Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia - STRENGTH

Contribution To Literature:

The STRENGTH trial failed to show that omega-3 CA was superior to placebo at reducing adverse cardiovascular outcomes.


It is uncertain if the combined omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. The goal of the trial was to evaluate the carboxylic acid formulation of EPA/DHA (omega-3 CA) compared with placebo among patients with dyslipidemia and high cardiovascular risk.

Study Design

  • Randomized
  • Parallel
  • Double-blind

Statin-treated patients with dyslipidemia and high cardiovascular risk were randomized to omega-3 CA 4 g/day (n = 6,539) versus placebo (n = 6,539).

  • Total number of enrollees: 13,078
  • Duration of follow-up: Median 42 months
  • Mean patient age: 63 years
  • Percentage female: 35%
  • Percentage with diabetes: 70%

Inclusion criteria:

  • Statin-treated patients ≥18 years of age with or at high risk for cardiovascular disease and triglycerides 180-500 mg/dl, high-density lipoprotein (HDL) <42 mg/dl (men) or 47 mg/dl (women)
  • High risk for a cardiovascular event defined as: (1) established coronary, peripheral, carotid, or aortic atherosclerosis; (2) type 1 or 2 diabetes and ≥40 years old for men or 50 years old for women, with ≥1 additional risk factor including smoking, hypertension, high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L, or albuminuria; or (3) ≥50 years old for men or 60 years old for women with ≥1 additional risk factor, including a family history of premature coronary artery disease, smoking, hs-CRP ≥2 mg/L, renal insufficiency, or coronary calcium score >300 Agatston units

Exclusion criteria:

  • Prior cardiovascular ischemic event within the last 30 days
  • Consumption of >1 capsule (1 g) per day of omega-3 dietary supplements or any EPA or DHA containing medication
  • Use of fibrates or weight loss drugs

Principal Findings:

The trial was terminated early due to interim analysis revealing low probability for benefit with omega-3 CA. The primary outcome of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina occurred in 12.0% of the omega-3 CA group compared with 12.2% of the placebo group (p = 0.84).

Secondary outcomes:

  • Atrial fibrillation: 2.2% in the omega-3 CA group vs. 1.3% in the placebo group (p < 0.001)
  • Gastrointestinal adverse events: 24.7% in the omega-3 CA group vs. 14.7% in the placebo group
  • TIMI major bleeding: 0.8% in the omega-3 CA group vs. 0.7% in the placebo group

Achieved EPA and DHA levels:

  • Among the tertile with the highest achieved EPA level (>116.4 μg/ml) vs. placebo, the adjusted hazard ratio (HR) for major adverse cardiac events (MACE) was 0.98 (p = 0.81).
  • Among the tertile with the highest achieved DHA level (>105.2 μg/ml) vs. placebo, the adjusted HR for MACE was 1.02 (p = 0.85).


Among statin-treated patients with dyslipidemia and high cardiovascular risk, omega-3 CA was not superior compared with placebo. This trial was terminated early due to assessment of futility for benefit of omega-3 CA. Cardiovascular events were similar between the treatment groups. Omega-3 CA was associated with more atrial fibrillation and gastrointestinal adverse events compared with placebo.

The reason for the neutral finding of this trial and the positive REDUCE-IT trial is likely due to the different drugs studied. The latter trial studied a purified formulation of high-dose EPA, which resulted in much higher EPA levels. The prior JELIS trial had also studied pure EPA and was positive. The STRENGTH trial used omega-3 CA, which is a combination of EPA and DHA, and it is possible that DHA could counteract the benefits of EPA though, sub-analysis did not find a harmful association among those with the highest achieved DHA tertile vs. placebo.


Nissen SE, Lincoff AM, Wolski K, et al. Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial. JAMA Cardiol 2021;May 16:[Epub ahead of print].

Presented by Dr. Steven E. Nissen at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 16, 2021.

Nicholls SJ, Lincoff M, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA 2020;324:2268-80.

Editorial: Sharma G, Martin SS, Blumenthal RS. Effects of Omega-3 Fatty Acids on Major Adverse Cardiovascular Events: What Matters Most: the Drug, the Dose, or the Placebo? JAMA 2020;324:2262-4.

Presented by Dr. A. Michael Lincoff at the American Heart Association Virtual Scientific Sessions, November 15, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease

Keywords: ACC21, ACC Annual Scientific Session, AHA20, AHA Annual Scientific Sessions, Albuminuria, Angina, Unstable, Atherosclerosis, Atrial Fibrillation, Cholesterol, HDL, Corn Oil, Coronary Artery Disease, C-Reactive Protein, Diabetes Mellitus, Docosahexaenoic Acids, Dyslipidemias, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Metabolic Syndrome, Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Risk Factors, Stroke, Triglycerides

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