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

JAMA. 2020 Apr 28;323(16):1565-1573. doi: 10.1001/jama.2020.3308.

Abstract

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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / complications
  • Acute Coronary Syndrome / drug therapy*
  • Blood Chemical Analysis
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control
  • Cholesterol, HDL / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Myocardial Infarction / etiology
  • Proteins / antagonists & inhibitors*
  • Quinazolinones / adverse effects
  • Quinazolinones / therapeutic use*
  • Stroke / etiology

Substances

  • Cholesterol, HDL
  • Proteins
  • Quinazolinones
  • bromodomain and extra-terminal domain protein, human
  • apabetalone

Associated data

  • ClinicalTrials.gov/NCT02586155