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FDA Investigates Major Bleeding Events in Dabigatran Patients


A little more than a year after the new anticoagulant dabigatran (Pradaxa) was approved for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients, the FDA is evaluating post-marketing reports of serious bleeds in patients taking the drug.

The FDA is trying to determine if patients on Pradaxa are experiencing severe bleeding more than expected based on results of the clinical trial that led to Pradaxa’s approval, according to FDA spokeswoman Sandy Walsh.

“At this time, FDA continues to believe that Pradaxa provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Pradaxa follow the recommendations in the approved drug label,” Walsh tells The Hospitalist.

It won’t cause me to take people who I have prescribed Pradaxa and switch them back to warfarin.

—Robert Pendleton, MD, director of the hospitalist program, University of Utah Healthcare; medical director, University Healthcare Thrombosis Service

Patients should not stop taking dabigatran without first talking to their doctors, the FDA announcement cautions. While “serious, even fatal events have been reported,” according to the FDA’s announcement, Walsh says the FDA isn’t prepared to say how many reports of serious bleeding events have been received because they’re still being reviewed.

“We often put out ‘early’ communications when we learn of drug safety issues,” she says. “We want to be transparent and make [the] public [aware of] what we do know, but our analysis is not final. At this point, the FDA is still evaluating this issue.”

Bleeding that leads to serious or fatal outcomes is a well-recognized complication of all anticoagulant therapies.

Dabigatran, a direct thrombin inhibitor, was approved in October 2010, becoming the first new oral anticoagulant approved in 50 years. It was the first approved among several new anti-coagulants that are poised to enter the market and are expected to challenge warfarin (Coumadin), the longtime standard of care.

Listen to Dr. Pendleton discuss the implications of the FDA’s statement on post-marketing serious bleeding events associated with Pradaxa.

The new drugs—including rivaroxaban (Xarelto), a Factor Xa-inhibitor that was approved in 2011—have been eagerly anticipated because they don’t require frequent blood draws for monitoring, as warfarin does. Hospitalists are especially interested in the new anticoagulant therapies because they treat numerous patients at an increased risk of clotting.

In the RE-LY trial, the 18,000-patient clinical trial comparing dabigatran and warfarin, major bleeding events occurred at similar rates with the two drugs.

Dabigatran manufacturer Boehringer Ingelheim is working with the FDA to evaluate the major bleeding reports, but spokeswoman Anna Moses says the drug has been performing according to expectations.

“Global data collected to date on major bleeding are consistent with our expectations based on the RE-LY trial and are in alignment with the U.S. Prescribing Information, which clearly state the benefits and risks associated with Pradaxa,” Moses says. “Overall, the positive-benefit-risk ratio of Pradaxa in NVAF remains unchanged.” (Visit the manufacturer website for prescribing information [PDF].)

Robert Pendleton, MD, director of the hospitalist program at the University of Utah Healthcare and Medical Director of the University Healthcare Thrombosis Service, expressed no surprise at the FDA’s statement.

“Although the data with new anticoagulants like Pradaxa is very favorable in a clinical trial setting, there’s great risk of enhanced demonstration of harm in the real-world setting if it’s not used optimally,” Dr. Pendleton says. “There will be more liberal sort of prescribing in a less-pure patient population.

So if people are not particularly cognizant of a patient’s renal function, their body weight, prior history of bleeding, etc., then you’re sort of applying new drugs in patients who are even more prone to bleed.”

Dr. Pendleton notes that in subgroup analyses, the slight benefits of the new drugs have come in patients with poor warfarin control, so if patients with good warfarin control are switched, outcomes could generally be expected not to be better, and could be worse.

“It won’t cause me to take people who I have prescribed Pradaxa and switch them back to warfarin,” he says, “but part of that is [that] here, in our healthcare system, we’re pretty cautious in who gets put on one of the new agents. And so those that do are patients who are most like those in the clinical trial.”

Tom Collins is a freelance writer in Florida.

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