Lip Gregory Y H, Al-Saady Naab, Ezekowitz Michael D, Banach Maciej, Goette Andreas
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Cardiovascular/Metabolic, Covance Inc, Osprey House, Maidenhead Park Office, Westacott Way, Littlewick Green, Maidenhead, United Kingdom.
Am Heart J. 2017 Nov;193:16-22. doi: 10.1016/j.ahj.2017.07.010. Epub 2017 Jul 20.
The ENSURE-AF study (NCT 02072434) of anticoagulation for electrical cardioversion in nonvalvular atrial fibrillation (NVAF) showed comparable low rates of bleeding and thromboembolism between the edoxaban and the enoxaparin-warfarin treatment arms. This post hoc analysis investigated the relationship between renal function and clinical outcomes.
ENSURE-AF was a multicenter, PROBE evaluation trial of edoxaban 60 mg, or dose reduced to 30 mg/d for weight≤60 kg, creatinine clearance (CrCl; Cockcroft-Gault) ≤50 mL/min, or concomitant P-glycoprotein inhibitors compared with therapeutically monitored enoxaparin-warfarin in 2,199 NVAF patients undergoing electrical cardioversion. Efficacy and safety outcomes and time in therapeutic range in the warfarin arm were analyzed in relation to CrCl in prespecified ranges ≥15 and ≤30, >30 and ≤50, >50 and <80, and ≥80 mL/min, and an exploratory ≥95-mL/min analysis.
A total of 1,095 subjects were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64.3±10 and 64.2±11 years. Mean time in therapeutic range was progressively lower with reducing CrCl strata, being 66.8% in those with CrCl >30 to ≤50 compared with 71.8% in those with CrCl ≥80. The odds ratios for the primary efficacy and safety end points were comparable for the different predefined renal function strata; given the small numbers, the 95% CI included 1.0. In the subset of those with CrCl ≥95, the odds ratios showed consistency with the other CrCl strata. When CrCl was assessed as a continuous variable, there was a nonsignificant trend toward higher major or clinically relevant nonmajor bleeding with reducing CrCl levels, with no significant differences between the 2 treatment arms. When we assessed CrCl at baseline compared with end of treatment, there were no significant differences in CrCl change between the edoxaban and enoxaparin-warfarin arms. The proportions with worsening of renal function (defined as a decrease of >20% from baseline) were similar in the 2 treatment arms.
Given the small number of events in ENSURE-AF, no effect of renal (dys)function was demonstrated in comparing edoxaban to enoxaparin-warfarin for cardioversion; efficacy and safety of edoxaban remained consistent even in patients with normal or supranormal renal function.
ENSURE - AF研究（NCT 02072434）针对非瓣膜性心房颤动（NVAF）患者电复律时的抗凝治疗，结果显示，依度沙班治疗组与依诺肝素 - 华法林治疗组的出血和血栓栓塞发生率相近且均较低。本事后分析旨在研究肾功能与临床结局之间的关系。
ENSURE - AF是一项多中心、探索性评估试验，纳入2199例接受电复律的NVAF患者，比较60 mg依度沙班，或体重≤60 kg、肌酐清除率（CrCl；Cockcroft - Gault法）≤50 mL/min或同时使用P - 糖蛋白抑制剂时剂量减至30 mg/d的依度沙班与经治疗监测的依诺肝素 - 华法林的疗效。根据预设CrCl范围≥15且≤30、>30且≤50、>50且<80以及≥80 mL/min，对华法林组的疗效和安全性结局及治疗范围内的时间进行分析，并进行一项探索性的≥95 mL/min分析。
共1095例受试者随机接受依度沙班治疗，1104例接受依诺肝素 - 华法林治疗。平均年龄分别为64.3±10岁和64.2±11岁。随着CrCl分层降低，平均治疗范围内时间逐渐降低，CrCl>30至≤50的患者为66.8%，而CrCl≥80的患者为71.8%。不同预设肾功能分层的主要疗效和安全性终点的比值比相当；由于样本量较小，95%置信区间包含1.0。在CrCl≥95的亚组中，比值比与其他CrCl分层一致。当将CrCl作为连续变量评估时，随着CrCl水平降低，严重或临床相关非严重出血有升高趋势但不显著，两组治疗之间无显著差异。当比较基线时与治疗结束时的CrCl时，依度沙班组与依诺肝素 - 华法林组的CrCl变化无显著差异。两组治疗中肾功能恶化（定义为较基线下降>20%）的比例相似。
鉴于ENSURE - AF研究中的事件数量较少，在比较依度沙班与依诺肝素 - 华法林用于电复律时，未显示肾功能（异常）的影响；即使在肾功能正常或超常的患者中，依度沙班的疗效和安全性仍保持一致。
