Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes,JAMA

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Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes
JAMA ( IF 63.1 ) Pub Date : 2020-04-28 , DOI: 10.1001/jama.2020.3308
Kausik K Ray ₁ , Stephen J Nicholls ₂ , Kevin A Buhr ₃ , Henry N Ginsberg ₄ , Jan O Johansson ₅ , Kamyar Kalantar-Zadeh ₆ , Ewelina Kulikowski ₅ , Peter P Toth ₇ , Norman Wong ₅ , Michael Sweeney ₅ , Gregory G Schwartz ₈ ,

Affiliation

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.

中文翻译：

Apabetalone 加入标准治疗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

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。Apabetalone 是一种选择性溴结构域和末端蛋白抑制剂，靶向溴结构域 2，并被假设对与动脉粥样硬化血栓形成相关的通路具有潜在的有利影响。汇总的 2 期数据表明对临床结果的有利影响。目的测试阿帕贝酮是否能显着减少主要不良心血管事件。设计、设置和参与者一项在 13 个国家/地区的 190 个地点进行的随机、双盲、安慰剂对照试验。在过去的 7 至 90 天内患有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有资格入组，从 2015 年 11 月 11 日开始，到 2018 年 7 月 4 日结束，随访结束—— 2019 年 7 月 3 日。干预除标准治疗外，患者被随机化 (1:1) 接受 apabetalone、100 mg 口服每天两次 (n = 1215) 或匹配的安慰剂 (n = 1210)。主要结果和测量主要结果是首次发生心血管死亡、非致命性心肌梗死或中风的时间的复合。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，2320 名（95.7%）完全确定了主要结局。在中位随访 26.5 个月期间，发生了 274 个主要终点：125 个（10.3%）在阿帕贝酮治疗的患者中，149 个（12.4%）在安慰剂治疗的患者中（风险比，0.82 [95% CI，0.65-1.04 ]；P = .11)。由于肝酶水平升高（35 [2.5%]）等原因，分配至阿帕贝酮组的患者多于安慰剂（114 [9.4%] vs 69 [5.7%]）停止研究药物。9%] vs 11 [0.9%]）。结论和相关性在近期患有急性冠脉综合征、2 型糖尿病和低高密度脂蛋白胆固醇的患者中，选择性溴结构域和末端蛋白抑制剂 apabetalone 添加到标准治疗中并没有显着降低主要不良心血管事件的风险。试验注册 ClinicalTrials.gov 标识符：NCT02586155。

更新日期：2020-04-28

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