Dabigatran: 260 Fatal Bleeds Since Approval Worldwide

Shelley Wood

November 17, 2011

November 17, 2011 (Ridgefield, Connecticut) UPDATED — A total of 260 people worldwide have had a fatal bleed while taking dabigatran (Pradaxa), according to an analysis of the worldwide postmarketing database conducted by the drug's manufacturer, Boehringer Ingelheim. In response, the European Medicines Agency (EMA) has issued a statement saying that it believes the deaths need to be viewed in the context of dabigatran's rapid uptake and increased awareness of possible side effects [1].

Events occurred between March 2008 and October 31, 2011, a spokesperson confirmed for heartwire . Dabigatran was granted US marketing approval in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation, but the drug has been available for longer and for different indications in other countries.

"During the same period of time, treatment exposure to Pradaxa worldwide was estimated at 410 000 patient-treatment-years, which translates into a rate of 63 events per 100 000 patient-treatment-years," spokesperson Kate O'Connor said in an email.

This is in line with expectations for bleeding events based on the pivotal RE-LY trial, she added, "and are in alignment with the US prescribing information, which clearly states the benefits and risks associated with Pradaxa. Overall, the positive benefit/risk ratio of Pradaxa in nonvalvular atrial fibrillation remains unchanged."

In RE-LY, rates of fatal bleeding were numerically lower with the higher dose tested in the trial--150 mg twice daily--at 0.23% per year (230 per 100 000 patient-years) compared with warfarin at 0.33% per year (330 per 100 000 patient-years). Life-threatening bleeds in RE-LY were more common, numerically, in the 150-mg group than in the 110-mg group tested in the trial; the lower dose was not approved by the FDA, although it is on other worldwide markets.

Bleeding events with dabigatran have prompted safety advisories in Japan and Australia and have led to labeling updates in Europe and the US focusing on the need for monitoring renal function, since renal impairment can increase bleeding risk.

In Europe, dabigatran was first authorized in March 2008 for primary prevention of venous thromboembolic events in adults following orthopedic surgery. In early November, the EMA, in conjunction with the manufacturer, agreed to strengthen packaging information and to send an update to physicians emphasizing the need for renal assessment. On November 18, the EMA followed this with a press release stating that the Committee for Medicinal Products for Human Use (CHMP) is aware of the media interest in Pradaxa bleeding events, that it is closely monitoring the issue, and that the drug's current labeling "adequately manage[s] the risk of bleeding."

The release continues: "The number of reports of bleeding in patients treated with Pradaxa has to be seen in the context of the rapidly increasing use of Pradaxa worldwide as a result of approval of a new indication . . . in several regions of the world and also the increased awareness about the drug, a factor that is known to lead to higher-than-usual reporting of side effects."

According to O'Connor, "we frequently communicate with the FDA and regulatory agencies around the world to ensure they have the most up-to-date information regarding the safety profile of Pradaxa."