A startling article entitled, “Conflict of Interest in the Assessment of Thromboprophylaxis” appeared in the January 2012 issue of The Journal of Bone & Joint Surgery. A group of investigators were curious about the possibility of bias during evidence-based reviews and they conducted a retrospective study, centering on prescription choice for the treatment of tromboprophylaxis after total joint arthroplasty, which is one of the indications for the use of Pradaxa. Because of Dr. Lee’s concern about a financial conflict of interest tread of bias that seemed to be commonly woven through the fabric of evidence-based studies, he spearheaded a comprehensive review of previous studies.

After conducting that review, Dr. Lee found a significant association between the funding source of studies and qualitative conclusions. Out of 71 studies, the pharmaceutical industry had funded 52 of them; and low and behold, only two of the 52 industry sponsored studies reached unfavorable conclusions.

Pradaxa’s manufacturer, Boehringer-Ingelheim, sponsored the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) study that led to the FDA’s approval of Pradaxa. For example, the following conflict statement, “The authors are paid consultants of Boehringer Ingelheim” appeared in the 2011 Open Orthopedics Journal article, “Oral Thromboprophylaxis Following Total Hip or Knee Replacement:  Review and Multicentre Experience with Dabigatran Etexilate.”  The authors of the Open Orthopedics paper concluded that, “In general, the efficacy and safety of dabigatran were deemed to be good or very good by the clinics and were thought to be comparable to the parenteral anticoagulants used.”

Notwithstanding all that had previously emerged, concerning the questionable safety of using Pradaxa, the authors stated the following. “Since dabigatran is administered orally as a fixed dose, it was found to be easy to use. At three of the centres no notable safety complications with dabigatran were reported.  However, one clinic reported rare cases of intestinal tract bleeding in patients receiving dabigatran, but a connection between the two was deemed questionable by the clinic.”

In contrast to the Open Orthopedics paper, on January 9, 2012, ONLINE FIRST published, “Dabigatran: Do We Have Sufficient Data?” an article authored by Jeremy M. Jacobs, MBBS and Jochanan Stressman, MD. In that article,  Jacobs and Stressman search identified more than 500 publications, with 307 being published since the start of 2011, as well as a large direct to consumer advertising campaign. The following link provides a good example of Boehringer-Ingelheim’s direct to consumer effort:

 

Recently, on December 7, 2011, Medscape ran the following story online, “FDA Investigating Serious Bleeding Events with Dabigatran.” The story contained the following quote, “FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa,” according to the drug safety communication issued by the agency.” Finally, Boehringer-Ingelheim has now confirmed that between March 2008 and October 31, 2011 there were 260 fatal bleeding events worldwide.

In yet another 2011 ONLINE FIRST story entitled, “Dabigatran Association with Higher Risk Acute Coronary Events,” Doctors Ken Uchino and Adrian Hernandez questioned Boehringer-Ingelheim’s RE-LY study that led to FDA approval of Pradaxa. After searching PubMed, Scopus and the Web of Science for randomized controlled trials of Dabigatran that reported on Myocardial Infarction (MI) or Acute Coronary Syndrome (ACS), they concluded that “dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.”

In conclusion, physicians should heed Dr. Uchino’s advice, and be very careful to thoroughly evaluate patients before prescribing Pradaxa, or before considering off label use of that drug (for further reference to off label use of Pradaxa, see “Rushed Pharma leads to Bad Karma” here.