阿巴他用于标准治疗的添加对近期急性冠状动脉综合征和 2 型糖尿病患者主要不良心血管事件的影响：一项随机临床试验。
Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.
机构信息
Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, United Kingdom.
Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia.
出版信息
JAMA. 2020 Apr 28;323(16):1565-1573. doi: 10.1001/jama.2020.3308.
IMPORTANCE
Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes.
OBJECTIVE
To test whether apabetalone significantly reduces major adverse cardiovascular events.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019.
INTERVENTIONS
Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke.
RESULTS
Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]).
CONCLUSIONS AND RELEVANCE
Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02586155.
重要性
溴结构域和末端蛋白是基因转录的表观遗传调节剂。阿帕他酮是一种针对溴结构域 2 的选择性溴结构域和末端蛋白抑制剂，据推测对与动脉血栓形成相关的途径有潜在的有利影响。汇总的 2 期数据表明对临床结局有有利影响。
目的
测试阿帕他酮是否能显著降低主要不良心血管事件。
设计、地点和参与者：这是一项在 13 个国家的 190 个地点进行的随机、双盲、安慰剂对照试验。急性冠状动脉综合征发病后 7 至 90 天、2 型糖尿病且低高密度脂蛋白胆固醇水平的患者有资格入组，入组时间为 2015 年 11 月 11 日，结束时间为 2018 年 7 月 4 日，随访结束时间为 2019 年 7 月 3 日。
干预
患者被随机（1:1）分配接受阿帕他酮，每日两次口服 100mg（n=1215）或匹配的安慰剂（n=1210），外加标准护理。
主要结局和测量指标
主要结局是首次发生心血管死亡、非致死性心肌梗死或中风的时间复合终点。
结果
在随机分组的 2425 名患者（平均年龄 62 岁；618 名女性[25.6%]）中，有 2320 名（95.7%）患者对主要结局进行了完整的确定。在中位随访 26.5 个月期间，发生了 274 例主要终点事件：阿帕他酮治疗组 125 例（10.3%），安慰剂治疗组 149 例（12.4%）（风险比，0.82[95%CI，0.65-1.04]；P=0.11）。与安慰剂组相比，更多接受阿帕他酮治疗的患者因肝酶水平升高（35[2.9%] vs 11[0.9%]）等原因停止了研究药物（114[9.4%] vs 69[5.7%]）。
结论和相关性
在近期发生急性冠状动脉综合征、2 型糖尿病和低高密度脂蛋白胆固醇水平的患者中，添加标准治疗的选择性溴结构域和末端蛋白抑制剂阿帕他酮并未显著降低主要不良心血管事件的风险。
试验注册
ClinicalTrials.gov 标识符：NCT02586155。
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