The anticoagulant dabigatran is more effective than warfarin in the prevention of stroke in patients with atrial fibrillation, according to results from the RE-LY study (Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran).
“Although researchers have been looking for a replacement for warfarin for several decades, nothing has been successful as an oral blood thinner,” said Stuart Connolly, director of the Division of Cardiology at McMaster University, Canada, and one of the leading investigators of the study.
Results from the RE-LY study were presented for the first time at the European Society of Cardiology Congress (ESC), in Barcelona, Spain, and published online in the New England Journal of Medicine. The primary objective was to assess the safety and efficacy of the investigational oral direct thrombin inhibitor, dabigatran etexilate (Pradaxa, Boehringer Ingelheim) against warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke in patients with non-valvular atrial fibrillation.
“In patients with atrial fibrillation, dabigatran 110mg was associated with similar rates of stroke and systemic embolism to warfarin, and lower rates of major haemorrhage. Dabigatran 150mg was associated with lower rates of stroke and systemic embolism than warfarin, and similar rates of major haemorrhage,” said Connolly at the ESC Congress.
The RE-LY study results have shown that both doses of dabigatran etexilate were non-inferior to warfarin on the primary endpoint of reducing the incidence of stroke (including haemorrhagic) and systemic embolism (p<0.001). Dabigatran etexilate 150mg BID (twice daily) was superior to warfarin in reducing the incidence of stroke (including haemorrhagic) and systemic embolism by 34% (p<0.001). There was no significant difference in the rate of major bleeding for dabigatran 150mg BID compared to warfarin (3.11%/year, 3.36%/year, respectively, p=0.31). The rate of major bleeding with dabigatran etexilate 110mg BID (2.71%/year) was 20% lower compared to warfarin (p=0.003).
Also presented and published were results in other outcomes from the RE-LY trial, including significantly lower incidence of haemorrhagic strokes with both 150mg and 110mg BID doses, and a lower incidence of vascular mortality with the 150mg BID dose. Abnormal liver function did not occur more frequently among patients taking dabigatran etexilate 110mg BID, 150mg BID than warfarin (0.2%, 0.2%, and 0.3% respectively).
“Up to 20% of strokes in the US each year are associated with atrial fibrillation. As clinicians, our main objective in managing patients with atrial fibrillation is to prevent stroke without increasing the risk of dangerous or life-threatening bleeds,” said Michael Ezekowitz, professor and vice president, Lankenau Institute for Medical Research and vice president for clinical research, Main Line Health System. “The study results seen with the two respective doses of dabigatran evaluated in RE-LY indicate that this compound has the potential to improve patient care.”
The RE-LY trial
RE-LY was a global, phase III, randomised trial of 18,113 patients enrolled in more than 900 centres in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0–3.0 – (open label) for stroke prevention. Patients with non-valvular AF and at least one other risk factor for stroke (ie, previous ischaemic stroke, transient ischaemic attack, or systemic embolism, left ventricular dysfunction, age greater than or equal to 75 years, age greater than or equal to 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years with a minimum follow-up period of one year.
The primary endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures included a composite of incidence of stroke (including haemorrhagic), systemic embolism and all death, as well as a composite of incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding). Additional safety endpoints included bleeding events (major and minor), intracerebral haemorrhage, other intracranial haemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction, and other adverse events.
The primary analysis was designed to test whether either dose of dabigatran was non-inferior to warfarin. After non-inferiority of both doses of dabigatran was established, statistical analysis allowed testing of superiority.