"It may be that a direct thrombin inhibitor [such as dabigatran] is not the drug of choice for preventing clots from forming on the surface of valves," Dr. Ezekowtiz said in an interview. "We have nearly 50 years of experience using warfarin for patients with mechanical heart valves, and that is clearly the drug of choice. This [RE-ALIGN] was probably a high-risk trial" in terms of trying to show that a new drug was at least as safe and effective as warfarin for heart valve patients.
Dr. Ezekowitz stressed that he has not been privy to any details of the RE-ALIGN results, but he suggested that it is hard to imagine that higher dabigatran dosages than the 300 mg b.i.d tested in RE-ALIGN could be used safely. "I was principal investigator for a phase II dabigatran study in atrial fibrillation, the PETRO [Prevention of Embolic and Thrombotic Events in Patients With Persistent AF] study (Am. J. Cardiol. 2007;100:1419-26). We tested up to 300 mg b.i.d., and in older atrial fibrillation patients this caused an excess of gastrointestinal bleeds and we decided to abandon that dosage in further testing. From a purely practical standpoint, I doubt whether a dabigatran dosage of more than 150 mg b.i.d would be tolerable," said Dr. Ezekowitz, professor of medicine at Jefferson Medical College in Philadelphia and director of atrial fibrillation research and education at the Cardiovascular Research Foundation in New York.
Some community physicians seem to have been mistakenly lured into prescribing dabigatran or other new anticoagulants to mechanical heart valve patients, perhaps because these physicians equated the newer drugs with better performance, Dr. Boodhwani said. But extrapolating the atrial fibrillation experience to heart-valve patients is premature, he warned.
"There is the potential for patients to die on these drugs. The off-label use can potentially be quite dangerous."
The FDA’s action and termination of the RE-ALIGN trial should send physicians a strong warning, he said. "This doesn’t close the door to future use of these drugs for mechanical valve patients, but physicians and industry need to be more cautious. The problems with warfarin need solutions, but only in a step-by-step way."
Dr. Boodhwani said he had no relevant financial disclosures. Dr. Ezekowitz said he has been a consultant to, has received honoraria as a lecturer on behalf of, and has received research funding from Boehringer Ingelheim, as well as from other drug companies that market antithrombotic drugs.
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