Can High-Dose Eicosapentaenoic Acid Get a Place as a Plaque Modifier?

Despite the established anti-atherosclerotic benefits of lowering low-density lipoprotein-cholesterol (LDL-C) with a statin, atherosclerotic coronary artery disease still remains one of the leading causes of death in developed countries, which underscores the need to modify additional residual risks. The n-3 fatty acids (eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA)) have been considered as a potential therapeutic target to prevent atherosclerotic cardiovascular diseases. Although the JELIS study reported a significant reduction in cardiovascular events with EPA in Japanese subjects,¹ 2 recent randomized controlled trials (RCTs: REDUSE-IT study² and STRENGTH study³) have reported inconsistent findings about the clinical benefits of agents modulating EPA and/or DHA in the secondary prevention setting under statin therapy. In addition, a recent cohort study reported that these contrasting results were driven partly by differences of comparator oils.⁴ These observations indicate further need to conduct dedicated studies for elucidating the efficacy of targeting EPA and/or DHA.

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In this issue of the Journal, Motoyama et al⁵ used serial coronary computed tomography angiography (CCTA) to compare atheroma progression in 210 acute coronary syndrome (ACS) statin-treated subjects receiving different doses of EPA/DHA. The main findings of their study are: (1) types of statin differed in the 4 groups, and a lower on-treatment LDL-C level was observed in those treated with high-dose EPA+DHA or high-dose EPA alone, (2) on serial CCTA imaging analysis, the frequency of plaque progression was 0% and 7.1% in the high-dose EPA+DHA and high-dose EPA alone groups, respectively, (3) when patients were stratified into 3 groups according to the dose of EPA, less plaque progression was observed in the high-dose EPA group, (4) the dose of DHA was not associated with the degree of plaque progression, and (5) the use of high-dose EPA more likely induced reduction of fibrous, fibrofatty and low-attenuation plaque volumes with less calcification.

Although this study provides additional clinical data to support the favorable anti-atherosclerotic effect of high-dose EPA, several limitations should be considered when interpreting the findings. First, this was a single-center, observational study, not a randomized controlled clinical trial. The type and dose of statin and the use of EPA/DHA agents were decided at each physician’s discretion not by randomization. As a consequence, significant differences exist in the type of statin and on-treatment LDL-C among the 4 groups. In particular, given that patients receiving high-dose EPA+DHA and high-dose EPA exhibited a lower on-treatment LDL-C level, this lipid management may slow their plaque progression rate. Second, it is important to evaluate the efficacy of therapies under guideline-recommended LDL-C control, whereas the on-treatment LDL-C level in the current study subjects was >70 mg/dL. Whether high-dose EPA still works even in ACS patients who achieve on-treatment LDL-C <70 mg/dL remains unknown. Third, calcification is considered as a contributor to plaque stabilization, but in the high-dose EPA and high-EPA groups, calcification was not promoted. Further investigation is required into whether high-dose EPA truly stabilizes coronary atherosclerosis after ACS. Further studies are required to clarify whether high-dose EPA favorably modifies plaque quality and quantity in statin-treated ACS patients with optimal LDL-C control.

To date, several RCTs have used a variety of plaque imaging modalities to investigate the efficacy of n-3 fatty acids on coronary atherosclerosis^6–14 (Table). Although 6 studies reported a reduction of plaque volume or a plaque stabilization effect in those receiving EPA, others did not show any positive findings. In addition, subanalysis of the STRENGTH study reported that achieving a greater EPA level with the agent did not necessarily reduce cardiovascular events.¹⁵ These inconsistent observations indicate the complicated properties of EPA and DHA in vivo. Further elucidation of their physiological and biological effects in circulation is needed to determine whether “high-dose” EPA truly modulates coronary atherosclerosis under statin therapy.

Table. Randomized Control Trials Evaluating the Effects of n-3 Fatty Acids on Coronary Plaque

