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. 2021 Aug 1;6(8):910-917.
doi: 10.1001/jamacardio.2021.1157.

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

Steven E Nissen  1 , A Michael Lincoff  1 , Kathy Wolski  1 , Christie M Ballantyne  2 , John J P Kastelein  3 , Paul M Ridker  4 , Kausik K Ray  5 , Darren K McGuire  6 , Dariush Mozaffarian  7 , Wolfgang Koenig  8   9 , Michael H Davidson  10 , Michelle Garcia  1 , Brian G Katona  11 , Anders Himmelmann  12 , Larrye E Loss  11 , Matthew Poole  12 , Venu Menon  1 , Stephen J Nicholls  13
Affiliations

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

Steven E Nissen et al. JAMA Cardiol. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Drs Nissen reported grants from AstraZeneca during the conduct of the study. Dr Lincoff reported grants from AstraZeneca during the conduct of the study; grants from Esperion, CSL Behring, and AbbVie; and personal fees from Novo Nordisk, Novartis, and Eli Lilly and Company outside the submitted work. Ms Wolski reported grants from AstraZeneca outside the submitted work. Dr Ballantyne reported grants from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostic and personal fees from Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo outside the submitted work. Dr Kastelein reported personal fees from AstraZeneca, Matinas Biopharma, and 89Bio during the conduct of the study and from New Amsterdam and Staten Biotech outside the submitted work. Dr Ridker reported personal fees from AstraZeneca during the conduct of the study; personal fees from Flame, Agepha, Uppton, Novartis, Corvidia, and Novo Nordisk; and grants from Kowa and Amarin outside the submitted work. Dr Ray reported personal fees from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, Daiichi, Sanofi, and Regeneron; and personal fees from Kowa, Eli Lilly, Medicines Company/Novartis, Esperion, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, New Amsterdam, and Silence Therapeutics outside the submitted work. Dr McGuire reported personal fees from AstraZeneca during the conduct of the study; personal fees from Boehringer Ingelheim, Sanofi, AstraZeneca, Merck, Pfizer, Novo Nordisk, Esperion, Eli Lilly and Company, Lexicon, GlaxoSmithKline, Applied Therapeutics, Metavant, Afimmune, and CSL Behring outside the submitted work. Dr Mozaffarian reported grants from the National Institutes of Health, the Gates Foundation, the Rockefeller Foundation; personal fees from Acasti, America’s Test Kitchen, Barilla, Cleveland Clinic Foundation, Danone, GOED, Motif FoodWorks; and other support from Beren Therapeutics, Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, January Inc, Season, Tiny Organics, and UpToDate outside the submitted work. Dr Koenig reported personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, Berlin-Chemie, Sanofi, and Bristol Myers Squibb, and nonfinancial support from Abbott, Roche Diagnostics, Beckmann, and Singulex outside the submitted work. Dr Davidson reported other support from AstraZeneca during the conduct of the study. Ms Garcia reported grants from Cleveland Clinic and AstraZeneca during the conduct of the study. Dr Katona reported being an employee and shareholder of AstraZeneca during the conduct of the study and outside the submitted work. Drs Himmelmann, Loss, and Poole report being an employee of AstraZeneca during the conduct of the study and outside the submitted work. Dr Nicholls reported grants from AstraZeneca during the conduct of the study; grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience; and personal fees from AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Time to Event of First Incidence of Any Component of the Primary Composite End Point
A, Time to event of first incidence of any component of the primary composite end point for patients in the top tertile of achieved plasma eicosapentaenoic acid (EPA) level. B, Time to event of first incidence of any component of the primary composite end point for patients in the top tertile of achieved plasma docosahexaenoic acid (DHA) level.
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