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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ray reports receiving personal fees from Resverlogix during the conduct of the study; grants and personal fees from Amgen, Sanofi, Regeneron, MSD, Daiichi Sankyo, and Pfizer outside the submitted work; and personal fees from Aegerion, Cerenis Therapeutics, Akcea Therapeutics, The Medicines Company, Kowa, Novartis, Cipla, Lilly, Algorithm, Takeda, Boehringer Ingelheim, AbbVie, Silence Therapeutics, Dr Reddy’s, Bayer, Esperion, and Zuellig Pharma outside the submitted work. Dr Nicholls reports receiving grants from AstraZeneca, Amgen, Anthera Pharmaceuticals, Eli Lilly and Company, Esperion, Novartis, Cerenis Therapeutics, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron, and LipoScience, and personal fees from AstraZeneca, Akcea Therapeutics, Eli Lilly and Company, Anthera Pharmaceuticals, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim during the conduct of the study. Dr Buhr reports receiving grants from Resverlogix during the conduct of the study, and grants from The Medicines Company, GlaxoSmithKline, Pfizer, BioCardia, Amgen, and Cytokinetics outside the submitted work. Dr Ginsberg reports receiving personal fees from Resverlogix during the conduct of the study. Dr Johansson reports being an employee of Resverlogix and outside of this trial owns stock options. Dr Kalantar-Zadeh reports receiving personal fees from Resverlogix during the conduct of the study and receiving honoraria or support from Abbott, AbbVie, ACI Clinical (Cara Therapeutics), Akebia, Alexion, Amgen, American Society of Nephrology, AstraZeneca, Aveo, B. Braun, Chugai, Cytokinetics, Daiichi, DaVita, Fresenius, Genentech, Haymarket Media, Hofstra Medical School, International Federation of Kidney Foundations, International Society of Hemodialysis, International Society of Renal Nutrition and Metabolism, Japanese Society of Dialysis Therapy, Hospira, Kabi, Keryx, Kissei, Novartis, OPKO, National Institutes of Health, National Kidney Foundation, Pfizer, Regulus, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, Shire, Veterans Affairs, Vifor Pharma, UpToDate, and ZS Pharma. Dr Kulikowski reports receiving personal fees and other from Resverlogix during the conduct of the study and personal fees and other from Resverlogix outside the submitted work. Dr Toth reports receiving personal fees from Resverlogix during the conduct of the study, personal fees and nonfinancial support from Amarin, and personal fees from Amgen, Kowa, Merck, Regeneron, and Sanofi outside the submitted work. Dr Wong reports receiving personal fees and other from Resverlogix during the conduct of the study. Dr Sweeney reports receiving personal fees from Resverlogix during the conduct of the study. Dr Schwartz reports receiving grants from Resverlogix during the conduct of the study and grants from F. Hoffmann-La Roche, Sanofi, and The Medicines Company outside the submitted work; in addition, he reports having a patent to US 62/806,313 “Method to Reduce Cardiovascular Risk” assigned in full to the University of Colorado, pending.

Figures

Figure 1.. Patient Recruitment, Randomization, and Flow in the BETonMACE Trial of Apabetalone for Reduction of Adverse Cardiovascular Events in Patients With Acute Coronary Syndrome and Type 2 Diabetes

aReasons for exclusion varied, primarily failure to return for randomization visit. Reasons for discontinuation were due to patient preference.

Figure 2.. Kaplan-Meier Estimate of Time to First Occurrence of the Primary Efficacy End Point

The primary end point was time to cardiovascular death or nonfatal myocardial infarction or stroke. Median observation time for the apabetalone group was 781 days (interquartile range [IQR], 566-967) and for the placebo group, 772 days (IQR, 560-960).