New data from the RELY-ABLE (Long term multicentre extension of dabigatran treatment in patients with atrial fibrillation) study have provided additional support to the safety profile and efficacy of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) for stroke prevention in patients with non-valvular atrial fibrillation (AF) over a period in excess of 2 years.
The new long-term results presented at the American Heart Association’s (AHA) Scientific Sessions, are consistent with the findings from the landmark RE-LY trial. The rates of stroke and haemorrhage observed during an additional 2.3 years of blinded follow-up in RELY-ABLE correspond to the initial RE-LY results, with the benefit of both doses of dabigatran etexilate sustained throughout the study duration.
The combined data from RE-LY and RELY-ABLE provides over four years of clinical trial experience and constitutes the longest evaluation of the benefits and safety of any novel oral anticoagulant for stroke prevention in AF to date.
The international multicentre RELY-ABLE study followed 5,851 patients on dabigatran etexilate for a further 28 months after completion of the RE-LY trial. It examined the long-term benefits of the two treatment doses (110mg bid and 150mg bid) in an ongoing randomised and blinded approach.
The results from RELY-ABLE support sustained dose benefits in the long-term use of dabigatran etexilate:
- Rates of ischaemic stroke
1.15%/year on 150mg bid and 1.24%/year on 110mg bid
- Incidence of haemorrhagic stroke
0.13%/year on 150mg bid and 0.14%/year on 110mg bid
- Incidence of major bleeding
3.74%/year on 150mg bid and 2.99%/year on 110mg bid
The consistent incidences of ischaemic and haemorrhagic stroke as well as rates of intracranial bleeding observed indicate that dabigatran etexilate provides sustained benefits. Furthermore, both doses of dabigatran etexilate had a similar net clinical benefit and mortality rates. The safety profile of dabigatran etexilate was consistent with the findings from the RE-LY trial.
“Most patients with atrial fibrillation need life-long anticoagulant treatment to reduce the risk of ischaemic stroke. The long-term data we now have for dabigatran etexilate are reassuring for both patients and physicians,” said RELY-ABLE lead investigator, Stuart Connolly, director of the Division of Cardiology at McMaster University, Hamilton, Ontario, Canada. “RELY-ABLE shows that the results seen in RE-LY continue to be observed during longer-term follow-up. We see similar rates of stroke and systemic embolism and similar rates of major bleeding with similar rates of intracerebral bleeding and intracranial haemorrhage.”
“The results from RELY-ABLE will be a valuable contribution to evidence-based decision-making in the selection of a treatment that is effective in patients with AF over the longer term,” said Gregory Lip, professor of Cardiovascular Medicine at the University of Birmingham, UK. “Despite the prevalence of AF and the associated five-fold increase in risk of stroke, there remains significant scope for improvement in reducing the risk of stroke in the AF patient population.
RELY-ABLE will serve to give added confidence to physicians in the appropriate prescribing of dabigatran etexilate.”
In March 2012, the National Institute for Health and Clinical Excellence (NICE) issued final guidance recommending dabigatran etexilate as a cost-effective option for the prevention of stroke and systemic embolism in adult patients with non-valvular AF and one or more risk factors.
RELY-ABLE was designed to provide additional information on the long-term effects of the two doses of dabigatran etexilate in patients who had completed RE-LY. Enrolled patients continued to receive the same double-blind dose with 2,937 patients on dabigatran 150mg bid and 2,914 patients on dabigatran 110mg bid. Patients randomised to warfarin in RE-LY were not eligible for RELY-ABLE. The study provides 2.3 years of additional double-blind, randomised follow-up of patients, after RE-LY.
Patients continuing from RE-LY into RELY-ABLE differed in several respects from those RE-LY patients who did not. Continuing patients were more likely to have permanent AF (38% vs. 33%), less likely to have heart failure (27% vs. 35%) and were younger (71 vs. 72 years).
The primary outcomes were the occurrence of major ischaemic and haemorrhagic outcomes, as well as death and net clinical benefit (composite of all major ischaemic, haemorrhagic and fatal outcomes).
RE-LY (Randomized evaluation of long term anticoagulant therapy) was a global, phase III, PROBE (prospective, randomised, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%). Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.
The primary endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, myocardial infarction, and vascular death (including death from bleeding).
Compared to warfarin, dabigatran etexilate showed in the trial:
- Significant reduction in the risk of stroke and systemic embolism – including ischaemic strokes with dabigatran etexilate 150mg bid (1.11%/year, p<0.001 for superiority; compared to 1.69%/year in the warfarin group)
- Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid (1.53%/year, p<0.001 for non-inferiority; compared to 1.69%/year in the warfarin group)
- Significantly lower major bleeding events with dabigatran etexilate 110mg bid (2.71%/year, p=0.003; compared to 3.36%/year in the warfarin group)
- Significantly lower life threatening and intracranial bleeding with both doses (1.22%/year and 0.23%/year respectively, in the 110mg bid group; and 1.45%/year and 0.30%/year in the 150mg bid group; compared to 1.8%/year and 0.74%/year in the warfarin group)
- Significant reduction in mortality rate with dabigatran etexilate 150mg bid (3.64%/year, p=0.051; compared to 4.13%/year in the warfarin group)