Does anyone remember that great Jimmy Van Heusen-Sammy Cahn song, Call Me Irresponsible, recorded by the late and legendary Frank Sinatra?
It could have been the theme song for Boehringer-Ingelheim, the German-based pharmaceutical corporation that brought us the “blockbuster” drug Pradaxa (dabigatran). Pradaxa was initially lauded by the medical community largely due to its lack of interactions. This is understandable; keep in mind that most of the patients who take Pradaxa are elderly and are usually taking several different medications. Normally, physicians must monitor geriatric patients carefully for this reason. Because Pradaxa had interactions with relatively few other drugs (less than 300, only 50 of which were potentially serious), it was something that they could prescribe their patients and not have to worry about frequent monitoring.
Of course, as we know now, there have been other issues – namely, uncontrolled internal, Pradaxa bleeding. In nearly 500 cases so far, this has led to the death of the patient.
What has not been widely known is that some of the procedures used in clinical trials were questionable. It was over a year ago that researchers at the University of British Columbia Health Sciences department issued a letter to physicians across Canada highlighting serious flaws in the clinical studyknown as the RE-LY Trial (Randomized Evaluation of Long Term Anticoagulant TherapY) that was the basis used by Health Canada to approve the drug.
Published in the New England Journal of Medicine in September 2009, the RE-LY study concluded:
"Dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic
embolism that were similar to those associated with warfarin, as well as lower rates of
major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin,
was associated with lower rates of stroke and systemic embolism but similar rates of major
In other words, a lower dose of Pradaxa didn't protect patients from strokes any better than warfarin, but bleeding was less of a risk. The higher dose produced better outcomes as regards to stroke, but the rate of bleeding was about the same as it was with warfarin.
Of course, when warfarin causes excessive bleeding, doctors are able to stop it by giving large doses of Vitamin K – since warfarin suppresses the action of Vitamin K, the substance that allows blood clotting. This is not the case with Pradaxa, however, which acts directly on the clotting process – leaving doctors with few viable alternatives when a patient starts to hemorrhage.
But here's the kicker. According to the letter from UBC Health Sciences, the “comparison between warfarin and dabigatran was not blinded...outcomes are subject to performance and ascertainment bias favoring dabigatran” (italics mine).
In the U.S., the FDA noted a similar bias.
Significantly, a correction was published in the NEJM a little over a year later in which the “the study database was reevaluated for possible underreporting of events.” However, “newly identified events did not materially change the study results” and “the study conclusions remain unchanged.”
This past February, the lead researcher for the RE-LY Study disclosed that he had a “relevant financial relationship” with Pradaxa maker Boehringer-Ingelheim, for which he served as an “advisor or consultant.”
You can draw your own conclusions...
Connolly, Stuart J. MD et al. “ Dabigatran Versus Warfarin in Patients With Atrial Fibrillation.” New England Journal of Medicine, 17 September 2009.
Connolly, Stuart J. MD et al. “Newly Identified Events in the RE-LY Trial.” New England Journal of Medicine, 4 November 2010.
Myerburg, Robert J, MD and Stuart J. Connolly MD. “Balancing Safety and Efficacy in Appropriately Selected AF Patients” (Faculty and Disclosures). Medscape LLC, 16 February 2012. Available at http://www.medscape.org/viewarticle/758487_slide .
N/A. “Dabigatran for Atrial Fibrillation: Why We Can Not Rely on RE-LY.” Therapeutics Initiative, University of British Columbia Department of Anesthesiology, Pharmacology and Therapeutics (January - March 2011). Available at http://www.ti.ubc.ca/letter80.
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