Imaging modality	Coronary computed tomography angiography (CCTA)		Intravascular ultrasound (IVUS)			Optical coherence tomography			Cardiac magnetic resonance
Study	Alfaddagh et al6 (2017)	Budoff et al7 (2020)	Niki et al8 (2016)	Ahn et al9 (2016)	Watanabe et al10 (2017)	Nishio et al11 (2014)	Kita et al12 (2020)	Sugizaki et al13 (2020)	Nakao et al14 (2018)
Subjects	Stable CAD	Patients with coronary artery stenosis on CCTA, with elevated triglycerides	Stable CAD	Stable CAD and ACS	Stable CAD and ACS	Stable CAD and ACS	ACS	Stable CAD and ACS, with in-stent neoatherosclerosis	Proven or suspected CAD
Therapies	126:114 for EPA 1.86 g/day + DHA 1.5 g/day vs. no n-3 fatty acids	31:37 for EPA 4 g/day vs. placebo	29:30 for EPA 1.8 g/day vs. no n-3 fatty acids	38:36 for EPA 1.395 g/day + DHA 1.125 mg/day vs. placebo	97:96 for pitavastatin 4 mg/day + EPA 1.8 mg/day vs. pitavastatin 4 mg/day	16:15 for EPA 1.8 g/day + rosuvastatin vs. rosuvastatin only	31:31:35 for EPA 1.86 g/day vs. EPA 0.93 g/day + DHA 0.75 mg/day vs. no n-3 fatty acids	21:21 for EPA 1.8 g/day + rosuvastatin 10 mg/day vs. rosuvastatin 2.5 mg/day	50:50:50 for EPA 0.93 g/day + DHA 0.75 g/day vs. EPA 1.86 g/day + DHA 1.5 g/day vs. no n-3 fatty acids
Percentage of statin-treated patients	95%	100%	100%	100%	47%	0%	53%	61%	100%
Baseline LDL-C level in each group, mg/dL	78.5 vs. 77.5 (P=0.46)	Not shown but not significantly different between groups	97.7 vs. 100.0 (P=0.85)	127.0 vs. 113.8 (P=0.100)	107.1 vs. 98.6 (P=0.080)	138.0 vs. 130.3 (P=0.41)	120 vs. 118 vs. 125 (P=0.953)	90 vs. 89 (Not shown but not significant)	On-going
Type of statins	Both high- and low-intensity statins	Not shown	Atorvastatin or rosuvastatin or pitavastatin	Atorvastatin or rosuvastatin	Pitavastatin	Rosuvastatin	Rosuvastatin	Rosuvastatin	On-going
On-treatment LDL-C in each group, mg/dL	84.6 vs. 80.4 (P=0.76)	Not shown but increase not significantly different between groups	91.4 vs. 88.3 (Not evaluated)	86.8 vs 80.8 (P=0.525)	76.9 vs 76.0 (P=0.796)	80.1 vs. 83.2 (P=0.58)	78 vs. 82 vs. 78 (Not evaluated)	68 vs. 82 (P<0.001)	On-going
Primary outcome	Change in noncalcified plaque volume at 30 months	Change in low-attenuation plaque volume at 18 months	Changes in plaque components assessed by integrated backscatter-IVUS at 6 months	Changes in atheroma volume index and percent atheroma volume at 12 months	Coronary plaque volume and composition assessed by integrated backscatter-IVUS at 6–8 months	Morphologic changes of TCFAs at 9 months	Change in minimum fibrous-cap thickness at 8 months	Changes in the lipid index or macrophage grade of native coronary plaques at 12 months	Change in plaque-to-myocardium signal intensity ratio
Findings	Primary endpoint not significantly different between groups (−2.4% vs. 4.5%, P=0.14)	EPA group reduced low-attenuation plaque volume (−17% vs. +109%, P=0.0061)	EPA group reduced lipid plaque volume (−18.9% vs. +8.4%, P=0.002) and increased fibrous volume (+11.7% vs. −9.2%, P=0.01)	Primary endpoint not significantly different between groups (atheroma volume index: −12.65% vs. −8.51%, P=0.768 and percent atheroma volume: −4.36% vs. −9.98%, P=0.526)	EPA group reduced total atheroma volume (−9.3 mm3 vs. −1.7 mm3, P<0.001). Lipid volume decreased in EPA group only (−3.4%, P=0.045 vs. −1.3%, P=0.429)	EPA+statin group increased fibrous-cap thickness (+54.8 μm vs. +23.5 μm, P<0.001) and decreased lipid arc (−34.4 degrees vs. −12.7 degrees, P=0.007) and lipid length (−2.81 mm vs. −1.2 mm, P=0.009)	Primary endpoint not significantly different between groups (absolute change: 60 μm vs. 20 μm vs. 20 μm, P=0.1491 and percent change: 58.3% vs. 14.3% vs. 20.0%, P=0.1075)	EPA+statin group decreased lipid index (−112 vs. 29, P<0.001) and macrophage grade (−17 vs. 1, P<0.001)	On-going

ACS, acute coronary syndrome; CAD, coronary artery disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LDL-C, low-density lipoprotein-cholesterol.

Disclosures

T.N. is a member of Circulation Journal’s Editorial Team.

IRB Information

Not applicable.

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