Results from the ENGAGE AF-TIMI 48 clinical trial have found that the investigational, oral, once daily direct factor Xa-inhibitor edoxaban (Lixiana, Daiichi-Sankyo) met the primary efficacy endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular atrial fibrillation. Edoxaban also demonstrated significant reductions in major bleeding compared to warfarin, achieving superiority for the principal safety endpoint.
Robert Giugliano (Cardiovascular Medicine, Brigham and Women’s Hospital, associate professor of Medicine, Harvard Medical School, USA) presented results from the phase III study at a late-breaking clinical trials session at the American Heart Association Scientific Sessions (November 16–20, Dallas, USA). Data were also published in the New England Journal of Medicine.
ENGAGE AF-TIMI 48 (Effective anticoagulation with factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction 48) was a three-group, randomised, double-blind, double-dummy trial which compared two edoxaban treatment arms, 60mg and 30mg, with warfarin in 21,105 patients with non-valvular atrial fibrillation for a median of 2.8 years, at 1,393 centres in 46 countries. This represents the largest and longest trial with a novel anticoagulant in patients with atrial fibrillation performed to date, according to a company release.
The edoxaban 60mg treatment arm had an annual incidence of stroke or systemic embolic events of 1.18% vs. 1.50% for warfarin (hazard ratio [HR], 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; p<0.001 for non-inferiority), and significantly reduced major bleeding by 20% (2.75% vs. 3.43% per year, respectively) (HR, 0.80; 95% CI, 0.71 to 0.91; p<0.001 for superiority).
The edoxaban 30mg treatment arm had an annual incidence of stroke or systemic embolic events of 1.61% vs. 1.50% for warfarin (HR, 1.07; 97.5% CI, 0.87 to 1.31; p=0.005 for non-inferiority), and significantly reduced major bleeding by 53% (1.61% vs. 3.43% per year, respectively) (HR, 0.47; 95% CI, 0.41 to 0.55; p<0.001 for superiority).
In ENGAGE AF-TIMI 48, patient-specific dosing was applied according to the study protocol. In both edoxaban treatment arms, the edoxaban dose was halved for patients with clinical factors that were known to increase the risk of bleeding (renal impairment, low body weight or concomitant use of certain P-glycoprotein inhibitors). Patients receiving a reduced edoxaban dose in the 60mg treatment arm had an annual incidence of stroke or systemic embolic events of 2.32% vs. 2.68% for warfarin and a significantly reduced major bleeding incidence of 3.05% vs. 4.85%. Patients receiving a reduced edoxaban dose in the 30mg treatment arm had an annual incidence of stroke or systemic embolic events of 3.14% vs. 2.68% for warfarin and a significantly reduced major bleeding incidence of 1.50% vs. 4.85%.
“The results from the ENGAGE AF-TIMI 48 trial showed that edoxaban may provide a new treatment option for the prevention of stroke or systemic embolic events that demonstrates comparable efficacy to warfarin, while significantly reducing the risk of major bleeding. In addition, we identified an appropriate dose regimen for patients with clinical factors such as renal impairment and low-body weight,” says Giugliano, senior investigator with the TIMI Study Group and co-global lead investigator of the ENGAGE AF-TIMI 48 trial. “In conducting this landmark trial we sought to provide clinicians with robust data, evident by the trial size and follow-up, high percentage of time in therapeutic range for the warfarin treatment arm, and very low rate of missing data. In addition, we specifically designed a comprehensive transition plan to protect patients from the undue risk of stroke and bleeding when switching to open-label anticoagulation at the end of the trial.”
“The edoxaban clinical trial programme, the largest in the history of Daiichi Sankyo, has now yielded positive data for edoxaban in two major diseases, stroke prevention in atrial fibrillation and treatment of acute venous thromboembolism,” said Glenn Gormley, global head of Research and Development and senior executive officer, Daiichi Sankyo and executive chairman of Daiichi Sankyo in the USA. “Based on the findings from ENGAGE AF-TIMI 48 and Hokusai-VTE, we look forward to submitting New Drug Applications for edoxaban in both indications by the first quarter of 2014 in the USA, Japan and Europe.”