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Original Investigation
March 27, 2020

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

Author Affiliations
  • 1Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, United Kingdom
  • 2Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia
  • 3Statistical Data Analysis Center, University of Wisconsin–Madison
  • 4Irving Institute for Clinical and Translational Research, Columbia University, New York, New York
  • 5Resverlogix Corporation, Calgary, Alberta, Canada
  • 6Division of Nephrology and Hypertension, University of California–Irvine
  • 7CGH Medical Center, Sterling, Illinois, and Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 8Division of Cardiology, University of Colorado School of Medicine, Aurora
JAMA. 2020;323(16):1565-1573. doi:10.1001/jama.2020.3308
Key Points

Question  In patients with recent acute coronary syndrome, does apabetalone (a selective inhibitor of bromodomain and extraterminal proteins) reduce the risk of major adverse cardiovascular events when added to standard care?

Finding  In this randomized clinical trial that included 2425 patients with acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, treatment with apabetalone compared with placebo and added to standard therapy did not significantly reduce the risk of cardiovascular death, nonfatal myocardial infarction, or stroke (10.3% vs 12.4%, respectively; hazard ratio, 0.82).

Meaning  Apabetalone did not significantly reduce major adverse cardiovascular events after acute coronary syndrome.

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

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