Division of Cardiology, Medical University of Vienna, Austria (T.A.Z.).
Department of Medicine, Imperial College, London, United Kingdom (M.A.).
Circulation. 2021 Feb 16;143(7):673-684. doi: 10.1161/CIRCULATIONAHA.120.052216. Epub 2021 Feb 15.
Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men.
The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis-defined major bleeding (safety).
In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, <0.001). Treatment with edoxaban in women resulted in greater peak edoxaban concentration and inhibition of endogenous factor Xa in comparison with men, resulting in similar endogenous factor Xa activity between the sexes 2 to 4 hours after dose. Treatment with higher-dose edoxaban regimen (versus warfarin) resulted in similar reduction in the risk of stroke/systemic embolic events (women: hazard ratio [HR], 0.87 [0.69-1.11], men: HR, 0.87 [0.71-1.06]; -interaction=0.97) and major bleeding (women: HR, 0.74 [0.59-0.92], men: HR, 0.84 [0.72-0.99]; -interaction=0.34) in women and men. However, women assigned to higher-dose edoxaban regimen experienced greater reductions in hemorrhagic stroke (HR, 0.30 [95% CI, 0.15-0.59] versus HR, 0.70 [95% CI, 0.46-1.06]), intracranial bleeding (HR, 0.20 [95% CI, 0.10-0.39] versus HR, 0.63 [95% CI, 0.44-0.89]), and life-threatening or fatal bleeding (HR, 0.25 [95% CI, 0.15-0.42] versus HR, 0.72 [95% CI, 0.54-0.96]) than men (each -interaction<0.05).
Despite many differences in baseline characteristics between women and men and higher baseline endogenous factor Xa levels in women, the intensity of anticoagulation achieved with edoxaban between the sexes was similar. Treatment with higher-dose edoxaban regimen resulted in an even greater reduction in hemorrhagic stroke and several serious bleeding outcomes in women than in men, whereas the efficacy profile was similar between sexes.
女性是房颤患者发生中风和全身性栓塞事件的独立危险因素。本研究旨在探讨依度沙班在女性和男性中的疗效和安全性。
ENGAGE AF-TIMI 48 试验（房颤患者新型 Xa 因子抑制剂依度沙班与华法林的疗效-血栓栓塞事件和大出血比较 48 周）将 21105 例（8040 例女性）房颤且 CHADS 评分≥2 的患者随机分为高剂量依度沙班组、低剂量依度沙班组或华法林组。试验的主要终点为中风或全身性栓塞事件的复合终点（疗效）以及国际血栓与止血学会定义的大出血（安全性）。
与男性相比，女性年龄更大、体重更轻、高血压和肾功能不全的发生率更高，但吸烟、饮酒、糖尿病和冠心病的发生率更低。女性治疗前内源性 Xa 因子活性显著高于男性（92.5%比 86.1%，<0.001）。与男性相比，女性使用依度沙班治疗可使药物峰浓度更高，对内源性 Xa 因子的抑制作用更强，因此给药 2-4 小时后男女两性的内源性 Xa 因子活性相似。与华法林相比，高剂量依度沙班治疗方案（与华法林相比）可使中风/全身性栓塞事件风险降低（女性：HR 0.87 [0.69-1.11]，男性：HR 0.87 [0.71-1.06]；-交互作用=0.97）和大出血风险降低（女性：HR 0.74 [0.59-0.92]，男性：HR 0.84 [0.72-0.99]；-交互作用=0.34），但女性接受高剂量依度沙班治疗可使出血性中风（HR 0.30 [95%CI，0.15-0.59]比 HR 0.70 [95%CI，0.46-1.06]）、颅内出血（HR 0.20 [95%CI，0.10-0.39]比 HR 0.63 [95%CI，0.44-0.89]）和危及生命或致命性出血（HR 0.25 [95%CI，0.15-0.42]比 HR 0.72 [95%CI，0.54-0.96]）的风险降低更为显著（各 -交互作用<0.05）。
尽管女性和男性在基线特征方面存在许多差异，且女性的内源性 Xa 因子基线水平更高，但依度沙班在两性中的抗凝强度相似。高剂量依度沙班治疗可使女性的出血性中风和多种严重出血结局的风险降低程度大于男性，而两性的疗效相似。
