BACKGROUND Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of nonvitamin K antagonist oral anticoagulants in this population. METHODS We compared the safety of apixaban with warfarin in 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as creatinine clearance [CrCl] 25 to 30 mL/min) enrolled in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). Cox proportional models were used to estimate hazard ratios for major bleeding and major or clinically relevant nonmajor bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using nonlinear mixed effects models. RESULTS Among patients with CrCl 25 to 30 mL/min, apixaban caused less major bleeding (hazard ratio, 0.34 [95% CI, 0.14-0.80]) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 [95% CI, 0.17-0.72]) compared with warfarin. Patients with CrCl 25 to 30 mL/min randomized to apixaban demonstrated a trend toward lower rates of major bleeding when compared with those with CrCl >30 mL/min (P interaction=0.08) and major or clinically relevant nonmajor bleeding (P interaction=0.05). Median daily steady-state areas under the curve for apixaban 5 mg twice daily were 5512 ng/(mL·h) and 3406 ng/(mL·h) for patients with CrCl 25 to 30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/(mL·h) for patients with CrCl 25 to 30 mL/min. The area under the curve values for patients with CrCl 25 to 30 mL/min fell within the ranges demonstrated for patients with CrCl >30 mL/min. CONCLUSIONS Among patients with atrial fibrillation and CrCl 25 to 30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced chronic kidney disease, supporting conventional dosing in patients with CrCl 25 to 30 mL/min. Randomized, controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced chronic kidney disease, including those receiving dialysis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00412984.

中文翻译：

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心房颤动和晚期慢性肾脏病患者的阿哌沙班对华法林。

背景技术与普通人群相比，晚期慢性肾脏病患者的房颤负担高> 10倍。指导该人群非维生素K拮抗剂口服抗凝剂使用的有限数据。方法我们比较了ARISTOTLE试验（阿哌沙班减少卒中和其他血栓栓塞事件）入组的269例心房颤动和晚期慢性肾脏疾病（定义为肌酐清除率[CrCl] 25至30 mL / min）的阿哌沙班与华法林的安全性在房颤中）。使用Cox比例模型来估计重大出血和重大或临床相关的非重大出血的危险比。我们通过使用非线性混合效应模型评估暴露差异来表征阿哌沙班的药代动力学特征。结果在CrCl 25至30 mL / min的患者中，阿哌沙班引起的大出血较少（危险比，0.34 [95％CI，0.14-0.80]）和重大或临床上相关的非大出血（危险比率，0.35 [95％CI，0.17] -0.72]）与华法林相比。与CrCl> 30 mL / min（P相互作用= 0.08）且有重大或临床相关的非重大出血（P相互作用= 0.05）的患者相比，随机分配给apixaban的CrCl 25至30 mL / min的患者表现出大出血率降低的趋势）。对于CrCl 25至30 mL / min或> 30 mL / min的患者，每天两次两次的阿哌沙班5 mg曲线下的每日稳态中值分别为5512 ng /（mL·h）和3406 ng /（mL·h），分别。对于每天两次2.5 mg的apixaban，CrCl 25至30 mL / min的患者的中位暴露量为2780 ng /（mL·h）。CrCl 25至30 mL / min的患者曲线下面积落在CrCl> 30 mL / min的患者证实的范围内。结论在房颤和CrCl 25至30 mL / min的患者中，阿哌沙班引起的出血少于华法林，与CrCl> 30 mL / min的患者相比，出血减少的幅度更大。对于有或没有晚期慢性肾脏病的患者，我们观察到每天两次暴露于apixaban 5 mg的范围内存在明显重叠，这支持了CrCl 25至30 mL / min的患者的常规剂量。对于晚期慢性肾脏病患者，包括接受透析的患者，迫切需要评估阿哌沙班安全性和有效性的随机对照研究。注册：URL：https：//www.clinicaltrials.gov；唯一标识符：NCT00412984。