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evident
Original paper
2020JAMACardiology

STRENGTH

Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk

RCTResidual lipid risk

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Overview

High-dose EPA/DHA omega-3 carboxylic acids did not reduce cardiovascular events.

Clinical takeaway

STRENGTH is the key counterweight to REDUCE-IT: not all omega-3 formulations reduce residual cardiovascular risk.

Key result

Major adverse cardiovascular events were not reduced; HR 0.99.

Practice impact

Avoid treating REDUCE-IT as a class effect for all fish-oil or mixed omega-3 products.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial stopped for futility.

Enrollment

13,078

Follow-up

Median 42 months.

Geography

Multinational

Clinical question

Do high-dose omega-3 carboxylic acids reduce major cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL?

Population

  • Statin-treated patients at high cardiovascular risk with hypertriglyceridemia and low HDL cholesterol.

Intervention

Omega-3 carboxylic acids 4 g daily.

Comparator

Corn oil placebo.

Primary outcome

Composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

High-dose EPA/DHA omega-3 carboxylic acids did not reduce major cardiovascular events.

Hazard ratio / 0.99 / 95% CI 0.90-1.09 / p=0.84

Key results

  • Primary composite was not reduced with omega-3 carboxylic acids: 785 (12.0%) vs 795 (12.2%) with corn oil; HR 0.99 (95% CI 0.90-1.09; p=0.84).
  • The trial was stopped early for futility.
  • Atrial fibrillation was more frequent with omega-3 treatment.

Harms

  • Atrial fibrillation occurred more often with omega-3 therapy.
  • Gastrointestinal adverse events were more frequent with omega-3 therapy (24.7% vs 14.7% with corn oil).

Clinical Use

Practice impact

  • Helped distinguish icosapent ethyl evidence from mixed EPA/DHA omega-3 supplements or products.

Applicability

  • High-risk statin-treated patients with triglyceride-rich residual risk.

Limitations

  • Used a mixed EPA/DHA carboxylic acid product and corn oil placebo; results should not be collapsed with REDUCE-IT's icosapent ethyl trial.

Common misinterpretations

  • Do not cite REDUCE-IT to recommend generic fish oil; STRENGTH argues against a broad omega-3 class effect.

Related evidence

REDUCE-IT - Contrasting Result

Citation

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;324(22):2268-2280. doi:10.1001/jama.2020.22258

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).