The largest-ever clinical trial of a novel anticoagulant found that edoxaban, a direct oral factor Xa inhibitor, was noninferior to warfarin for stroke prevention in patients with atrial fibrillation. Edoxaban also reduced the risk of bleeding and cardiovascular-related mortality compared to warfarin, according to results of the ENGAGE AF-TIMI 48 Trial, presented Nov. 19 as part of AHA 2013, and published simultaneously in the New England Journal of Medicine.

The trial followed 21,105 patients with moderate- to high-risk atrial fibrillation for a mean of 2.8 years to compare high- and low-dose edoxaban treatments with warfarin. The primary end point was stroke or systemic embolism. The annualized rate of stroke or other systemic embolic event was 1.50 percent with warfarin, 1.18 percent with high-dose edoxaban (hazard ratio 0.79, p<0.001 for noninferiority) and 1.61 percent with low-dose edoxaban (hazard ratio 1.07, p=0.005 for noninferiority). The annualized rate of major bleeding was 3.43 percent with warfarin compared to 2.75 percent with high-dose edoxaban (hazard ratio 0.80, p<0.001) and 1.61 percent with low-dose edoxaban (hazard ratio 0.45, p<0.001).

The annualized rates of cardiovascular death were 3.17 percent for warfarin versus 2.74 percent for high-dose edoxaban (hazard ratio 0.85, p=0.001) and 2.71 percent for low-dose edoxaban (hazard ratio 0.85, p=0.008). Rates for the secondary endpoint, a composite of stroke, systemic embolism or cardiovascular death, were 4.43 percent for warfarin versus 3.85 percent for high-dose edoxaban (hazard ratio 0.87, p=0.005) and 4.23 percent for low-dose edoxaban (hazard radio 0.95, p=0.32).

"Both edoxaban regimens were noninferior to well-managed warfarin for the prevention of stroke or systemic embolic event; the high-dose edoxaban regimen tended to be more effective than warfarin," said lead author Robert Giugliano, MD, FACC, Brigham and Women's Hospital and Harvard Medical School, Boston. "Edoxaban appeared to be safe, had no unexpected side effects, had fewer side effects than warfarin and had a favorable net clinical outcome. Once-daily edoxaban may be an important alternative to warfarin."

The next steps are a detailed assessment of edoxaban's side effects, an analysis of which subpopulations might benefit most from the new agent and development of an effective reversing agent if needed. The drug is currently approved for use only in Japan in patients undergoing orthopedic surgery who are at risk for blood clots in the legs.

Keywords: Japan, Stroke, Orthopedics