Recent journal articles have questioned the reliability of the Randomized Evaluation of Long-Term Anticoagulant Therapy (“RE-LY”) study, which gave dabigatran, also known as Pradaxa, its footing in the Atrial Fibrillation (“AF” or “A. Fib”) market. Coleman et al., Effect of Pharmacological Therapies for Stroke Prevention on Major Gastrointestinal Bleeding in Patients with Atrial Fibrillation, 66 INT. J. CLIN. PRAC. 53 (2012), available at http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2011.02809.x/pdf
; Dabigatran for Atrial Fibrillation: Why We Can Not Rely on RE-LY, 80 THERAPEUTICS INITIATIVE (Mar. 2011), available at http://www.ti.ubc.ca/letter80
; and Mitchel L. Zoler, Dabigatran Outperforms Warfarin in AF Patients, FAMILY PRACTICE NEWS (2009), available at http://www.familypracticenews.com/news/more-top-news/single-view/dabigatran-outperforms-warfarin-in-af-patients/4ad2891e9f152480694b7f1f0defbb34.html
. The RE-LY study was a global, phase III, randomized trial of 18,113 patients designed to compare the safety and efficacy of two dosages of Pradaxa against warfarin in AF patients. Boehringer Ingelheim Pharmaceuticals funded the RE-LY study while developing Pradaxa.
PRADAXA’S HIGH RATE OF GASTROINTESTINAL BLEEDING IN CHALLENGED RE-LY STUDY
A 2012 study in Internal Journal of Clinical Practice, “Effect of Pharmacological Therapies for Stroke Prevention on Major Gastrointestinal Bleeding in Patients with Atrial Fibrillation,” questioned both the RE-LY study’s reliability and Pradaxa’s safety. This study searched research databases for randomized and controlled studies evaluating adults with AF in order to assess Pradaxa’s safety. This paper questioned whether RE-LY was subject to surveillance bias, bias which occurs when one group is followed more closely than another. Additionally, the paper noted that in RE-LY, Pradaxa showed increased rates of major gastrointestinal bleeding compared with warfarin, a serious concern. Whatever questions there might be about the reliability of the RE-LY study, the fact is that current data suggests that Pradaxa is associated with one of the highest rates of major gastrointestinal bleeding.
ALONG WITH PRADAXA’S SAFETY CONCERNS, RE-LY STUDY METHODS QUESTIONABLE
A 2011 letter in Therapeutics, “Dabigatran for AF: Why We Cannot Rely on RE-LY”, challenged both the RE-LY study’s data and its methods. Not only was the 150 mg dose of Pradaxa more harmful in that it caused a 1.1% absolute increase in bleeding leading to hospitalization, but warfarin outperformed Pradaxa in almost every outcomes category looked at in the study. Recent trials suggest the RE-LY data concerning Pradaxa’s superiority to warfarin with regard to intracranial hemorrhaging is questionable. Multiple comparable studies have shown significantly lower incidences of intracranial hemorrhaging than what was found in the RE-LY study. That’s not the only questionable data in the RE-LY study. The FDA clinical reviewer found that some investigator sites inadequately monitored warfarin, which lead the study to a false conclusion that warfarin had an increased mortality trend. When warfarin monitoring was actually within the therapeutic range suggested for warfarin usage, relative mortality risks favored warfarin over Pradaxa a majority of the time.
The RE-LY study’s methods have also been questioned. The study was not blinded between the Pradaxa and warfarin protocols, meaning both the investigator and the trial participant knew which drug the participant was taking. The fact that the study was not entirely blinded subjects the study to performance bias, which is the “differential treatment of patients during the study period”, and ascertainment bias, which is the failure to equally represent all classes of cases supposed to be represented in a sample. In fact, the FDA found these biases sufficient to invalidate RE-LY’s claim that the 150 mg dose of Pradaxa was superior in reducing the risk of stroke as compared with warfarin. These types of bias are not just theoretically damaging to a drug’s claimed benefits because empirical evidence demonstrates these types of bias have affected drug trial results. A similar drug, ximelagatran, manufactured by AstraZeneca was shown to have significantly lower risk factors in an unblinded study than it had in a follow-up double blinded trial. Furthermore, participants in the RE-LY study used other drugs which affect the incidence of major bleeding during the trial, creating even more questions about the reliability of the study.
RE-LY’S SUPPORTERS CONFLICTED
While an older article published in Family Practice News, “Dabigatran Outperforms Warfarin in AF Patients,” discusses Pradaxa’s performance in the RE-LY study in a more favorable light, one cannot overlook the fact that all of the doctors praising Pradaxa have ties to the pharmaceutical industry. Specifically, three of the five doctors, Dr. Connelly, Dr. Camm and Dr. Wallentin, received funds from Boehringer Ingelheim Pharmaceuticals, the company which developed Pradaxa. The only doctor, Dr. Yancy, cited in the article without ties to the pharmaceutical industry was the doctor who discussed the concerns with Pradaxa. Dr. Yancy also pointed out the increased risk of gastrointestinal bleeding, as highlighted in the 2012 article.
These more recent studies highlight the questionable methods and suspect data that makes the RE-LY study unreliable. They also call attention to the Pradaxa risks not fully analyzed in its pioneer study.
Attorneys at Schlichter Bogard and Denton are investigating whether Pradaxa is associated with an increase in severe bleeding compared to warfarin. If you or someone you know has been injured by Pradaxa, please contact the product liability lawyers of Schlichter, Bogard & Denton today to discuss your case.