（表1）患者的基线特征。不良事件分析（n=2419）包括另一名患者，该患者在没有确认剂量的研究药物的情况下退出，并且未能退还分配的药物。各治疗组之间平衡良好。中位年龄为62岁，25.6%为女性，87.6%为白人，糖尿病平均病程为8.5年，从急性冠状动脉综合征到随机分组的中位时间为38天。大多数指标事件是急性心肌梗死，在ST段抬高和非ST段抬高亚型之间大致均匀分布。
（表2）不良事件和不良反应的生物标志物。两个治疗组的总不良事件或严重不良事件的发生率相似。丙氨酸氨基转移酶、γ-谷氨酰转移酶和胆红素的水平如补充2中的图5所示。治疗组之间这些生物标志物的中位数水平差异很小。然而，在Apabetalone组和安慰剂组中，丙氨酸氨基转移酶升高超过正常上限5倍的病例分别为40例（3.3%）和9例（0.7%）。Apabetalone引起的丙氨酸氨基转移酶水平升高最常见于治疗4至16周之间。停用Apabetalone后，丙氨酸氨基转移酶水平在4周内降至正常值，除非有其他影响肝功能的持续性疾病，如活动性肝炎或胆石症。在24周时，两组的胆红素水平均高于基线水平，Apabetalone组从9.8μmol/L增加到11.4μmol/L，安慰剂组从9.9μmol/L增加到10.5μmol/L，与基线相比，调整后的变化差异表示Apabetalone与安慰剂相比增加了11.1%。
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.
