A recent meta-analysis published in EClinicalMedicine examined the effectiveness of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on cardiovascular (CV) outcomes [1]. Mixed EPA/DHA formulations were indicated to have moderate certainty in reducing CV mortality and outcomes. Greater relative reductions in incident CV events were observed with EPA alone trials. The authors conclude that EPA and DHA have inherently different physico-chemical properties that influence CV risk reduction.
Our concern is that the authors assert mixed EPA/DHA formulations remain a viable treatment to reduce CV risk in patients using contemporary care. This conclusion is derived from a meta-analysis disproportinately influenced by older trials conducted without broad statin use [1]. In particular, the large GISSI-P and GISSI-HF trials enrolled subjects with 5% and 23% on statins, respectively (Table 1) [2,3]. By contrast, STRENGTH tested an EPA/DHA formulation (4 g/d) in patients on maximum statin treatment and terminated early for futility [1]. Similarly, the OMEMI trial failed to meet its primary endpoint when EPA/DHA (1.8 g/d) was combined with high statin use (Table) [1]. Like other TG-lowering agents (e.g., fibrates, niacin), mixed EPA/DHA treatments do not add incremental benefit in risk reduction on top of statins [4]. The benefits of icosapent ethyl (IPE) are attributed to dose, formulation and direct effects of EPA on inflammation, platelet activity and endothelial function beyond changes in lipoprotein levels [5].
Table 1.
Cardiovascular outcome trials with omega-3 fatty acids since 1999.
| GISSI-P (11324) | JELIS (18645) | GISSI-HF (6975) | REDUCE-IT (8179) | OMEMI (1027) | STRENGTH (13078) | |
|---|---|---|---|---|---|---|
| Publication Date | 1999 | 2007 | 2008 | 2019 | 2020 | 2020 |
| Population | Recent MI (<3 months) | Hypercholesterolemic | Chronic HF (NYHA functional class II-IV) | High cardiovascular risk, elevated TG | Elderly patients w/recent acute MI | High cardiovascular risk, elevated TG, low HDL |
| Formulation† | EPA/DHA ethyl esters (850 mg/d) | IPE (1.8 g/d EPA) | EPA/DHA ethyl esters (850 mg/d) | IPE (4 g/d EPA) | EPA/DHA (1.8 g/d) | EPA/DHA carboxylic acids (4 g/d) |
| Statin Use | BL: 5%, EOS: 46% | 100% | 22.3–23.0% | 100% | 96.3–96.6% | 100% |
| Primary End Point | Death, non-fatal MI, non-fatal stroke | Major coronary events | Death, and death or CV hospitalization (co-primary endpoints) | Composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina | Composite of nonfatal AMI, unscheduled revascularization, stroke, all-cause death, HF hospitalization after 2 years | Composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina |
| HR, 95% CI of Primary Endpoint | 0.85, 0.74-0.98 (p=0.023) | 0.81, 0.69-0.95 (p=0.011) | Death – 0.91, 0.833-0.998 (p=0.041) Death or CV hospitalization – 0.92, 0.849-0.999 (p=0.009) | 0.75, 0.68-0.83 (p=0.00000001) | 1.08, 0.82-1.41 (p=0.60) | 0.99, 0.90-1.09 (p=0.84) |
IPE, icosapent ethyl. Abbreviations are: BL, baseline; EOS, end of study; HF, heart failure; MI, myocardial infarction; NHYA, New York Heart Association; TG, triglyceride(s).
We recommend that the authors repeat the meta-analysis after removing older trials performed without broad statin use to ascertain a potential role for omega-3 fatty acids as part of contemporary medical therapy in CV patients.
Declaration of Competing Interest
Dr. Mason reports research grants, consulting fees and honoraria from Amarin, Pfizer and HLS Therapeutics. Dr. Eckel has no conflicts of interest to report.
References
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