Oral Anticoagulants Redeemed? Daily Dabigatran "Safe" With Dual Antiplatelets After MI

November 19, 2009

November 19, 2009 (Orlando, Florida) — The oral anticoagulant that seems more congenial than warfarin and a better protector against stroke in the setting of atrial fibrillation looks like it could have a future in high-risk patients with recent acute coronary syndromes.

The randomized REDEEM trial, reported here at the American Heart Association 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran etexilate (Boehringer Ingelheim) that strikes a good balance between clinical effectiveness and bleeding risk in daily use with aspirin and clopidogrel after acute STEMI or non-STEMI.

Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with six-month rates of "major and clinically relevant minor bleeds" that the investigators called "low and acceptable"--no higher than 2%--despite a significant dose-related rise in the risk of bleeding complications (p<0.001). As reported by Dr Jonas Oldgren (Uppsala University Hospital, Sweden), clinical-event rates in the trial were also low, although REDEEM wasn't powered for clinical outcomes.

The two highest dosages in the study, 110 mg twice daily and 150 mg twice daily, had been tested against warfarin in the randomized RE-LY trial, the higher dosage showing superiority and the lower showing noninferiority in preventing stroke and embolic complications in patients with atrial fibrillation, as recently reported by heartwire . Oldgren emphasized that the confidence he and his colleagues have in dabigatran's level of safety is based on both REDEEM and RE-LY.

"Given that the dual antiplatelets and dabigatran up to 150 mg [twice daily] caused not more than a 1% absolute increase in major bleeds [compared with placebo], it’s a safe drug," Oldgren told heartwire . "We also have the RE-LY data, a different population, of course, but a large cohort with a lot of safety data and a good safety profile, an extremely low rate of intracranial bleeds, and a low rate of major bleeds. Given that, and the low increase in bleeding in this study, we think that it's okay to go forward with the 110-mg or 150-mg twice-daily dose. But you could argue that the 75-mg or 50-mg [twice-daily] dosages decreased anticoagulation activity and had a very safe profile concerning bleedings."

The trial entered 1861 patients with at least one cardiovascular risk factor aside from their acute event, which included prior MI in 29%, diabetes in 31%, and heart failure in 12%. They were randomized to placebo or to dabigatran at one of the four dosages starting within a few weeks (mean 7.4 days) of acute STEMI or non-STEMI and continuing for six months. Patients were already on aspirin and clopidogrel and about half had undergone PCI at the time of randomization.

REDEEM: Outcomes, Including Major Bleeding* or Clinically Relevant Minor Bleeding (Primary End Point) Over Six Months, by Dabigatran Randomization Group; Intention-to-Treat Analysis

End point Placebo, n=371 (%) 50 mg bid, n=369 (%) 75 mg bid, n=368 (%) 110 mg bid, n=406 (%) 150 mg bid, n=347 (%)
Primary end point 2.4 3.5 4.3 7.9 7.8
Major bleeding* 0.5 0.8 0.3 2.0 1.2
CV death, nonfatal MI, or stroke 3.8 4.6 4.9 3.0 3.5
*International Society of Thrombosis and Haemostasis criteria

As the invited discussant following Oldgren's presentation, Dr Elaine M Hylek (Boston University, MA) called for "a little caution in extrapolating an ACS trial to an atrial-fibrillation population, because we know that the mean age [in RE-LY] was 10 years greater, and there's a much higher chronic disease burden in the atrial-fibrillation population."

Still, "What's reassuring [about REDEEM] is that the major hemorrhage rates I think are acceptably low," although the importance of the minor bleeding risk shouldn't be overlooked--it's often the minor bleeding complications that make patients choose to go off such agents, she said.

Rates of serious adverse events were also "reassuring," although those data are inconclusive, given how few they were and that the trial wasn't designed to show differences in them, she noted.

Oldgren reports serving on an advisory board for and receiving research grants from Boehringer-Ingelheim. Hylek has disclosed that she served as an advisor or consultant to Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, and Sanofi-Aventis and has received honoraria from Bristol-Myers Squibb and Pfizer.

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