December 16, 2019
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Icosapent ethyl may act on plaque

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by Thomas Das, MD; Rachit M. Vakil, MD, MPH; Roger S. Blumenthal, MD; and Seth S. Martin, MD, MHS

Thomas Das
Rachit M. Vakil

Roger S. Blumenthal
Seth S. Martin

A potential target for improving residual lipid-related risk for atherosclerotic CVD is reduction in triglyceride levels. Studies have shown eicosapentaenoic acid is effective in lowering triglyceride levels and reducing the risk for ischemic events in patients with elevated triglyceride levels already taking statin therapy.

However, there are limited data demonstrating whether eicosapentaenoic acid (EPA) reduces coronary atherosclerotic progression via imaging. To this end, the EVAPORATE study by Matthew Budoff, MD, professor of medicine at David Geffen School of Medicine at University of California, Los Angeles, and investigator at the Lundquist Institute, and colleagues, presented at the American Heart Association Scientific Sessions in November, evaluates the effect of icosapent ethyl (Vascepa, Amarin), a high-purity prescription EPA ethyl ester, on low-attenuation plaque volume via multidetector CT angiography.

Remnant particle produced from lipolysis of triglyceride-rich VLDL particles can enter the arterial wall and worsen atherosclerotic plaque progression. This makes triglycerides an important target of lipid-lowering studies. Studies focusing on lowering triglyceride levels with niacin or fibrates have shown no significant improvement in CV outcomes in patients already on statin therapy. However, recent trials have shown a role for EPA as a potential additive medication.

Clinical trial data

High-dose EPA reduces triglyceride levels by decreasing hepatic production of VLDL, and by increasing VLDL clearance from the circulation. The JELIS trial studied a population of Japanese patients with hypercholesterolemia already on statin therapy and found a 19% reduction in major coronary events with the addition of 1.8 g EPA daily. After this result, the REDUCE-IT trial found a 25% risk reduction in major CV events in patients on background statin therapy taking 4 g daily icosapent ethyl compared with placebo.

This impressive result was recently further delineated with the REDUCE-IT USA analysis, which showed an even more robust effect in North American patients, with an RR reduction of 31%. Notably, the results seen in the REDUCE-IT trial exceeded the expected benefit from reduction of triglyceride levels, and it is possible that EPA provides beneficial anti-inflammatory or antithrombotic effects outside of its effect on lowering triglyceride levels.

The EVAPORATE trial aims to provide imaging-based data via multidetector CTA to add further relevance to the important clinical findings observed in REDUCE-IT and help clarify a possible mechanism by which high-dose EPA reduces CV risk.

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Prior imaging studies using invasive coronary angiography, IVUS, carotid ultrasound and OCT have shown a possible role for high-dose EPA in slowing the progression of atherosclerotic disease; however, multidetector CTA has been less studied in this context. Multidetector CTA is a highly reproducible and noninvasive methodology to examine plaque burden, composition, volume and distribution. In particular, multidetector CTA can identify lipid-rich low-attenuation plaque, as well as differentiate between calcified and noncalcified plaque. These imaging findings may have prognostic clinical impact, as nonobstructive low-attenuation plaque visualized on multidetector CTA was associated with ACS in patients with hypertension.

EVAPORATE trial

The EVAPORATE investigators are studying a group of North American patients aged 30 to 85 years. All patients had at entry known atherosclerosis — defined as narrowing of at least 20% in one coronary artery by either invasive angiography or multidetector CTA — elevated fasting triglyceride levels (200 mg/dL to 499 mg/dL) and LDL levels between 40 mg/dL and 115 mg/dL. Statin therapy, diet and exercise were stable for at least 4 weeks before study entry. A total of 80 patients were enrolled, with 40 patients in each arm.

Patients with known MI, stroke, life-threatening arrhythmia, HF, or BMI more than 40 kg/m2 were excluded, as well as pregnant patients, those with genetic polymorphisms affecting plasma lipid levels and those on medications or supplements affecting plasma lipid levels. At baseline, all patients were evaluated with lipid testing and multidetector CTA before randomization to 4 g icosapent ethyl daily or placebo. Lipid levels and multidetector CTA were repeated at 9 months after randomization. EVAPORATE’s primary outcome is progression of these high-risk plaques via multidetector CTA.

Results from the 9-month interim data collection of the ongoing EVAPORATE trial were presented at AHA. Although not statistically significant (P = .469), patients on icosapent ethyl had numerically lower progression of low-attenuation plaque volume, the primary outcome, by 21% compared with placebo.

Although the primary outcome was not met at 9 months, several secondary outcomes were significant, including a 57% reduction in fibrous plaque progression, an 89% reduction in calcified plaque progression, a 19% reduction in total noncalcified plaque progression and a 42% reduction in total plaque progression (Table). Total plaque volume increased by 20 mm3 in the EPA group and by 34 mm3 in the placebo group. Fibrofatty plaque progression increased in the icosapent ethyl group, although this result was not statistically significant (P = .65).

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Although the primary outcome of the EVAPORATE trial was not met at this initial time point, the trial will continue for 18 months before reporting final results. In the meantime, the reduction in overall plaque progression helps clarify a possible mechanism by which icosapent ethyl reduces CV events. Due to its lipophilic nature, EPA can become incorporated into atherosclerotic plaques, and may play a role increasing plaque stability. Perhaps by stabilizing plaque and slowing overall atherosclerotic progression, this is a mechanism by which high-dose EPA is able to exert part of the CV benefit.

These preliminary results are encouraging in elucidating the cardioprotective role of high-dose EPA and will need further confirmation. We look forward to seeing the 18-month CTA results of this innovative study.

Editor’s Note: On Dec. 13, 2019, the FDA approved the use of icosapent ethyl as an adjunctive therapy to reduce the risk for CV events among adults with elevated triglyceride levels. Read the full article here.

References:

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For more information:

Thomas Das, MD, is a resident in the department of medicine at Johns Hopkins University School of Medicine.

Rachit M. Vakil, MD, MPH, is a postdoctoral fellow in the department of medicine at Johns Hopkins University School of Medicine.

Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board and co-chair of the writing committee of the 2019 primary prevention guideline.

Seth S. Martin, MD, MHS, FACC, FAHA, FASPC, is director of the Johns Hopkins Ciccarone Center’s Lipid Program and associate professor of medicine at Johns Hopkins University School of Medicine. He is also a member of the Cardiology Today Editorial Board. The authors can be reached at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Halsted 560, Baltimore, MD 21827.

Disclosures: The authors report no relevant financial disclosures.