From Brigham and Women's Hospital and Harvard Medical School, Boston (R.P.G., C.T.R., E.B., S.A.M., S.D.W., L.T.G., E.M.A.); Mount Sinai Medical Center, New York (J.L.H.); University Hospitals Case Medical Center, Cleveland (A.L.W.); Thomas Jefferson Medical College, Philadelphia (M.D.E.); McMaster University, Hamilton, ON, Canada (J.I.W.); University Hospital, Jihlavska, Brno, Czech Republic (J.S.); Institute of Cardiology, Warsaw, Poland (W.R.); Cardiology Research Center, Moscow (M.R.); National Hospital Organization, Osaka National Hospital, Osaka, Japan (Y.K.); Quintiles, Durham, NC (J.B., S.P.P.); and Daiichi Sankyo Pharma Development, Edison, NJ (M.S., I.P., J.J.H., M.M.).
N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).
背景：依度沙班是一种已证实具有抗血栓作用的直接口服因子 Xa 抑制剂。在房颤患者中，与华法林相比，依度沙班的长期疗效和安全性尚不清楚。
方法：我们进行了一项随机、双盲、双模拟试验，比较了 21105 例中高危房颤患者两种每日一次的依度沙班方案与华法林的疗效。主要疗效终点是卒中或全身性栓塞。在治疗期间，每个依度沙班方案均进行了非劣效性检验。主要安全性终点是大出血。
结果：治疗期间主要终点的年发生率为华法林组 1.50%（治疗范围内中位时间 68.4%），与高剂量依度沙班组 1.18%（风险比 0.79；97.5%置信区间 [CI]，0.63 至 0.99；非劣效性 P<0.001）和低剂量依度沙班组 1.61%（风险比 1.07；97.5%CI，0.87 至 1.31；非劣效性 P=0.005）相比。意向治疗分析中，高剂量依度沙班与华法林相比有倾向于降低风险的趋势（风险比 0.87；97.5%CI，0.73 至 1.04；P=0.08），而低剂量依度沙班与华法林相比则有增加风险的趋势（风险比 1.13；97.5%CI，0.96 至 1.34；P=0.10）。华法林组大出血的年发生率为 3.43%，高剂量依度沙班组为 2.75%（风险比 0.80；95%CI，0.71 至 0.91；P<0.001），低剂量依度沙班组为 1.61%（风险比 0.47；95%CI，0.41 至 0.55；P<0.001）。心血管原因导致的死亡年发生率分别为华法林组 3.17%、高剂量依度沙班组 2.74%（风险比 0.86；95%CI，0.77 至 0.97；P=0.01）和低剂量依度沙班组 2.71%（风险比 0.85；95%CI，0.76 至 0.96；P=0.008），主要次要终点（卒中、全身性栓塞或心血管原因导致的死亡的复合终点）的年发生率分别为华法林组 4.43%、高剂量依度沙班组 3.85%（风险比 0.87；95%CI，0.78 至 0.96；P=0.005）和低剂量依度沙班组 4.23%（风险比 0.95；95%CI，0.86 至 1.05；P=0.32）。
结论：两种每日一次的依度沙班方案在预防卒中和全身性栓塞方面均不劣于华法林，且出血和心血管原因导致的死亡发生率显著降低。（由第一三共制药研发公司资助；ENGAGE AF-TIMI 48 临床试验.gov 编号，NCT00781391。）
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