Less coronary plaque progression with EPA but not EPA/DHA in statin-treated patients

EPA Versus Mixed EPA/DHA Plus Statin for Coronary Atherosclerosis: Meta-Analysis of Prospective Imaging Trials

Literature - Sheppard JP, Lakshmanan S, Dahal S, et al. - JACC Cardiovasc Imaging. 2022 Oct;15(10):1825-1828. doi: 10.1016/j.jcmg.2022.04.014

Introduction and methods


Treatment with polyunsaturated fatty acids (PUFAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has shown positive results in some but not all CV outcome studies [1,2]. While strong benefits have been described with pure EPA, EPA/DHA formulations have yielded mixed results, with many studies showing no benefit [2]. To find a biological explanation for these discrepant results, coronary imaging may be useful to assess plaque change during PUFA therapy.

Aim of the study

The study aim was to examine coronary plaque progression in patients receiving EPA or EPA/DHA in addition to statin therapy.


This was a systematic review and meta-analysis of 10 randomized prospective trials in which coronary plaques were longitudinally measured in a total of 860 statin-treated patients (72% stable coronary artery disease, 28% ACS) who were randomized to treatment with EPA (vs. placebo) or EPA/DHA (vs. placebo). For plaque measurement, coronary computed tomography angiography (CCTA; 3 studies), intravascular ultrasound (IVUS; 4 studies), or optical coherence tomography (OCT; 3 studies) was used. Mean follow-up time between baseline and repeat imaging was 12.3 months (SD: 7.1).


Primary endpoints were percent change in total and lipid plaque volumes. For studies employing CCTA, absolute volumetric plaque change was also estimated.

Main results

  • Patients receiving statin plus EPA treatment showed a greater percent reduction in total plaque volume compared with statin only–treated patients in the studies using CCTA (standardized mean difference (SMD): 0.8; 95%CI: 0.3–1.3; P=0.002) and the studies using IVUS (SMD: 0.5; 95%CI: 0.1–1.0; P=0.024).
  • Statin plus EPA treatment also led to a greater percent reduction in lipid volume compared with statin only therapy in the CCTA studies (SMD: 0.6; 95%CI: 0.1–1.1; P=0.023) and OCT studies (SMD: 0.9; 95%CI: 0.3–1.6; P=0.006) but not the IVUS studies (SMD: 1.9; 95%CI: –1.6 to 5.5; P=0.29).
  • For statin plus EPA/DHA versus statin only, however, there were no significant differences in percent change in total or lipid plaque volume for any imaging modality, regardless of whether individual studies or pooled effects were considered.
  • In 1 CCTA study, the effect of treatment with statin plus EPA was compared with that of statin only. Statin plus EPA therapy resulted in greater reductions in absolute total plaque volume (SMD: 0.9; 95%CI: 0.4–1.5; P=0.002) and absolute lipid plaque volume (SMD: 0.7; 95%CI: 0.2–1.1; P=0.009) compared with statin only.
  • However, no differences in absolute total or lipid plaque volume change were found in the 2 CCTA studies comparing statin plus EPA/DHA with statin only.


This systematic review and meta-analysis of 10 randomized prospective trials employing coronary imaging showed a greater percent reduction in total and lipid plaque volumes in patients receiving statin plus EPA treatment compared with statin only–treated patients in several but not all studies. Statin plus EPA therapy also resulted in greater absolute reductions in total and lipid plaque volumes. In contrast, statin plus EPA/DHA therapy did not alter any of the plaque parameters compared with statin only therapy.

The authors conclude that “[t]he imaging literature lends support for pure EPA but not EPA/DHA as adjunct to statins, providing a biological basis for clinical endpoint observations.” As EPA and DHA compete for incorporation into lipid bilayers and have different downstream effects, it is possible that DHA dilutes or otherwise interferes with EPA’s beneficial effects in atherosclerosis.


1. Bernasconi AA, Lavie CJ, Milani RV, Laukkanen JA. Omega-3 benefits remain strong post-STRENGTH. Mayo Clin Proc. 2021;96:1371–1372.

2. Khan SU, Bhatt DL. Meta-analysis of contemporary trials of omega-3 fatty acids containing both eicosapentaenoic and docosahexaenoic acids. EClinicalMedicine. 2021;39:101110. https://doi.org/10.1016/j.eclinm.2021.101110

Find this article online at JACC Cardiovasc Imaging.

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