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Macrovascular Residual Risk Studies

4 January 2021
STRENGTH: a neutral outcomes trial for omega-3 fatty acids
Treatment with high-dose omega-3 fatty acids (a carboxylic acid formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) did not reduce major adverse cardiovascular events (MACE) in statin-treated patients with atherogenic dyslipidaemia and at high cardiovascular risk.
Nicholls SJ, Lincoff AM, Garcia M, et al. 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. JAMA 2020; doi: 10.1001/jama.2020.22258.
Objective: To evaluate the effects of a carboxylic acid formulation of EPA and DHA (omega-3 CA) on cardiovascular outcomes in high-risk statin-treated patients with atherogenic dyslipidaemia.
Study design: Randomized, double-blind, multicentre, comparator trial. Eligible patients were randomly allocated (1:1) to treatment with 4 g/day of omega-3 CA or corn oil (i.e. an inert comparator), on top of background evidence-based treatment, including statins.
Study population: Patients aged >18 years at high cardiovascular risk, with low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL (<2.6 mmol/L) or treated with maximally tolerated statin therapy for at least 4 weeks; and with atherogenic dyslipidaemia (i.e. triglyceride level [TG] 180 to <500 mg/dL and high-density lipoprotein cholesterol [HDL-C] <42 mg/dL for men or <47 mg/dL for women) were eligible. High cardiovascular risk was defined as: 

-  the presence of established atherosclerotic cardiovascular disease (ASCVD);

- type 1 or 2 diabetes AND aged ≥40 years for men and ≥50 years for women with at least 1 additional risk factor, i.e. smoking, hypertension, high-sensitivity C-reactive protein (hs-CRP) ≥2mg/L or moderately increased albuminuria; 

- high-risk primary prevention patients ≥50 years for men or ≥60 years for women with at least 1 additional risk factor, i.e. family history of premature coronary artery disease, chronic smoking, hs-CRP level ≥ 2 mg/L, impaired kidney function, or coronary calcium score >300 Agatston units.
Study Outcome: The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

-The trial was designed to enrol 13000 patients with positive adjudication of 1600 primary endpoints providing 90% power to detect a 15% reduction in relative risk in the omega-3 CA group.The full analysis set included all patients according to their randomization group. A safety analysis population was defined as any patient who took at least 1 dose of study drug. Estimates of hazard ratios (HRs) and 95% confidence intervals (Cis) were calculated using Cox proportional hazards models with covariates for established cardiovascular disease at baseline and region.



The study was prematurely terminated on 8 January 2020 after 1384 primary endpoints had been recorded in 13,078 randomized patients (6539 allocated to each treatment), because of futility, based on the recommendation of the independent Data Monitoring Committee.

Overall, the patient population had a mean age of 62.5 years, 35% were women, 70% had diabetes and 56% had established ASCVD at baseline. About 50% of patients were on high-intensity statin treatment. At baseline, median lipid values were 75mg/dL for LDL-C, 240 mg/dL for TG and 36 mg/dL for HDL-C.

Treatment with omega-3 CA reduced TG by 19% versus 0.9% in the corn oil comparator group. The primary endpoint occurred in 785 patients (12.0%) treated with omega-3 CA and 795 (12.2%) treated with corn oil (HR 0.99 [95% CI, 95% CI 0.90-1.09; p= 0.84). There were no significant effects on any other study endpoints. Treatment with omega-3 CA was also associated with 69% increase in relative risk for atrial fibrillation (HR 1.69, 95% CI 1.29-2.21, p<0.001).


Conclusion: 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.


These disappointing findings from STRENGTH follow demonstration of significant clinical benefit with high-dose EPA in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) (1), and raise many questions about the use of omega-3 fatty acids in cardiovascular disease prevention. This month’s Editorial focuses on many of these questions: are the discrepant findings from these trials explained by differences in EPA dose (and on-treatment blood levels), patient populations or effects – or lack thereof- of the comparator?

Beyond the lack of efficacy in STRENGTH, there was also a key safety concern, notably almost 70% increase in the risk of atrial fibrillation (AF) in the omega-3 CA group. A similar adverse signal was reported in REDUCE-IT, for both the rate of AF events (5.3% versus 3.9% in the comparator group), and hospitalization for AF or atrial flutter (3.1% versus 2.1%, p=0.004) (1). Furthermore, the OMEMI Trial (OMega-3 fatty acids in Elderly patients with Myocardial Infarction) in elderly patients with a recent myocardial infarction, showed that omega-3 fatty acids (1.8 g/day) were not beneficial in preventing cardiovascular events and also increased the incidence of AF (7.2% versus 4.0% with the comparator, p=0.06) (2). Clearly, further investigation of this effect on AF observed with omega-3 fatty acids warrants further study, especially as the prevalence of AF is likely to be higher among the anticipated patient populations due to their older age (3). 


1. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

2. Kalstad AA, Myhre PL, Laake K, et al, on behalf of the OMEMI Investigators. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlled trial. Circulation 2020; doi/10.1161/CIRCULATIONAHA.120.052209.

3. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27:949-53.

Key words STRENGTH; REDUCE-IT; omega-3 fatty acids; atrial fibrillation