JAMA December 08, 2020

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, A. Michael Lincoff, Michelle Garcia, Dianna Bash, Christie M. Ballantyne, et al.

Bottom Line

In statin-treated patients at high cardiovascular risk with atherogenic dyslipidemia, the addition of 4 g/day of omega-3 carboxylic acids compared with a corn oil placebo did not reduce the risk of major adverse cardiovascular events and was associated with an increased incidence of atrial fibrillation and gastrointestinal adverse events.

Key Findings

1. The primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) occurred in 12.0% of the omega-3 CA group compared to 12.2% of the corn oil placebo group (HR 0.99, 95% CI 0.90-1.09; P=0.84) [2.2.5].

2. Treatment with high-dose omega-3 CA significantly increased the risk of new-onset atrial fibrillation compared with corn oil (2.2% vs 1.3%; HR 1.69, 95% CI 1.29-2.21; P<0.001).

3. Gastrointestinal adverse events were significantly more frequent in patients receiving omega-3 CA than in those receiving the corn oil placebo (24.7% vs 14.7%).

4. Despite robust reductions in triglyceride levels and high-sensitivity C-reactive protein in the omega-3 CA arm, no corresponding clinical cardiovascular benefit was observed, leading to premature termination of the trial for futility after 1,384 primary endpoint events had occurred.

Study Design

Design

RCT

Double-Blind

Sample

13,078

Patients

Duration

42 mo

Median

Setting

Multicenter, 22 countries

Population Statin-treated adults with high cardiovascular risk (established ASCVD, diabetes plus additional risk factors, or high-risk primary prevention), hypertriglyceridemia (TG 180 to <500 mg/dL), and low HDL-C (<42 mg/dL for men, <47 mg/dL for women).

Intervention Omega-3 carboxylic acids (a mixture of EPA and DHA) 4 g daily.

Comparator Corn oil placebo 4 g daily.

Outcome Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Study Limitations

• The trial was halted prematurely for futility, which limits the assessment of potential long-term effects; however, given the complete lack of a trend toward benefit at a median of 42 months, a late emergence of efficacy was highly improbable.

• The intervention used a mixed EPA and DHA carboxylic acid formulation, preventing researchers from isolating the specific cardiovascular effects of EPA alone, as some mechanistic theories hypothesize that DHA might counteract EPA's potential benefits.

• The study lacked a 'no treatment' control arm, though corn oil is widely accepted as a neutral comparator in lipid trials, avoiding the confounding inflammatory issues suspected with the mineral oil placebo used in previous studies.

Clinical Significance

The STRENGTH trial decisively demonstrated that high-dose, mixed EPA and DHA omega-3 carboxylic acids offer no cardiovascular protective effect in statin-treated patients with hypertriglyceridemia and high cardiovascular risk. This directly contradicts the hypothesis that any high-dose omega-3 therapy will reduce cardiovascular events, distinguishing the neutral results of mixed EPA/DHA from the dramatic benefits seen with purified EPA (icosapent ethyl) in the REDUCE-IT trial. Furthermore, the trial reinforced a crucial safety signal—a significantly increased risk of new-onset atrial fibrillation with high-dose omega-3 therapies. Clinically, these findings urge physicians to avoid prescribing mixed EPA/DHA products for cardiovascular risk reduction and to carefully consider the increased risk of arrhythmias when contemplating any high-dose marine oil supplementation.

Historical Context

For decades, epidemiological data and early open-label trials like GISSI-Prevenzione suggested that omega-3 fatty acids might confer cardioprotection. However, modern blinded randomized trials involving patients on contemporary background medical therapies (e.g., statins) consistently yielded neutral results for low-dose mixed EPA/DHA formulations. The field experienced a dramatic paradigm shift in 2018 with the REDUCE-IT trial, which reported a striking 25% relative risk reduction in major adverse cardiovascular events using 4 g/day of highly purified EPA (icosapent ethyl) compared to a mineral oil placebo. The STRENGTH trial was heavily anticipated to confirm whether another high-dose omega-3 formulation—a carboxylic acid mixture of EPA and DHA—could replicate these benefits. Its emphatically neutral results, contrasting sharply with REDUCE-IT, sparked intense scientific debate. Experts remain divided on whether the divergent outcomes stem from the pharmacological differences between EPA alone versus EPA plus DHA, or if the mineral oil placebo used in REDUCE-IT artificially inflated its observed benefits by negatively impacting the control group's lipid and inflammatory biomarkers.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the primary mechanisms by which omega-3 fatty acids lower serum triglycerides, and why might adding them to a statin theoretically reduce cardiovascular risk in patients with atherogenic dyslipidemia?

Key Response

Omega-3s reduce hepatic VLDL production and enhance lipid clearance via lipoprotein lipase. Theoretically, lowering triglycerides addresses the 'residual cardiovascular risk' that remains even after LDL-C is aggressively lowered by statins.

