Article

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk

Stephen J. NichollsMonash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, AustraliaA. Michael LincoffCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OhioMichelle GarciaCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OhioDianna BashCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OhioChristie M. BallantyneBaylor College of Medicine, Houston, TexasPhilip J. BarterUniversity of New South Wales, Sydney, AustraliaMichael H. DavidsonUniversity of Chicago, Chicago, IllinoisJohn J.P. KasteleinAcademic Medical Center, Amsterdam, the NetherlandsWolfgang KöenigDeutsches 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, GermanyDarren K. McGuireDivision of Cardiology, University of Texas Southwestern Medical Center, DallasDariush MozaffarianFriedman School of Nutrition Science and Policy, Tufts University, Boston, MassachusettsPaul M. RidkerCenter for Cardiovascular Disease Prevention, Harvard Medical School, Boston, MassachusettsKausik K. RayImperial College of London, London, United KingdomBrian G. KatonaAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gaithersburg, MarylandAnders HimmelmännAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, SwedenLarrye E. LossAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gaithersburg, MarylandMartin RensfeldtAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, SwedenTorbjörn LundströmAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, SwedenRahul AgrawalAstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, SwedenVenu MenonCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OhioKathy WolskiCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OhioSteven E. NissenCleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio

2020en

ABI

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.

Identifiers

DOI: 10.1001/jama.2020.22258

Citations and references

Cited by 20 references

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