Unic@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Université de Lorraine, Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
JACC Heart Fail. 2022 Nov;10(11):842-850. doi: 10.1016/j.jchf.2022.06.010. Epub 2022 Sep 7.
Mineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain.
The goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials.
This study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula.
A total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002).
Steroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m.
在肾功能障碍患者中，醛固酮受体拮抗剂（MRA）的使用不足，其在慢性肾脏病（CKD）患者中的疗效尚不确定。
本研究旨在分析在随机对照试验中，跨越估计肾小球滤过率（eGFR）范围的甾体 MRA 的疗效和安全性。研究纳入了参加 RALES（螺内酯随机评价研究）、EMPHASIS-HF（依普利酮在心力衰竭住院和生存研究中的轻度患者）、TOPCAT（用醛固酮拮抗剂治疗保留心功能的心力衰竭）的心力衰竭（HF）或心肌梗死和晚期 CKD 患者，以及 EPHESUS（依普利酮后急性心肌梗死心力衰竭疗效和生存研究）试验。
本研究使用个体患者数据的荟萃分析，使用 Cox 模型按试验分层，并使用治疗与 eGFR 交互作用项。通过使用慢性肾脏病流行病学合作组肌酐公式重新计算 eGFR。
共纳入 12700 名患者，其中 331 名（2.6%）的 eGFR≤30ml/min/1.73m（平均 eGFR：26.8±3.2ml/min/1.73m）。晚期 CKD 患者所有研究结局的年化事件发生率均较高：与 eGFR＞90ml/min/1.73m 相比，eGFR≤30ml/min/1.73m 的患者复合终点（心血管死亡或 HF 住院）的安慰剂事件率高约 3 倍：分别为 41.6 和 14.6 例/100 人年。MRA（与安慰剂相比）降低了心血管死亡或 HF 住院的复合终点，但随着 eGFR 的降低，效果减弱：按 eGFR 类别计算的相应 HR 分别为：eGFR＞90ml/min/1.73m：0.62（95%CI：0.49-0.78）；eGFR 为 61-90ml/min/1.73m：0.69（95%CI：0.61-0.77）；eGFR 为 46-60ml/min/1.73m：0.84（95%CI：0.74-0.95）；eGFR 为 31-45ml/min/1.73m：0.79（95%CI：0.68-0.91）；eGFR≤30ml/min/1.73m：0.96（95%CI：0.70-1.32）（治疗与 eGFR 交互作用 P 趋势=0.033）。MRA 使用者更频繁地出现研究者报告的高钾血症和肾功能恶化（2-3 倍），随着 eGFR 降低，高钾血症的发生率也更高（治疗与 eGFR 交互作用 P 趋势=0.002）。
甾体 MRA 降低了广泛 eGFR 范围内 HF 住院和死亡率。然而，疗效下降和安全性恶化可能限制其在 eGFR 较低的患者中的应用，特别是 eGFR 水平≤30ml/min/1.73m 的患者。
