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FDA Again Defends Pradaxa, Downplays Lack of Bleeding Antidote

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Pradaxa bleeding risk

The U.S. Food and Drug Administration (FDA) continues to endorse Pradaxa as a safe treatment for the most common heart rhythm abnormality, despite the absence of an effective antidote for potentially fatal bleeding events with the drug.

Patients, doctors and others in the medical community began voicing concerns about the safety of Boehringer Ingelheim’s popular blood thinner shortly after the drug was approved by the FDA in 2010. Within several months, the agency fielded an unusually high number of reports of serious and fatal Pradaxa bleeding events.

When FDA officials announced that 3,781 serious adverse events and 542 deaths from Pradaxa use were reported in 2011, worries about the drug reverberated. The FDA, however, maintained its position that Pradaxa offers important health benefits when used as directed.

FDA Blames Stimulated Reporting

According to the agency, the elevated number of Pradaxa bleeding incidents can be attributed to stimulated reporting, and does not reflect an elevated bleeding risk for Pradaxa patients compared with those taking its predecessor, warfarin.

In a perspective article published this month in the New England Journal of Medicine, the FDA said that “newly marketed products, by virtue of their novelty alone, may elicit adverse-event reports at high rates; reporting rates tend to decrease over time.”

The agency added that warfarin, which has been marketed for nearly 60 years and is known to cause bleeding, “would be far less likely to elicit adverse-event reports than would a newer drug with a similar risk.”

To support this stance, the FDA cites comparable bleeding rates observed among Pradaxa and warfarin patients in RE-LY, a pivotal clinical trial that led to Pradaxa’s approval. RE-LY compared the effectiveness of Pradaxa and warfarin in 18,000 patients with non-valvular atrial fibrillation, a heart rhythm abnormality associated with a higher risk for stroke.

Although serious gastrointestinal bleeding was more frequent in the Pradaxa group than the warfarin group in the study, Pradaxa proved superior at preventing intracranial bleeding and minimizing the risk for stroke.

Approved without an Antidote

Some cardiologists have sided with the FDA and contend that Pradaxa offers worthwhile benefits over warfarin.

“I think the benefit of the drug clearly exceeds the risk because to me, a disabling stroke has a greater weight than a bleeding complication,” said Dr. Sanjay Kaul, who voted on the FDA committee responsible for approving Pradaxa.

Critics, on the other hand, don’t believe the drug’s use is worth the added risk — especially considering that the FDA has yet to approve a treatment that reverses the drug’s potentially fatal bleeding incidents. While Pradaxa and warfarin effectively prevent strokes in high-risk patients by thinning their blood, doing so can also cause them to bleed out after suffering minor injuries.

For warfarin patients, doctors can administer a dose of vitamin K to stop uncontrollable bleeding and save lives. No such antidote is currently available for Pradaxa patients, which has caused many to question how the FDA can allow Boehringer Ingelheim to market the drug as a safe alternative to warfarin.

Boehringer is currently testing a promising antidote for Pradaxa bleeding incidents, but its safety and effectiveness has yet to be confirmed in human clinical trials.

Safety Investigation Continues

A November 2012 study called the Sentinel Initiative revealed more evidence that Pradaxa and warfarin present similar bleeding risks, yet the FDA investigation into Pradaxa’s safety is ongoing.

Drawing from administrative and insurance-claim data collected from the FDA’s Mini-Sentinel database from October 2010 to December 2011, the Sentinel Initiative revealed no greater bleeding risk with Pradaxa than with warfarin.

The finding supports the FDA’s statement that the unusually high number of Pradaxa bleeding incidents “provided a distorted estimate of the comparative bleeding rates associated with [Pradaxa] and warfarin in clinical practice.”

Even with positive results from the Sentinel Initiative, the FDA has recognized some possible limitations of the study. To compensate for the study’s lack of a detailed medical record review and its failure to adjust for critical variables, the FDA is now conducting two protocol-based assessments with data from the Mini-Sentinel database. In addition, the agency will continue postmarketing surveillance of Pradaxa and keep consumers informed about any updates related to the drug’s bleeding risk.