Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine School of Medicine, Orange, California.
Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.
Clin J Am Soc Nephrol. 2021 May 8;16(5):705-716. doi: 10.2215/CJN.16751020. Epub 2021 Apr 27.
CKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (, cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.
Median follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was =0.03 for major adverse cardiovascular events, and =0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; =0.02) in the apabetalone group.
Apabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease.
慢性肾脏病（CKD）和 2 型糖尿病相互作用会增加主要不良心血管事件（心血管死亡、非致死性心肌梗死或中风）和充血性心力衰竭的风险。适应性表观遗传反应可能是心血管风险的驱动因素，并可以通过阿帕他胺（一种溴结构域和末端结构域转录系统的选择性调节剂）进行修饰。我们在 BETonMACE 的预设分析中检验了这个问题，这是一项 3 期试验。
设计、地点、参与者和测量：BETonMACE 是一项事件驱动、随机、双盲、安慰剂对照试验，比较了阿帕他胺与安慰剂对 2425 例患有 2 型糖尿病和近期急性冠状动脉综合征的患者（包括 288 例基线时 eGFR<60 ml/min/1.73m 的 CKD 患者）的主要不良心血管事件和心力衰竭住院的影响。BETonMACE 的主要终点是首次主要不良心血管事件的时间，次要终点是心力衰竭住院的时间。
中位随访时间为 27 个月（四分位间距，20-32 个月）。在 CKD 患者中，与安慰剂相比，阿帕他胺与较少的主要不良心血管事件相关（13 例事件发生在 124 例患者中[11%]，35 例事件发生在 164 例患者中[21%]；风险比，0.50；95%置信区间，0.26 至 0.96）和较少的心力衰竭相关住院（124 例患者中有 3 例住院[3%]，164 例患者中有 14 例住院[9%]；风险比，0.48；95%置信区间，0.26 至 0.86）。在非 CKD 组中，主要不良心血管事件的相应风险比为 0.96（95%置信区间，0.74 至 1.24），心力衰竭相关住院的风险比为 0.76（95%置信区间，0.46 至 1.27）。CKD 对治疗效果的交互作用为主要不良心血管事件为 0.03，心力衰竭相关住院为 0.12。无论随机分配到阿帕他胺还是安慰剂，CKD 患者的不良事件数量相似（119 [73%]例患者与 88 [71%]例患者），且阿帕他胺组的严重不良事件较少（29%比 43%；=0.02）。
阿帕他胺可能降低伴有高心血管疾病负担的 CKD 和 2 型糖尿病患者的主要不良心血管事件发生率。
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