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Original Investigation
November 15, 2020

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

Author Affiliations
  • 1Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, Australia
  • 2Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 3Baylor College of Medicine, Houston, Texas
  • 4University of New South Wales, Sydney, Australia
  • 5University of Chicago, Chicago, Illinois
  • 6Academic Medical Center, Amsterdam, the Netherlands
  • 7Deutsches Herzzentrum München, Technische Universität München, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  • 8Division of Cardiology, University of Texas Southwestern Medical Center, Dallas
  • 9Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
  • 10Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts
  • 11Imperial College of London, London, United Kingdom
  • 12AstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gaithersburg, Maryland
  • 13AstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, Sweden
JAMA. 2020;324(22):2268-2280. doi:10.1001/jama.2020.22258
Visual Abstract. High-Dose Omega-3 Fatty Acids to Reduce Cardiovascular Events in Patients at High Risk
High-Dose Omega-3 Fatty Acids to Reduce Cardiovascular Events in Patients at High Risk
Key Points

Question  In statin-treated patients with high cardiovascular risk, high triglycerides, and low HDL cholesterol levels, does adding a carboxylic acid formulation of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) to background therapy improve cardiovascular outcomes?

Findings  In this randomized clinical trial of 13 078 patients that was stopped early, daily supplementation with omega-3 fatty acids, compared with corn oil, resulted in no significant difference in a composite outcome of major adverse cardiovascular events (hazard ratio, 0.99).

Meaning  These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in patients with high cardiovascular risk.

Abstract

Importance  It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk.

Objective  To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk.

Design, Setting, and Participants  A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa.

Interventions  Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins.

Main Outcomes and Measures  The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Results  When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%).

Conclusions and Relevance  Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.

Trial Registration  ClinicalTrials.gov Identifier: NCT02104817

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