The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial
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Apabetalone is a selective bromodomain and extra-terminal (BET) inhibitor which modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated coronary atherosclerotic plaque (AP), a measure of vulnerability, is unknown.
The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE; NCT01067820) study employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in 281 patients treated with apabetalone or placebo for 26 weeks. AP was measured at baseline and follow-up. Factors associated with changes in AP were investigated.
AP was observed in 31 patients (11%) [27 (13.0%) in the apabetalone group and four (5.5%) in the placebo group]. The apabetalone group demonstrated reductions in AP length by − 1 mm [interquartile range (IQR) − 4, 1] (p = 0.03), AP arc by − 37.0° (IQR − 59.2, 8.2) (p = 0.003) and the AP index by − 34.6 mm° (IQR − 52.6, 10.1) (p = 0.003) from baseline. The change in AP index correlated with on-treatment concentration of high-density lipoprotein (HDL) particles (r = − 0.52, p = 0.006), but not HDL cholesterol (r = − 0.11, p = 0.60) or apolipoprotein A-1 (r = − 0.16, p = 0.43). Multivariable analysis revealed that on-treatment concentrations of HDL particles (p = 0.03) and very low-density lipoprotein particles (p = 0.01) were independently associated with changes in AP index.
Apabetalone favorably modulated ultrasonic measures of plaque vulnerability in the population studied, which may relate to an increase in HDL particle concentrations. The clinical implications are currently being investigated in the phase 3 major adverse cardiac event outcomes trial BETonMACE.
Peter J. Psaltis is supported by a Future Leader Fellowship from the National Heart Foundation of Australia and project Grant funding from the National Health and Medical Research Council and National Heart Foundation of Australia. Stephen J. Nicholls is supported by a Principal Research Fellowship from the National Health and Medical Research Council of Australia.
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Conflict of interest
Peter J. Psaltis has received research support from Abbott Vascular and speaker honoraria from AstraZeneca, Merck and Bayer. Stephen J. Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck Schering-Plough and Takeda, consulting fees from AstraZeneca, Abbott, Atheronova, Esperion, Amgen, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, Pfizer, Merck Schering-Plough, Takeda, Roche, NovoNordisk, LipoScience and Anthera and research support from Anthera, AstraZeneca, Cerenis, EliLilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. Jan Johansson, Ewelina Kulikowski, Norman Wong and Michael Sweeney are employees of Resverlogix Corp. Other authors (Daisuke Shishikura, Yu Kataoka, Satoshi Honda, Kohei Takata, Susan W. Kim, and Jordan Andrews) have nothing to disclose.
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