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Randomized Controlled Trial
. 2020 Dec 8;324(22):2268-2280.
doi: 10.1001/jama.2020.22258.

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

Stephen J Nicholls  1 , A Michael Lincoff  2 , Michelle Garcia  2 , Dianna Bash  2 , Christie M Ballantyne  3 , Philip J Barter  4 , Michael H Davidson  5 , John J P Kastelein  6 , Wolfgang Koenig  7 , Darren K McGuire  8 , Dariush Mozaffarian  9 , Paul M Ridker  10 , Kausik K Ray  11 , Brian G Katona  12 , Anders Himmelmann  13 , Larrye E Loss  12 , Martin Rensfeldt  13 , Torbjörn Lundström  13 , Rahul Agrawal  13 , Venu Menon  2 , Kathy Wolski  2 , Steven E Nissen  2
Affiliations
Randomized Controlled Trial

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

Stephen J Nicholls et al. JAMA. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nicholls reported receiving grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and receiving personal fees from AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim during the conduct of the study. Dr Lincoff reported receiving grants from AstraZeneca during the conduct of the study, and Esperion, Novartis, CSL, and AbbVie outside the submitted work; and personal fees from Novo Nordisk and Eli Lilly. Dr Garcia reported receiving grants from Cleveland Clinic during the conduct of the study. Dr Ballantyne reported receiving personal fees from AstraZeneca during the conduct of the study; grants from Akcea, Amgen, Esperion, Novartis, and Regeneron; and personal fees from Akcea, Althera, Amarin, Amgen, Arrowhead, Corvidia, Denka Seiken, Esperion, Gilead, Janssen, Matinas BioPharma Inc, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi-Synthelabo outside the submitted work. Dr Davidson reported receiving personal fees from AstraZeneca during the conduct of the study; and was the founder and chief medical officer of Omthera Pharmaceuticals that developed Epanova, acquired by AstraZeneca in 2013; from 2013 to 2015, Dr Davidson was an employee of AstraZeneca and worked for the NDA submission and FDA approval of Epanova as well as the initiation of the STRENGTH trial. Since 2015, Dr Davidson has served on the steering committee of STRENGTH and received a $10 000 yearly honorarium since 2015 but has not received nor will receive additional monetary compensation for Epanova. Dr Kastelein reported receiving personal fees from AstraZeneca, CSL-Behring, Esperion, Matinas Biopharma, Novartis, Novo Nordisk, Omeicos, Pfizer, Regeneron, and 89Bio outside the submitted work. Dr Koenig reported receiving personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin Chemie, Sanofi, and Bristol-Myers Squibb; Dr Koenig also reported receiving grants and nonfinancial support from Singulex, Abbott, Beckmann, and Roche Diagnostics outside the submitted work. Dr McGuire reported receiving personal fees from AstraZeneca during the conduct of the study; personal fees from Boehringer Ingelheim, Sanofi, AstraZeneca, Merck & Co, Novo Nordisk, Esperion, Lexicon, Lilly USA, GlaxoSmithKline, Applied Therapeutics, Metavant, and Afimmune outside the submitted work; and nonfinancial support from Pfizer. Dr Mozaffarian reported receiving personal fees and other from Cleveland Clinic Foundation during the conduct of the study; grants from National Institutes of Health, Gates Foundation, and Rockefeller Foundation; personal fees from GOED, Danone, Indigo Agriculture, Motif FoodWorks, Amarin, Acasti Pharma, and America’s Test Kitchen; serving on the scientific advisory board for Beren Therapeutics, Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, January.ai, and Tiny Organics; and receiving chapter royalties from UpToDate outside the submitted work. Dr Ridker reported receiving grants from Kowa and Amarin during the conduct of the study; and personal fees from Novartis, Flame, Janssen, AstraZeneca, Agepha, Corvidia, Omeicos, CiviBio, and Inflazome outside the submitted work. Dr Ray reported receiving personal fees from C5 during the conduct of the study; consulting fees from Abbott, Kowa, Lilly, Akcea, Medicines Company/Novartis, Novo Nordisk, Boehringer Ingelheim, Bayer, Esperion, Resverlogix; and grants and consulting fees from Daiichi Sankyo, Amgen, and Sanofi/ Regeneron, outside the submitted work. Dr Katona reported owning shares in AstraZeneca during the conduct of the study. Dr Himmelmann reported owning shares in AstraZeneca outside the submitted work. Dr Loss reported owning stock in AstraZeneca outside the submitted work. Dr Rensfeldt reported other from AstraZeneca during the conduct of the study; other from AstraZeneca outside the submitted work. Ms Wolski reported receiving grants from AstraZeneca during the conduct of the study. Dr Nissen reported receiving grants from AstraZeneca during the conduct of the study; grants from Novartis, Abbvie, Silence Therapeutics, Medtronic, MyoKardia, Esperion, Eli Lily, Amgen, Novo Nordisk, Pfizer, Cerenis, and The Medicines company outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Randomization, and Patient Flow in the STRENGTH Clinical Trial
CA indicates carboxylic acid formulation; CVD, cardiovascular disease. aOther reasons for not meeting inclusion/exclusion criteria include not meeting age requirement; elevated liver enzymes; use of fibrates, bile acid sequestrants, or niacin within 4 weeks of randomization; not following a stable diet; poorly controlled hypertension; and occurrence of myocardial infarction or coronary bypass graft surgery within 30 days of randomization. bAdverse events leading to study drug discontinuation by system organ class (omega-3 CA/corn oil; multiple events are possible): gastrointestinal (403/202), neoplasms (81/78), cardiac (39/46), nervous system (36/42), infections (32/30), skin (24/20), kidney/urinary (16/25), investigations (21/14), metabolic disorders (18/17), musculoskeletal (14/18), hepatobiliary (13/14), injury (11/13), vascular (13/11), respiratory (13/10), and psychiatric (11/7). cOther reasons abstracted from free text (omega-3 CA/corn oil): investigator decision (22/22), patient decision (26/33), potential lost to follow-up (113/129), reached end point (18/18), moved (31/36), social reasons (7/13), comorbid condition (11/8), pill burden (5/10), study terminated (9/4), and site closed (4/5).
Figure 2.
Figure 2.. Time to First Incidence of Any Component of the Primary Composite End Point and Time to Core MACE
A, The primary composite end point consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina. Median (Q1-Q3) observation time was 41.3 (36.0-47.5) months for patients receiving omega-3 CA and 41.4 (35.9-47.4) months for patients receiving corn oil. B, Core major adverse cardiovascular events (MACE) included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Median (Q1-Q3) observation time of 41.5 (36.6-47.8) months for patients receiving omega-3 CA and 41.6 (36.8-47.4) months for patients receiving corn oil.
Figure 3.
Figure 3.. Effect of Omega-3 CA on the Primary Composite Cardiovascular End Point in Prespecified Subgroups
BSA, body surface area; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; and VLDL, very low-density lipoprotein. SI conversion factors are in Table 4. aP value estimated using a Cox proportional hazards model with factors for treatment, established cardiovascular status at baseline, region, subgroup (only if not one of the covariates), and treatment × subgroup interaction in the model.
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