A major phase III trial - ENGAGE AF-TIMI 48 - is investigating once-daily treatment with the new oral factor Xa inhibitor edoxaban in patients with atrial fibrillation (AF) with the potential for providing substantial improvements compared to the current standard of care in preventing stroke, specialists announced this week.

ENGAGE AF-TIMI 48 is comparing two doses of edoxaban (30mg and 60mg once daily) with warfarin in patients with AF. "Approximately 16,500 patients will be enrolled, from 1400 sites worldwide," reported Robert Giugliano, Senior Investigator with the TIMI study group, and Associate Physician and Assistant Professor in Medicine, at Brigham and Women's Hospital, Harvard Medical School, Boston, USA. The patients included will all have AF and be at moderate to high risk of stroke, with a CHADS2 score of at least two.

"The study is intended to show that atrial fibrillation patients can be treated simply, effectively and safely with once-daily administration of edoxaban," he told a meeting at the European Society of Cardiology Congress (29 August - 2 September, 2009; Barcelona, Spain). People with AF have significantly increased risk of stroke, with a risk about five times greater than the general population.

Patients taking part in ENGAGE AF-TIMI 48 will be assigned, on a double-blind, double-dummy basis, to one of three treatment groups: 30mg edoxaban once daily, 60mg edoxaban once daily or warfarin, the current standard of care. Edoxaban will be given in fixed doses without coagulation monitoring, while the dose of warfarin will be adjusted to maintain an international normalised ratio (INR) of 2.0-3.0.

The primary efficacy endpoint is stroke and systemic embolic events, while the primary safety endpoint is major and clinically relevant non-major bleeding. Professor Giugliano said that the expected median duration for patients to remain in the study is 24 months, with the trial likely to conclude in 2012.

"There is a definite need for new and improved oral anticoagulants for stroke prevention in patients with AF," said Jeffrey Weitz, Professor of Medicine and Biochemistry at McMaster University, Ontario, Canada. "Edoxaban could offer significant improvements over the current standard of care," he suggested, pointing out that warfarin, the most widely used anticoagulant, has a slow onset of action, a narrow therapeutic window and individual variation in response, which is affected by drug and food interactions and requires regular monitoring.

Previous trials have shown that edoxaban, which is being developed by Daiichi Sankyo, achieves dose-dependent anticoagulation over a range of doses, with no significant dose-related increase in bleeding. A randomised study in patients with non-valvular AF has shown that the incidence of major and clinically relevant non-major bleeding with 30mg or 60mg edoxaban once daily was similar to, or less than, that with warfarin.

Source
Susan Mayor PhD, freelance medical journalist, London, UK


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