The New Data on Dabigatran: Are We Reassured or Still Questioning?

Results from the large (>18,000 patients) RE-LY randomized trial,¹ published in the NEJM in 2009, gave us the first indication that the direct oral anticoagulants used in the treatment of nonvalvular atrial fibrillation (AF) may be associated with lower rates of stroke and systemic embolism as compared with warfarin (RR 0.66 for 150 mg BID dose). The rate of hemorrhagic stroke, one of the most feared complications of warfarin therapy, was lower with dabigatran therapy (0.10% vs 0.38% per year) without exerting an impact on the efficacy for ischemic stroke.

This impotant finding largely contributed to the success of the drug. 

However, a mysterious signal for an increased incidence of myocardial infarction (MI) emerged (0.74% with dabigatran 150 mg BID vs 0.53% with warfarin) and has not been easy to understand mechanistically although many explanations have been proposed.²

Registry data, real world

Since FDA approval of dabigatran in 2010, ongoing surveillance studies have provided further insight into the drug’s safety and efficacy. Observational reports, however, have been conflicting. A recent study of “real world” registry data, reported by Go et al online in the Annals of Internal Medicine, has improved our understanding the drug’s mechanism of action in contemporary clinical practice, offering the advantage of large sample size and rigorous propensity matching. In this retrospective observational study, 25,289 adults on dabigatran therapy were identified from the National US FDA Sentinel Network and compared to a similar number of propensity-matched adults on warfarin therapy.

Similar to the original randomized controlled trial, there was no significant difference in rates of ischemic stroke (0.80 vs 0.90 events per 100 person-years) or extracranial hemorrhage (2.12 vs 2.63 events per 100 person-years). As before, dabigatran continued to show a signal for lower incidence of intracranial bleeding (HR 0.51, CI 0.33-0.79) and the signal for MI also persisted but with a hazard that was almost double that in RE-LY (HR 1.88, CI 1.22-2.90), although absolute event rates remained low (0.77 vs 0.43 events per 100 person-years). To investigate this further, the authors performed multiple sensitivity analyses and found that the risk of MI varied by exposure definition and in some sensitivity analyses, the difference became statistically insignificant. However, factors contributing to this risk were not readily identified.

Other findings that remained similar to those from the original RE-LY study were the rate of overall bleeding and elevated risk of GI bleeding, neither of which were different between the dabigatran and warfarin groups. Dabigatran requires an acidic environment for optimal absorption and is formulated as a capsule containing pellets of tartaric acid and active drug in a 1:1 ratio. Perhaps the risk of both dyspepsia and gastrointestinal bleeding in some patients is a result of exposure of the gastric mucosa to the more acidic environment created by the drug. Not surprisingly, older patients (age ≥ 75 years) and those with chronic kidney disease had higher rates of bleeding with dabigatran.

One of the obvious limitations of this study is the inability to determine time in therapeutic range (TTR) for those patients on warfarin; presumably the TTR reflects a “real world” value. But, this study still leaves me with unanswered questions about the small (but consistent) risk of increased MI 8 years after the drug has been on the market.

For now, when deciding between dabigatran and warfarin therapy, the mysterious higher rates of MI and GI bleeding should be weighed against the lower risk of hemorrhagic stroke and similar rates of overall bleeding and prevention of ischemic stroke.

References:

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients wtih atrial fibrillation. N Engl J Med 2009; 361:1139-1151. DOI: 10. 1056/NEJMoa0905561.

2. Kohli P, Cannon CP. Dabigatran associated with increased risk of acute coronary events. Evidence-Based Medicine 2013;18:e9.

3. Go AS, Singer DE, Toh S, et al. Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice: a retrospective cohort study. Ann Intern Med.  [Epub ahead of print 14 November 2017] doi: 10. 7326/M16-1157