benefits when discussing treatment options with patients.
"What I really worry about," Callans said, "is that people would be falsely concerned by the smaller risk and not take medicine, whether it's dabigatran or rivaroxaban or warfarin, to prevent the much bigger risk, which is stroke from atrial fibrillation."