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Original Investigation
May 16, 2021

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

Author Affiliations
  • 1Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 2Baylor College of Medicine, Houston, Texas
  • 3Academic Medical Center, Amsterdam, the Netherlands
  • 4Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts
  • 5Imperial College of London, London, England
  • 6University of Texas Southwestern Medical Center, Dallas
  • 7Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
  • 8Deutsches Herzzentrum München, Technische Universität München, DZHK (German Centre for Cardiovascular Research) Munich Heart Alliance, Munich, Germany
  • 9Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  • 10University of Chicago, Chicago, Illinois
  • 11AstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gaithersburg, Maryland
  • 12AstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, Sweden
  • 13Monash Cardiovascular Research Centre, Melbourne, Victoria, Australia
JAMA Cardiol. 2021;6(8):910-917. doi:10.1001/jamacardio.2021.1157
Key Points

Question  In statin-treated patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol treated with ω-3 fatty acids, are achieved levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) associated with cardiovascular outcomes?

Findings  In a secondary analysis of a randomized clinical trial studying a carboxylic acid formulation of ω-3 fatty acids, plasma levels of EPA and DHA were measured 12 months after randomization in 10 382 patients. There was no association between achieved or change in level of either ω-3 fatty acid and major adverse cardiovascular events.

Meaning  These findings do not support the concept that achieving higher EPA plasma levels through pharmacological means reduces adverse cardiovascular outcomes, nor were higher DHA levels associated with harm.


Importance  In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes.

Objective  To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo.

Design, Setting, and Participants  A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020).

Interventions  Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil.

Main Outcomes and Measures  The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization.

Results  Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil–treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 μg/mL (interquartile range [IQR], 46-131 μg/mL) for EPA and 91 μg/mL (IQR, 71-114 μg/mL) for DHA with top tertile levels of 151 μg/mL (IQR, 132-181 μg/mL) and 118 μg/mL (IQR, 102-143 μg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results.

Conclusions and Relevance  Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.

Trial Registration  ClinicalTrials.gov Identifier: NCT02104817

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