Resident

Given the negative results of the STRENGTH trial and the contrasting positive results of the REDUCE-IT trial, how should you approach prescribing prescription omega-3 fatty acids for cardiovascular risk reduction, and what specific adverse effect must you monitor for?

Key Response

Clinicians should prescribe pure EPA (icosapent ethyl) as proven in REDUCE-IT, rather than mixed EPA/DHA products like those in STRENGTH, which showed no MACE benefit. With both formulations, there is a significantly increased risk of incident atrial fibrillation that requires active clinical monitoring.

Fellow

The STRENGTH trial used corn oil as a placebo, whereas REDUCE-IT used mineral oil. How might the choice of placebo, alongside the differing pharmacological profiles of EPA versus DHA, explain the divergent MACE outcomes between these two landmark trials?

Key Response

Mineral oil in REDUCE-IT may have interfered with statin absorption, raising LDL-C and CRP in the control arm and potentially exaggerating the intervention's benefit. Conversely, the DHA component in STRENGTH's formulation may counteract the membrane-stabilizing benefits of EPA or independently raise LDL-C, contributing to the lack of cardiovascular benefit.

Attending

With the definitive lack of benefit and increased risk of atrial fibrillation seen with mixed omega-3 carboxylic acids in STRENGTH, how should we systematically approach the de-prescribing of over-the-counter fish oil supplements in our high-risk cardiovascular patients?

Key Response

OTC fish oils are predominantly mixed EPA/DHA formulations analogous to the STRENGTH study drug. Given the lack of MACE reduction and the undeniable, dose-dependent risk of atrial fibrillation, attendings should proactively discontinue these unproven supplements and transition eligible patients to evidence-based therapies like icosapent ethyl or other proven lipid-lowering adjuncts.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The STRENGTH trial was halted early for futility by the Data and Safety Monitoring Board. From a methodological standpoint, how does early termination for futility impact the statistical power to detect secondary safety signals, and what are the limitations of the post-hoc analyses linking achieved EPA levels to outcomes?

Key Response

Stopping early truncates follow-up, which widens confidence intervals for safety outcomes like atrial fibrillation, potentially underestimating long-term harm. Furthermore, post-hoc analyses of achieved EPA levels break randomization, introducing survivor bias and confounding by metabolism or adherence, rather than isolating the true causal effect of the intervention.

Journal Editor

A major editorial controversy in lipid-lowering trials is the selection of an appropriate placebo. How does the use of a corn oil placebo in STRENGTH circumvent the criticisms leveled against the mineral oil placebo in REDUCE-IT, and what criteria should editors demand for placebo validation in future trials?

Key Response

Corn oil is biochemically neutral regarding statin absorption and systemic inflammation, avoiding the artefactual rise in LDL-C and CRP seen with mineral oil in REDUCE-IT. Editors must demand rigorous preliminary data demonstrating that a chosen placebo is truly inert on all relevant lipid and inflammatory biomarkers to ensure the validity of the trial's control arm.

Guideline Committee

How should current lipid management guidelines stratify recommendations for omega-3 fatty acids in patients with atherogenic dyslipidemia, and does the STRENGTH data justify a formal recommendation against the use of mixed EPA/DHA formulations?

Key Response

Current ACC/AHA guidelines give a Class IIa recommendation for icosapent ethyl (pure EPA) based on REDUCE-IT. The STRENGTH trial necessitates adding a Class III (No Benefit) recommendation against mixed EPA/DHA formulations or OTC fish oil supplements for cardiovascular risk reduction, explicitly differentiating the class based on formulation and highlighting the atrial fibrillation risk.

Clinical Landscape

Noteworthy Related Trials

2018

REDUCE-IT Trial

n = 8,179 · NEJM

Tested

Icosapent ethyl 4g daily

Population

Patients with elevated triglycerides and established CV disease or diabetes

Comparator

Mineral oil placebo

Endpoint

5-point MACE

Key result: Icosapent ethyl significantly reduced the risk of first and subsequent ischemic events by 25 percent compared to placebo.

2018

VITAL Trial

n = 25,871 · NEJM

Tested

Omega-3 fatty acids 1g daily

Population

Adults with no history of cardiovascular disease or cancer

Comparator

Placebo

Endpoint

Major cardiovascular events and invasive cancer

Key result: Supplementation with standard-dose omega-3 fatty acids did not lower the incidence of major cardiovascular events or cancer compared to placebo.

2018

ASCEND Trial

n = 15,480 · NEJM

Tested

Omega-3 fatty acids 1g daily

Population

Patients with diabetes but no known cardiovascular disease

Comparator

Olive oil placebo

Endpoint

First serious vascular event

Key result: There was no significant difference in the risk of serious vascular events between those assigned to omega-3 fatty acids and those assigned to placebo.

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