Results from the RELY-ABLE trial, a long-term extension of the pivotal RE-LY study of dabigatran (Pradaxa / Boehringer Ingelheim) in patients with non-valvular atrial fibrillation, have provided additional information showing long-term safety of dabigatran. However, a higher dose (150mg) twice daily compared to 110mg showed a higher rate of major bleeding. The results were published online on 14 June in Circulation.
The RELY-ABLE trial was designed to evaluate the long-term safety of ongoing dabigatran therapy in patients with non-valvular atrial fibrillation, following RE-LY. Accordingly, patients enrolled in RELY-ABLE continued dabigatran therapy, as dosed in RE-LY, for an additional 2.3 years, bringing the mean duration of treatment to 4.3 years. A total of 5,851 patients participated in the extension study: 2,937 received dabigatran 150mg twice daily and 2,914 received dabigatran 110mg twice daily.
“Before RELY-ABLE, little was known about the long-term effects of dabigatran in patients with non-valvular atrial fibrillation,” said Stuart Connolly, professor, Department of Medicine, McMaster University, Ontario, Canada. “The long-term data from RELY-ABLE provide additional safety information for a large group of patients continuing the same dose of dabigatran.”
Rates of major bleeding, the primary endpoint, were 3.74% (n=238) per year with dabigatran 150mg and 2.99% (n=190) per year with dabigatran 110mg (HR 1.26, 95% CI: 1.04-1.53). Major gastrointestinal bleeding occurred at rates of 1.54% (n=98) per year with dabigatran 150mg and 1.56% (n=99) per year with dabigatran 110mg.
Secondary endpoints included other key safety outcomes, such as total bleeding and life-threatening bleeding, and showed similar results as RE-LY, with no new safety findings.
Additional findings include:
- Rates of stroke or systemic embolism, on dabigatran 150mg and 110mg, were 1.46% (n=93) and 1.60% (n=102) per year in RELY-ABLE, respectively (HR 0.91, 95% CI: 0.69-1.20).
- Rates of ischaemic stroke or unspecified stroke were 1.15% (n=73) and 1.24% (n=79) per year on dabigatran 150mg and 110mg, respectively (HR 0.92, 95% CI: 0.67-1.27).
- Rates of haemorrhagic stroke were similar in the two treatment arms and were very low at 0.13% (n=8) and 0.14% (n=9) per year on dabigatran 150mg and 110mg, respectively (HR 0.89, 95% CI: 0.34-2.30).
- Rates of myocardial infarction were also low and similar between the two groups at 0.69% (n=44) and 0.72% (n=46) per year on dabigatran 150mg and 110mg, respectively (HR 0.96, 95% CI: 0.63-1.45).
- Dyspeptic symptoms were reported in 5.3% (n=156) and 4.8% (n=141) of patients on dabigatran 150mg and 110mg, respectively during the RELY-ABLE follow-up.
- Total mortality rate was 3.02% (n=192) and 3.10% (n=197) per year in patients on dabigatran 150mg and 110mg, respectively (HR 0.97, 95% CI: 0.80-1.19).
- During RELY-ABLE, serious adverse events occurred in 36.3% (n=1,067) and 33.7% (n=982) of patients on dabigatran 150mg and 110mg, respectively.
The rates of stroke or systemic embolism were slightly higher in RELY-ABLE than RE-LY partly due to the fact that there was no event adjudication, the authors wrote. In RE-LY, adjudication either confirmed reported events or rejected them.
RELY-ABLE was a global, extension trial of 5,851 dabigatran-treated patients across 35 countries who continued on from the 12,091 patients in the original RE-LY study.
There were some limitations to the RELY-ABLE trial. Only half of the patients continued from RE-LY to RELY-ABLE. Patients were eligible if they did not prematurely discontinue dabigatran therapy. Also, it was at the investigator’s discretion to determine if it was clinically appropriate for patients to continue receiving long-term oral anticoagulant treatment. Patients randomised to warfarin (n=6,022) in RE-LY were not eligible for RELY-ABLE.
Also, there was no event adjudication, meaning confirmation by an independent team or group, in RELY-ABLE, whereas there was event adjudication in RE-LY. Lastly, patients enrolled in RELY-ABLE were different from those in RE-LY and may have been at lower risk of events.