Introduction

Despite the effectiveness of statin therapy in reducing the incidence and progression of atherosclerotic cardiovascular disease (ASCVD), considerable residual risk remains for patients with hypertriglyceridemia.¹ Recently, an omega-3 fatty acid (n3-FA) based therapy of eicosapentaenoic acid (EPA) (and its highly purified ethyl ester derivative, icosapent ethyl [IPE]) has emerged as a potent adjunct to statin therapy to reduce this persistent risk.

The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) showed a 31% reduction in total ischemic events compared to placebo in at-risk patients with triglycerides (TG) above 100 mg/dL despite statin therapy.² The significant relative and absolute risk reductions seen across various endpoints from REDUCE-IT appeared disproportionate to expected benefits from TG-lowering alone, thus prompting further research into EPA's protective mechanism.³

The Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy (EVAPORATE) trial was designed to evaluate the effect of high dose (2 grams twice daily) IPE on coronary plaque volume and composition by coronary computed tomographic angiography (CCTA); the hypothesis was that IPE's ASCVD benefit derived from anti-atherosclerotic properties.⁴ Results of the EVAPORATE trial were recently presented at the European Society of Cardiology (ESC) Scientific Sessions and simultaneously published in the European Heart Journal and showed a small but statistically significant reduction in low-attenuation plaque at 18 months in patients treated with IPE compared those treated with placebo.⁵

These results shed light onto EPA's mechanism of action, while also raising additional considerations for future studies. We provide a brief review of n3-FA based therapies prior to exploring the implications of the EVAPORATE trial. 

A Brief History of Omega-3 Fatty Acids and ASCVD
EPA, along with docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA), constitute the class of n3-FAs that have long been associated with TG reduction alongside anti-thrombotic, anti-arrhythmic, membrane-stabilizing, and anti-inflammatory effects.⁶ Historically, populations with diets high in n3-FAs have lower incident CVD; however, studies exploring potential cardioprotective qualities have yielded mixed results.⁷

The GISSI-Prevenzione trial and GISSI-HF trials showed significant reductions in death, nonfatal myocardial infarction (MI), nonfatal stroke, and heart failure hospitalization among patients treated with EPA/DHA, although these early studies enrolled relatively few (5 to 22%) patients on concurrent statin therapy.^8,9 Subsequently two primary-prevention trials,  ASCEND and VITAL, included a far greater proportion of patients already receiving statin therapy (75%), yet showed no difference in the rates of major vascular events or all-cause mortality among patients receiving a combination EPA/DHA compound.^10,11

One explanation offered for these negative studies was the use of a mixed DHA/EPA product, as DHA has been shown to mildly increase LDL-C levels.¹² To this end, the STRENGTH trial investing another combination product against a corn oil placebo was recently  halted early after meeting threshold for futility. Furthermore, sub-analyses within REDUCE-IT have shown that much of the cardiovascular benefit from high dose EPA is mediated by the higher achieved on-treatment blood levels.

The first trial investigating the effect of a pure EPA medication on cardiovascular outcomes was the JELIS trial, which randomized patients with hypercholesteremia (total cholesterol ≥250 mg/dL) to receive 1.8 g of EPA daily plus statin therapy versus statin alone without. The relative risk reduction of major adverse cardiac events (MACE) events in the EPA group was 19%, with a more pronounced risk reduction of 53% seen in a prespecified subgroup analysis of patients with TG ≥150mg/dL and HDL <40mg/dL.¹³

These impressive findings provided the rationale for the REDUCE-IT trial, wherein patients with fasting TG levels of 135 to 499 mg/dL and LDL-c levels of 41 to 100 mg/dL were randomized to receive 4g daily of IPE (Vascepa®) in addition to maximally tolerated statin therapy versus a mineral oil placebo. REDUCE-IT demonstrated an impressive 25% (P=0.00000001) relative risk reduction in first and 31% (P=0.0000000004) reduction in total  major cardiovascular events in patients receiving IPE.

