The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl

This commentary refers to ‘Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial’, by M MJ Budoff et al., doi:10.1093/eurheartj/ehaa652 and the discussion piece ‘Underlying mechanisms involved in the icosapent ethyl reduction of cardiovascular events still cannot be attributed to an anti-atherosclerotic effect', G.A. Rodriguez-Granillo and H.M. Garcia-Garcia, doi:10.1093/eurheartj/ehab230. We appreciate the comments made regarding the potential mechanistic benefits attributable to icosapent ethyl (IPE) on cardiovascular event reduction. The authors claim several reasons why the EVAPORATE (NCT02926027) trial does not provide absolute evidence of an anti-atherosclerotic effect of icosapent ethyl. However, the evidence supporting the cardiovascular benefits of IPE is overwhelming. First and foremost, the EVAPORATE trial, using multi-detector computed tomography (MDCT), is actually one of seven trials using eicosapentaenoic acid (EPA) demonstrating either slowing of plaque progression or induction of regression, with modalities including intravascular ultrasound, quantitative coronary angiography, optimal coherence tomography and MDCT.1 Furthermore, a second blinded analysis of the MDCT images using a novel software validated using histology in an independent core laboratory also demonstrated that, relative to placebo, patients on IPE had decreased wall volume (−7.2 vs. +28.4 mm3) and decreased lipid rich necrotic core (−1.4 vs. +9.7 mm3).2 The authors point out that the EVAPORATE trial demonstrated progression in the statin only arm and compared it with a study using different populations, software, and treatments done almost a decade earlier. The EVAPORATE trial was largely a population of hypertriglyceridemic persons with diabetes, not uniformly on high potency statins.3 We, along with many others, have demonstrated that persons with diabetes and/or hypertriglyceridaemia have higher rates of plaque progression, even with statin treatment.1,3,4 The use of a 20% stenosis as a threshold for MDCT progression studies is well established, with many trials demonstrating significant changes under the influence of different therapies.3,5 In regards to methodology, we have previously demonstrated excellent reproducibility (R = 0.99) in a similar study design by the same computed tomography (CT) core laboratory.5 The authors suggest that without volume normalization, which accounts for different lengths of the segments, the data are not valid. We have subsequently demonstrated that the results remain unchanged when normalization is applied to this study. Multivariable analysis, after adjustment for baseline plaque and cardiovascular (CV) risk factors, revealed that those on IPE have lower total plaque and lower total non-calcified plaque progression compared with placebo (P < 0.01), similar to our primary published results. The core laboratory utilized in the EVAPORATE trial has extensive experience conducting more than a dozen prospective, randomized, double-blind studies using serial MDCT and used standardized methodologies to perform this study. Trying to compare the methods used in MDCT to intravascular ultrasound is a flawed argument, as the modalities measure plaque differently, over different segments, and using different software, and study a much different population. Thus, we are very confident that the results of the EVAPORATE trial, replicating those done in Japan with pure EPA, are valid and explain mechanistically at least part of the substantial cardiovascular benefits of EPA seen in REDUCE-IT. Conflict of interest: D.L.B. discloses the following relationships—advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; chair: American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, Novo Nordisk, and Takeda. M.B. discloses the following: Amarin grant support and speakers bureau, General electric grant support. No other authors have any conflicts of interest.