Dabigatran etexilate (Pradaxa), an oral, direct thrombin inhibitor, was approved in October 2010 by the U.S. Food and Drug Administration (FDA) for prevention of stroke and thrombosis in patients with nonvalvular atrial fibrillation (AF). This marked a new era in the development of fixed-dose novel oral anticoagulants (NOACs) with the hope of achieving improved safety and clinical outcomes compared with warfarin.
In the standard-of-care treatment, warfarin, it is difficult to manage anticoagulation, which, if not well controlled, can result in serious adverse events including major bleeds and thrombotic events. Dabigatran was developed to overcome these limitations and provide patients with an alternative to warfarin with more convenience, better efficacy, and a better safety profile. In a recent article in Clinical Chemistry, Mayo Clinic researchers, Hemamalini Ketha, Ph.D., and John Mills, Ph.D., discuss whether dabigatran is a risk to patient safety.
Upon FDA approval, manufacturer Boehringer Ingelheim quickly released its blockbuster drug, dabigatran. Fixed-dose dabigatran demonstrated non-inferior performance compared with dose-optimized warfarin therapy in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial for prevention of stroke and thrombosis in patients with nonvalvular AF, thus providing the bulk of support for FDA approval.
However, although dabigatran's popularity grew quickly, there were still some red flags. An investigation by the British Medical Journal revealed that as far back as 2010, dabigatran caused severe and fatal bleeding in patients. Boehringer Ingelheim had knowledge that adjusting the dose of dabigatran might provide patients with superior efficacy and safety compared with a fixed dose. This raised serious concerns about what the manufacturer chose not to disclose as it sought regulatory approval.
Despite the problems and questions uncovered by the investigation, both the FDA and Boehringer Ingelheim maintain that dabigatran is a safe and effective replacement for warfarin in patients with nonvalvular AF. Additional data collected by the FDA postapproval corroborate that dabigatran is safer than warfarin.
However, it is important to recognize that some patients will likely achieve superior benefit–risk balance when doses are optimized to achieve specific trough dabigatran concentrations. Prospective studies are required to better define the ideal therapeutic concentration and confirm whether targeting these therapeutic concentrations results in superior outcomes.
Read the full article for more information about monitoring dabigatran.