Dabigatran (Pradaxa) was the first novel oral anticoagulant (NOAC) to be approved by the FDA (October 2010) for treatment of non-valvular atrial fibrillation (AF). Approval was based on results of the RE-LY study1 which showed that dabigatran was non-inferior to warfarin for the prevention of stroke and systemic embolism. Subsequently, there was a concern for increased risk of myocardial infarction with dabigatran that later was not endorsed by the FDA.1
Now, an analysis2 published in Canadian Medical Association Journal has highlighted a possible drug-drug interaction with dabigatran and two statins—lovastatin and simvastatin. The conclusions are based on examination of two large administrative databases from Ontario. There were a total of 7567 patients; all were Ontario residents at least 66 years of age who started dabigatran between May 1, 2012 and March 31, 2014 and had received a single statin within 60 days preceding their index date. The study concluded that there was a no difference in the risk of stroke or TIA with the use of dabigatran and lovastatin or simvastatin compared to other statins (atorvastatin, pravastatin, fluvastatin, or rosuvastatin). However, there was a signal for increased risk of major hemorrhage (adjusted OR 1.46) with these two statins compared with others. The mechanism of this interaction is thought to be a result of the potent inhibition of intestinal P-glycoprotein by lovastatin and simvastatin, which increases the bioavailability of dabigatran.
Although the study was well-received and raised some important issues, critics caution that this is an observational study and therefore, is subject to confounding. Furthermore, similar findings were not reported in the RELY trial, which was a large randomized trial of patients with non-valvular AF. Overall, these conclusions in this study were drawn based on a very small number of patients and small number of events (of 1985 patients with stroke or TIA, only 177 were on simvastatin and 12 on lovastatin; of 5582 patients with major hemorrhage, only 502 were on simvastatin and 27 on lovastatin). Atorvastatin was much more commonly used than either simvastatin or lovastatin.
Finally, no adjustment was made for renal function, duration of statin therapy, or compliance with dabigatran, which could alter these conclusions.
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;17;361:1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.
2. Food and Drug Administration. FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin [press release]. May 13, 2014.
3. Antoniou T, Macdonald EM, Yao Z, et al; for the Canadian Drug Safety and Effectiveness Research Network. Association between statin us and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation. CMAJ. 2016 Nov 21. doi:10.1503/cmaj.160303 [Epub ahead of print].