This trial heralded in a new era of cardiovascular therapeutics as IPE was approved by the FDA as an adjunctive medication to maximally tolerated statin therapy in adult patients with TG levels >150mg/dL and established cardiovascular disease or diabetes mellitus and two or more additional risk factors. However, given the risk reduction seen in REDUCE-IT seemed to exceed what would be expected by TG reduction alone, questions emerged regarding IPE's exact mechanism of benefit.

Previous pre-clinical studies had shown that EPA may play a role in slowing atherosclerotic plaque progression as well as inhibiting platelet aggregation and foam-cell formation.¹⁴ These pre-clinical findings, combined with the results of REDUCE-IT, led to the design of the EVAPORATE trial to evaluate possible anti-atherosclerotic properties of IPE.

EVAPORATE: Study Design, Methods, and Results
Designed to mimic the REDUCE-IT trial, EVAPORATE randomized 80 patients aged 30-85 years old with known coronary atherosclerosis, elevated fasting TG levels of 135-499 mg/dL, and LDL-C levels of 40-115 to either maximally tolerated statin therapy plus 4g daily of IPE versus statin therapy plus the same mineral oil placebo used in REDUCE-IT. The primary endpoint was change in low-attenuation plaque (LAP) volume by multidetector CCTA after 18 months of therapy; changes in total plaque, total non-calcified plaque, fibrofatty plaque, fibrous plaque, and calcified plaque were secondary outcomes.

Previous studies have demonstrated CCTA as a valid tool for measuring atherosclerosis, and have shown high burdens of low-attenuation plaque are associated with worse cardiovascular outcomes.^15,16 The enrolled participants had an elevated mean baseline TG level of 259, with no significant differences in baseline distribution of LAP (5.1% and 6.5% of total plaque volume in IPE and placebo groups, respectively).

Sixty-eight patients completed the 18-month follow-up visit and repeat CCTA. The primary endpoint of changes in LAP volume after 18 months of therapy was statistically significant, with 17% reduction in LAP in the IPE arm, and 109% increase in LAP in the placebo arm (adjusted p=0.0061). Significant reductions were also seen in fibro-fatty plaque (34% reduction vs. 32% increase, adjusted P=0.0002), fibrous plaque (20% reduction vs. 1% increase, adjusted P= 0.0028), total non-calcified plaque (19% reduction vs. 9% increase, adjusted P=0.005), and total plaque (9% reduction vs. 11% increase, adjusted P=0.0019).

No significant difference was seen in calcified plaque (1% reduction vs. 15% increase, adjusted P=0.0531). Surprisingly, TG levels did not significantly change in either arm (decrease of 89.3 ± 91.1 mg/dL in the IPE group and 92.1±104.3 mg/dL in the placebo group, P=0.91). No other significant in basic lipid measurements were observed from baseline to follow-up.  

Plaque Type	IPE Group Percent Change	Placebo Group Percent Change	Adjusted P value
Calcification	-1%	15%	0.0531
Fibro-fatty	-34%	32%	0.0002
Fibrous	-20%	1%	0.0028
Low-attenuation plaque	-17%	109%	0.0061
Total non-calcified plaque	-19%	9%	0.0005
Total Plaque	-9%	11%	0.0019
Adapted from Budoff et al., 20205 P values adjusted for age, gender, diabetes mellitus, hypertension, and baseline triglyceride level

Reflections on the EVAPORATE outcomes, and future directions
Demonstrating the phenomenon of atherosclerotic plaque regression and stabilization with lipid-lowering therapies has long been a topic of great interest, paralleling the maturation of coronary imaging techniques from invasive intravascular ultrasound (IVUS) to more recently CCTA. From the KOBE study of pravastatin in 1997 to the most recent GLAGOV study of PCSK9 inhibitor therapy in 2016, such research helped to provide the mechanistic insight that have rendered LDL-c lowering as the cornerstone of preventive pharmacotherapy.

