Dabigatran bleeding events subject of new published data


Two new analyses result in conflicting findings


Two separate analyses of information reported to FDA about bleeding events and dabigatran resulted in conflicting findings. A new analysis of the FDA Mini-Sentinel database has given reassuring results on the rates of gastrointestinal (GI) and intracranial bleeds connected with dabigatran. However, a separate analysis of dabigatran bleeding reports submitted to FDA, presented at the American College of Cardiology (ACC) 2013 Scientific Sessions, has suggested a much higher case-fatality rate than that reported in the major clinical trials of the drug.

The Mini-Sentinel analysis was conducted by three FDA employees in response to the high numbers of bleeding reports associated with dabigatran when it was first approved in the United States. Results showed that bleeding rates associated with dabigatran use during the study period did not appear to be higher than those associated with warfarin.

The other analysis, presented at the ACC meeting, examined publicly available data from adverse-event reports on dabigatran submitted to FDA between January 1, 2010, and June 30, 2012. Of the 2,453 adverse events associated with dabigatran bleeding that were reported to FDA, 393 (16%) were fatal, almost double the case-fatality rate of patients who had bleeding episodes in the five phase 3 trials of the drug. 

Both authors noted limitations of their studies and cautioned against using the data to draw definite conclusions. Post-marketing surveillance is ongoing. 

Sources: Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. Accessed March 30, 2013.

Hughes S. Mixed messages on new bleeding data with dabigatran. Accessed March 30, 2013. 


Clopidogrel/atorvastatin combination may improve outcomes after stenting 

A recently published study evaluated a clopidogrel loading dose combined with a high-dose atorvastatin reload for efficacy in preventing stroke, transient ischemic attack, or new ischemic lesions in patients who have undergone carotid stenting. 

A total of 156 patients was randomized to receive either a 600-mg or 300-mg clopidogrel load given six hours before the intervention and either an atorvastatin reload (80 mg + 40 mg 12 hours before the procedure) or no statin reload. The primary endpoint was the 30-day incidence of transient ischemic attack/stroke or new ischemic lesions on cerebral diffusion-weighted magnetic resonance imaging performed at 24 hours to 48 hours.

Occurrence of the primary outcome measure was significantly lower in the 600-mg clopidogrel arm (18% vs. 35.9% in the 300-mg group; P = 0.019) and in the atorvastatin reload arm (18.4% vs. 35.0% in the no statin reload group; P = 0.031). High-dose clopidogrel also significantly reduced the transient ischemic attack/stroke rate at 30 days without an increase in bleeding risk.

Source: Patti G, Tomai F, Melfi R, et al. Strategies of clopidogrel load and atorvastatin reload to prevent ischemic cerebral events in patients undergoing protected carotid stenting. J Am Coll Cardiol. 2013;61(13):1379–1387. 


European committee recommends approval of rivaroxaban for ACS


The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended extending the indications for rivaroxaban to include prevention of atherothrombotic events in adult patients with acute coronary syndromes. The recommendation stated that the drug could be co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine in adult patients after an acute coronary syndrome (ACS).  


The committee also recommended a new 2.5 mg strength of rivaroxaban. This recommendation was based on the dosage strengths tested in the pivotal ATLAS ACS 2 TIMI 51 trial. In this trial, the 2.5-mg dose showed a reduction in overall and cardiovascular mortality vs placebo, despite an increased risk of bleeding and intracranial hemorrhage (ICH). The higher 5-mg dose was associated with bleeding risks that outweighed the benefits.


This European recommendation comes shortly after the news that FDA decided not to approve the drug for this indication at this time. The CHMP recommendations must have final approval by the European Commission.


Source: Wood S. Rivaroxaban gets ACS indication recommendation from European regulators (press release). London, U.K. March 22, 2013. . Accessed March 30, 2013.

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