Longer follow-up of dabigatran treatment gives largely similar results to RE-LY trial

Connolly SJ, Wallentin L, Ezekowitz MD et al.
CIRCULATION  June 14, 2013, doi: 10.1161/​CIRCULATIONAHA.112.001139

Background

Antithrombotic medication reduces the increased risk of ischemic stroke that accompanies atrial fibrillation (AF)[1,2]. The new direct thrombin inhibitor dabigatran and inhibitors of Factor Xa have been evaluated as possible substitutes for the less safe and inconvenient vitamin K antagonists. In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial patients with AF and at least one risk factor for stroke were randomized  to either 110 mg or 150 mg dabigatran twice daily, or adjusted dose warfarin. RE-LY showed that dabigatran 150 mg twice daily was superior to warfarin for prevention of stroke or systemic embolism and that 110 mg was non-inferior [3]. Incidence of hemorrhagic stroke was greatly reduced at both doses of dabigatran, and 110 mg twice daily significantly reduced major bleeding as compared to warfarin.
Based on these findings, dabigatran has been approved for patients with AF in many countries. Information is needed on the consistency of effects of dabigatran over a longer period of follow-up. The Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study was therefore set up to examine the long-term effects of the two doses of dabigatran in patients completing RE-LY, by an additional 2.25 years.

Main results

• During RELY-ABLE, the annual rates of stroke or systemic embolism were 1.46% per year on dabigatran 150 mg and 1.60%/year for 110 mg (HR: 0.91, 95%CI: 0.69-1.20). Annual rates of ischemic stroke were 1.15 and 1.24%/year on dabigatran 150 and 110 mg, respectively (HR: 0.92, 95%CI: 0.67-1.27). The incidences of hemorrhagic stroke were similar in the two treatment groups (0.13 and 0.14%/year), just like myocardial infarction (0.69 and 0.72%/year).
• Annual rates of major bleeding were 3.74 and 2.99%/year on dabigatran 150 and 100 mg respectively (HR: 1.26, 95%CI: 1.04-1.53). Major gastrointestinal bleeding rates were similar for the 150 and 110 mg groups (3.02 and 3.10%/year).
• Serious adverse events occurred in 1067 (36.3%) patients on dabigatran 150 mg and 982 33.7%) receiving 110 mg. Dyspeptic symptoms were reported in 141 (4.8%) and 156 (5.3%) of patients respectively.

Conclusion

RELY-ABLE provides additional safety information on the use of dabigatran 110 or 150 mg twice daily, accumulating to a total mean follow-up up 4.3 years. The rates of major ischemic, hemorrhagic and fatal outcomes that occurred in the additional follow-up period are not inconsistent with those seen in RE-LY. Rates of stroke or systemic embolism on dabigatran 150 or 110 were slightly higher in RELY-ABLE than in RE-LY, but this is partly due to the absence of event adjudication in RELY-ABLE.
There was no significant difference in stroke or mortality but a higher rate of major bleeding with 150 mg as compared to 110 mg. No difference was observed between the two doses when considering the composite of stroke, bleeding and death. 

References

1. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation -executive summary: a report of the American College of Cardiology Committee for Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee t Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol. 2006;48:854-906. [Erratum, J Am Coll Cardiol 2007;50:562.]
2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

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