Study (Year)	Treatment	N	Follow-up	IVUS Assessment	Results	P value
KOBE (1997)17	Pravastatin 10mg	13	3 years	Plaque Area	-7%	(p<0.001)
	Control	12			+27%
REVERSAL (2004)18	Atorvastatin 80mg	253	18 months	Change in % atheroma volume	-0.4%	(p=0.02)
	Pravastatin 40mg	249			2.7%
ASTEROID (2006)19	Rosuvastatin 40mg	349	24 months	Change in % atheroma volume	-0.98%	(p=0.001 vs. baseline)
SATURN (2011)20	Atorvastatin 80mg	519	24 months	Change in % atheroma volume	-0.99%	(p=0.17)
	Rosuvastatin 40mg	520			-1.22%
ZEUS (2014)21	Statin + ezetimibe	45	6 months	% change in plaque volume	-12.5%	(p=0.06)
	Atorvastatin alone	50			-7.50%
PRECISE-IVUS(2015)22	Statin + ezetimibe	100	10 months	Change in % atheroma volume	-5.2%	(p<0.001)
	Atorvastatin alone	102			-1.3%
GLAGOV (2016)23	Statin + PCSK9i	423	18 months	Change in % atheroma volume	-0.95%	(p<0.0001)
	Statin alone	423			0.05%
Adapted from Daida et al. (2019)24

The EVAPORATE investigators are to be congratulated on undertaking a mechanistic study which, under the ethos of "seeing is believing," helps to bolster IPE into a unique group of nonstatin therapies (including only PCSK9i and ezetimibe) that have been proven to induce plaque stabilization and possibly some minor regression.

While the outcomes of the EVAPORATE trial suggest that the cardiovascular benefit of IPE may be partially derived by a reduction in coronary plaque burden, these results pose additional questions. The lack of significant reduction in TG levels in either arm once again challenges the notion that IPE's benefit is primarily tied to TG reduction. This notion is supported by the often overlooked finding from REDUCE-IT that EPA therapy yielded a beneficial effect even among the approximate 10% of participants with normal TGs.

Furthermore, in the CHERRY study, the combination of EPA and pitavastatin showed a greater reduction in total atheroma volume by IVUS when compared to pitavastatin alone, albeit no significant reduction in TG levels in either arm.²⁵ No significant reduction in events were noted in the EPA arm of CHERRY and these participants had overall lower TG levels (105 mg/dL in the control group, 110 mg/dL in the EPA group). It is therefore plausible that elevated TGs identifies a subset of higher risk individuals who would appear to benefit from  the pleotropic effects of EPA therapy.

Of note, there was a significant but modest increase in plaque burden seen in the placebo arm; despite maximally tolerated statin therapy in the control group; the burden of all measured plaque types slightly increased after 18 months, and the LAP burden more than doubled. These findings may be surprising given the wealth of evidence supporting the modest regression of plaque volume with high intensity statin therapy alone, despite a modest increase in calcified plaque (and hence, Agatston score).

It has been suggested that the mineral oil placebo used in both EVAPORATE and REDUCE-IT may have modestly inhibited the benefits of statin therapy in the placebo group since the hsCRP values and LDL-values increased. This was addressed by the EVAPORATE investigators, who performed an additional investigation comparing the rates of plaque progression among individuals administered the same mineral oil placebo as the clinical trials compared to a cellulose-based placebo; they found no difference in the progression of plaque between the two forms of placebo.¹⁸

The EVAPORATE study provides valuable information about the clinical effects and anti-atherosclerotic mechanisms of IPE, establishing it even more firmly within the armamentarium of preventive cardiovascular therapeutics. The FDA approval of high dose EPA in 2019 suggests that its use will become even more widespread in the coming years. Larger scale trials with longer durations of study will be crucial to build upon the results presented in EVAPORATE, as we learn more about the potential benefits and mechanisms of EPA therapy and its potential benefit across a broader range of patient populations.

References

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Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), EP Basic Science, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Eicosapentaenoic Acid, Plaque, Atherosclerotic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Docosahexaenoic Acids, Coronary Artery Disease, alpha-Linolenic Acid, Mineral Oil, Cholesterol, LDL, Anti-Arrhythmia Agents, Corn Oil, Hypercholesterolemia, Fatty Acids, Omega-3, Risk Factors, Control Groups, Cellulose, Quinolines, Disease Progression, Atherosclerosis, Plaque, Amyloid

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