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Macrovascular Residual Risk THROUGH LANDMARK STUDY

5 October 2020
EVAPORATE: Icosapent ethyl 4 g/day slows atherosclerosis progression

The results of EVAPORATE (Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy) provide insights into the mechanism of benefit of high-dose icosapent ethyl demonstrated in the landmark REDUCE-IT study.

Budoff MJ, Bhatt DL, Kinninger A et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J 2020; doi:10.1093/eurheartj/ehaa652
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate whether icosapent ethyl 4 g/day, adjunctive to diet and statin treatment, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in patients with coronary atherosclerosis.
Study design: Randomized, double-blind, placebo-controlled trial. Eligible patients were randomly allocated (1:1) to treatment with icosapent ethyl 4 g/day or placebo (Pharmaceutical grade mineral oil) for 18 months. Low-attenuation plaque (LAP) volume was measured by MDCT at baseline, and 9 and 18 months.
Study population: Patients aged 30–85 years with known coronary atherosclerosis (narrowing of ≥20% in 1 coronary artery), elevated fasting triglyceride (TG) (135–499 mg/dL), and low-density lipoprotein cholesterol levels (LDL-C) between ≥40 and ≤115 mg/dL. Patients were on stable statin therapy, with or without ezetimibe, diet, and exercise for ≥4 weeks before entry to the study.
Study Outcome: •The pre-specified primary endpoint was the change in LAP volume at 18 months between icosapent ethyl and placebo groups.
•Secondary variables assessed included total plaque, total non-calcified plaque, and fibrofatty, fibrous and calcified plaque.
Methods: Plaque volume was assessed per slice in all affected coronary segments measured by semi-automated quantification software. For each lesion, minimal lumen diameter was summed, and plaque reported as non-calcified, low attenuation, fibrous, fibrofatty, or calcified. Univariable analysis and multiple linear regression were used to compare the change in plaque volumes between the groups. Multivariable models were adjusted by baseline plaque, age, sex, diabetes status, hypertension, and baseline TG levels.
Main results:

In total, 80 patients were enrolled of whom 68 completed the 18-month study. Baseline characteristics of the two groups were similar: mean age 57.4 years, 54% male, 69% with diabetes, and mean baseline TG 259.1±78.1 mg/dL. Plaque characteristics at baseline were similar in the two groups, with the most common plaque type fibrous plaque (74.7% of total plaque in the icosapent ethyl group and 57.9% in the placebo group). LAP accounted for 5.1% and 6.5%, respectively of the total plaque at baseline.

The change in LAP from baseline to 18 months was significantly reduced in the icosapent ethyl group versus placebo (-0.3 ± 1.5 mm3 vs. 0.9 ± 1.7 mm3, p=0.006). Treatment with icosapent ethyl was also associated with significant reductions versus placebo in total plaque, total non-calcified plaque, fibrofatty plaque and fibrous plaque. Mean percent changes for each plaque type are summarized in Table 1.

Table 1. Percent changefor each type of plaque composition

Plaque type

Icosapent ethyl 4 g/day

Placebo

p-value

LAP

-17

+109

0.0061

Fibrofatty

-34

+32

0.0002

Fibrous

-20

+1

0.028

Calcification

-1

+15

0.053

Total noncalcified

-19

+9

0.0005

Total

-9

+11

0.019

 

Conclusion: The ability to retard progression and induce regression of atherosclerosis, as demonstrated by the EVAPORATE results, provides important mechanistic data on the clinical effects of icosapent ethyl on plaque characteristics and vulnerability.

COMMENT

REDUCE-IT was a landmark trial demonstrating significant clinical benefit by lowering TG in high-risk patients (the majority with established atherosclerotic cardiovascular disease). Treatment with high-dose icosapent ethyl (4 g/day) reduced major adverse cardiovascular events by 25% (p<0.001) (1). Importantly, REDUCE-IT differed from earlier trials using fibrates, which did not show significant clinical benefit, in ensuring that patients in the study did indeed have clinical hypertriglyceridemia (median TG at baseline 216 mg/dL or 2.4 mmol/L). The results engendered much debate, however, given that the extent of reduction in TG (median placebo-corrected reduction 19.7% or 44.5 mg/dL) did not explain the magnitude of clinical benefit, implying the involvement of other mechanisms. 
To address this issue, the EVAPORATE study investigated whether high-dose icosapent ethyl may have anti-atherosclerotic properties (2,3). The final results of EVAPORATE demonstrated significant improvement in all of the defined study plaque characteristics except calcified plaque with high-dose icosapent ethyl versus placebo, against a statin background. Over the course of the study, icosapent ethyl treatment slowed plaque progression and even induced plaque regression, compared with placebo. Importantly, significant reduction in LAP, the primary endpoint, suggests the potential for plaque stabilization, given that LAP is associated with plaque vulnerability (4), as well as risk for myocardial infarction (5). 


Although EVAPORATE had a small patient number, it was adequately powered to detect a significant difference in the primary endpoint. Moreover, the duration of treatment (18 months) was appropriate and consistent with other studies (18-24 months) which used intravascular ultrasound for serial assessment of serial plaque progression. In conclusion, the findings of EVAPORATE provide important mechanistic insights into the effects of icosapent ethyl on plaque characteristics and vulnerability.

References 1. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
2. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis 2015;242:357–366.
3. Budoff M, Muhlestein BJ, Le VT, et al. Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: rationale and design of the EVAPORATE study. Clin Cardiol 2018;41:13–19.
4. Voros S, Rinehart S, Qian Z, et al. Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovasc Imaging 2011;4:537–548. 
5. Williams MC, Dweck MR, Dey D. Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction. Results from the Multicenter SCOT-HEART Trial (Scottish Computed Tomography of the HEART). Circulation 2020;141:1452–1462.
Key words icosapent ethyl; REDUCE-IT; EVAPORATE; atherosclerosis regression