Icosapent ethyl and plaque regression: insights from the EVAPORATE-FFRCT study

This editorial refers to ‘Benefit of icosapent ethyl on coronary physiology assessed by computed tomography angiography fractional flow reserve: EVAPORATE-FFRCT’, by M.G.Rabbat et al., https://doi.org/10.1093/ehjci/jead063. Atherosclerosis contributes significantly to cardiovascular disease, the leading cause of death worldwide.1 Plaque regression, or reducing atherosclerotic plaque burden, is an important therapeutic target to lower cardiovascular risk.2 Icosapent ethyl (Vascepa), a highly purified form of eicosapentaenoic acid (EPA), an omega-3 fatty acid found in fatty fish, has gained attention for its potential to reduce cardiovascular risk by modifying lipid metabolism and reducing inflammation.3 In addition, EPA reduces triglyceride levels and modifies lipid metabolism, contributing to its beneficial effects on cardiovascular risk,4 and also has anti-inflammatory effects, reducing plaque formation and progression.5 The EVAPORATE study evaluated the effect of icosapent ethyl vs. placebo on plaque progression in high-risk patients with high triglycerides already taking statin therapy.6 The EVAPORATE-FFRCT sub-study examined the effect of icosapent ethyl on computed tomography fractional flow reserve (FFRCT) at baseline, 9 months, and 18 months.7 A total of 47 patients with 507 coronary lesions were studied using coronary CT angiography and FFRCT. The study found that icosapent ethyl significantly improved the primary endpoint at 9 and 18 months and improved ΔFFRCT in 140 coronary lesions compared to placebo. These results suggest that icosapent ethyl significantly benefits coronary physiology compared to placebo. Several studies have investigated the use of FFRCT in assessing the severity of coronary artery disease and its potential role in predicting plaque burden reduction. The PLATFORM trial examined FFRCT-guided management in patients with stable chest pain and found a lower rate of coronary revascularization without an increase in major adverse cardiovascular events (MACE).8 The ADVANCE registry showed that FFRCT had a high diagnostic accuracy in detecting significant stenosis and predicting subsequent MACE.9 The FLOW-PROMOTE study (NCT04737408), due to finish recruiting this year, will investigate the effect of ezetimibe on FFRCT in addition to atorvastatin over 18 months. Icosapent ethyl reduces cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, stroke, coronary revascularization, and unstable angina in high-risk patients with established cardiovascular disease or those at high risk for cardiovascular events. The EVAPORATE study showed a reduction in the volume of low-attenuation plaque, a marker of high-risk plaque with icosapent ethyl.6 The FFRCT sub-study, although limited by a small sample size, adds physiological functional significance to this finding. The CHERRY study, a population-based cohort, examined the combination therapy of EPA and pitavastatin for coronary plaque regression using integrated backscatter-intravascular ultrasound (IB-IVUS).10 This combination therapy achieved significant lipid volume reduction, while pitavastatin alone did not. Volumetric IVUS analysis showed a significant total atheroma volume (TAV) reduction in the combination therapy group compared to that of the pitavastatin group, suggesting EPA’s lipid reduction contributed to TAV reduction in patients with cardiovascular disease. However, the incidence of adverse events was comparable between the groups. Icosapent ethyl may have direct effects on plaque regression and direct anti-atherosclerotic, lipid-lowering, and anti-inflammatory effects. These findings have been demonstrated in several large randomized controlled trials, including the REDUCE-IT trial.11 The ratio of coronary artery lumen volume to left ventricular myocardial mass (V/M) is associated with coronary microvascular function and myocardial ischaemia.12,13 Icosapent ethyl (Vascepa) has demonstrated benefits in reducing cardiovascular events and plaque burden, but the effect on the V/M ratio as a marker of coronary microvascular function has not previously been investigated. The EVAPORATE FFRCT study observed no difference in V/M ratio between icosapent ethyl and placebo groups between baseline and interval imaging (mean difference 23.8 ± 4.6 vs. 24 ± 6.4, P = 0.92). A lower V/M ratio predicts FFR reduction in patients with and without focal stenoses exhibiting reduced FFR across the artery despite non-obstructive or diffuse plaque. However, a greater sample size may be required to assess the benefit of icosapent ethyl on more diffuse disease. Icosapent ethyl has a favourable safety profile, and the most common adverse event reported is gastrointestinal symptoms, such as diarrhoea and nausea, which are generally mild and transient.4,6,11 Based on the current evidence, icosapent ethyl has demonstrated significant benefits in reducing cardiovascular events, improving lipid profiles, and reducing plaque burden in high-risk patients with elevated triglycerides. However, the decision to use it in clinical practice should be individualized considering each patient’s medical history, risk factors, and concomitant medications. The cost of icosapent ethyl should also be considered, and while promising, a cost–benefit analysis is yet to be undertaken. All authors contributed to the drafting and revision of the editorial. Patient consent for publication: Not applicable. Ethics approval: Not applicable. Provenance and peer review: Commissioned; internally peer-reviewed. No new data were generated or analysed in support of this research.