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|Objective:||To evaluate the effects of icosapent ethyl 4 g/day on atherosclerotic plaque in statin-treated patients with elevated triglycerides (TGs, 200–499 mg/dL or 2.23-5.63 mmol/L) and controlled low-density lipoprotein cholesterol (LDL-C) levels.|
|Study design:||Randomized, double-blind, placebo-controlled trial conducted at 2 centres in the USA. Eligible patients will be randomly assigned to icosapent ethyl 4 g/day or placebo and will be followed for ≥9 months or up to 18 months (if efficacy is not achieved at 9 months).|
|Study population:||Patients aged 30 to 85 years with coronary atherosclerosis (narrowing of ≥20% in 1 coronary artery by either invasive angiography or MDCTA) and elevated fasting TGs (200–499 mg/dL) and LDL-C levels ≥40 and ≤115 mg/dL (≥1.0 to 3.0 mmol/L). Statin therapy (with or without ezetimibe) as well as diet and exercise must be stable for ≥4 weeks prior to study entry.|
The primary endpoint is the rate of change in low-attenuation plaque volume from baseline to final assessment as measured by MDCTA.
Secondary endpoints are:
· Incident plaque rates; quantitative changes in different plaque types and morphology
· Changes in markers of inflammation including lipoprotein-associated phospholipase A2 and high-sensitivity C-reactive protein
· Changes in lipids and lipoproteins including standard lipid panel, lipoproteins, remnants, Apolipoprotein-A1/remnant ratio, EPA, arachidonic acid (AA), and EPA/AA ratio
· Relationship between changes in the above with noncalcified coronary plaque burden and/or plaque-vulnerability features
Assuming 80% power, an α of 0.05, and a dropout rate of 15%, a total of 80 patients (40 per arm) are needed to evaluate the primary outcome of the study. The sample size was estimated based on MDCTA data showing 24% ± 13% reduction in coronary artery plaque volume with moderate-dose statin therapy.1
The primary analysis will be performed on an intention-to-treat basis. An interim analysis will be conducted at 9 months, and if the P value of ≤0.006 is achieved, then the study will terminate.
|Main results:||Study is ongoing.|
|Authors’ conclusion:||EVAPORATE will be the first study using MDCTA to evaluate the effects of icosapent ethyl on atherosclerotic plaque as an adjunct to statin therapy in a North American population with persistent high TGs, and it will assess whether these effects correlate with lipid changes and inflammatory markers. The clinical implications of icosapent ethyl 4 g/day as an adjunct to statin therapy on cardiovascular endpoints are also being evaluated in the large cardiovascular outcomes study REDUCE-IT.2 EVAPORATE will provide important mechanistic data that may have relevance to the REDUCE-IT results.|
While statin therapy is undoubtedly efficacious in lowering LDL-C levels, reducing the progression and promoting regression of atherosclerosis, and reducing cardiovascular risk, it is also recognized that a substantial residual cardiovascular risk persists.3 This underlines the need for additional intervention, targeting other risk factors beyond LDL-C. EPA has been shown to exert a number of beneficial effects on plaque development, including improvement of inflammatory mediators,4,5 as well as reduction in elevated TGs and remnant cholesterol associated with atherogenic dyslipidaemia, without raising LDL-C levels.6 Additionally, in the Japan EPA Lipid Intervention Study (JELIS) in more than 18,000 statin-treated Japanese patients with hypercholesterolaemia, 1.8 g/day of high-purity EPA significantly decreased major coronary events by 19% (p = 0.011) compared with placebo.7
Thus, a growing body of evidence provides support for investigating whether intervention with high-purity EPA (icosapent ethyl) at a dose known to lower TGs will favourably impact the progression of atherosclerosis in statin-treated individuals with persistently elevated TGs, and potentially impact the high residual cardiovascular risk that persists in these patients. The EVAPORATE study will provide important mechanistic support for ongoing cardiovascular outcomes studies such as REDUCE-IT, which is due to report later this year.2
1. Burgstahler C, Reimann A, Beck T, et al. Influence of a lipid-lowering therapy on calcified and noncalcified coronary plaques monitored by multislice detector computed tomography: results of the New Age II Pilot Study. Invest Radiol 2007;42:189–195.
2. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial. Clin Cardiol 2017;40:138–148.
3. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
4. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis 2015;242:357–366.
5. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag 2016;12:171–183.
6. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol 2012;110:984–992.
7. Yokoyama M, Origasa H, Matsuzaki M, et al; JELIS Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098.
|Key words||residual cardiovascular risk; triglycerides; icosapent ethyl; atherosclerosis; imaging study; REDUCE-IT|