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Macrovascular Residual Risk Studies

7 September 2021
Teasing out the reasons for lack of cardiovascular benefit in STRENGTH
A new analysis from STRENGTH shows no association between achieved levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and major cardiovascular outcomes.
Nissen SE, Lincoff AM, Wolski K, et al. 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. JAMA Cardiol 2021; doi:10.1001/jamacardio.2021.1157
Objective: To investigate the association between plasma levels of EPA and DHA and cardiovascular outcomes in STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia). Identifier: NCT02104817
Study design: STRENGTH was a double-blind, multicentre trial in statin-treated patients at high cardiovascular risk with elevated triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDL-C). Patients were randomized to treatment with 4 g daily of an EPA/DHA carboxylic acid formulation or an inert comparator, corn oil. The study was terminated early on the recommendation of the independent data monitoring committee due to a low probability of demonstrating a clinical benefit.
Study population: 13,078 patients were randomized, 6539 (50%) each to treatment with the EPA/DHA formulation or corn oil. EPA and DHA levels were available in 10 382 patients at both baseline and 12 months after randomization.
Study outcome: • Primary efficacy endpoint: a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina.
• Achieved levels and changes in plasma EPA and DHA levels
Methods: This was a post hoc analysis to evaluate the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids. Event rates were compared by tertiles of achieved plasma EPA and DHA for patients in the EPA/DHA and placebo groups. Estimates of adjusted hazard ratios (HR) and 95% confidence intervals (CI) for each tertile in each group were calculated using Cox proportional hazards models with covariates identified with multivariate modelling. Each tertile of fatty acid was compared with placebo using the Wald χ2 statistic.
Main results:

There was no association between achieved levels of EPA or DHA and major adverse cardiovascular events (Table 1). Sensitivity analyses based on changes in plasma levels of EPA and DHA showed similar results.


Table. Association between tertiles of achieved plasma EPA and DHA levels and cardiovascular events*


Plasma fatty acid (mg/mL)

HR (95% CI) **

Achieved EPA



Corn oil


1 (reference)

EPA tertiles




0.99 (0.84-1.18)

1.10 (0.93-1.28)

0.98 (0.83-1.16)

Achieved DHA



Corn oil



DHA tertiles


1.03 (0.87-1.22)



1.03 (0.87-1.21)



1.02 (0.86-1.20)

Authors’ conclusion:

* Primary event as defined above; ** adjusted for baseline fatty acid levels, region, cardiovascular disease, age, sex, diabetes, creatinine, non–HDL-C, high-sensitivity C-reactive protein, antiplatelets agents, β-blockers, and renin angiotensin inhibitors.


Among patients treated with an EPA/DHA carboxylic acid formulation in the STRENGTH trial, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.


The contrasting results of STRENGTH (a neutral trial) and REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial, a positive trial) have engendered much debate (1-3). Among the proposed hypotheses for the differing results were that higher plasma levels of EPA in REDUCE-IT were responsible for the observed benefit, and/or that harmful effects from the DHA component in STRENGTH counteracted the potential benefit from EPA (3).

The results of this post hoc analysis do not provide support for either hypothesis. First, there was no evidence to suggest that EPA levels were higher in REDUCE-IT than STRENGTH, given that the top tertile of achieved median EPA level was 151 μg/mL and 144 μg/mL, respectively (1,2). Second, the results of the current analysis show no support for an association between plasma DHA levels and potential harm. Similar findings were reported for the change in plasma EPA and DHA levels, as well as absolute change in red blood cell EPA and DHA membrane content, which may better reflect tissue levels of EPA or DHA.

In the light of these findings, other hypotheses for the divergent results of these trials have been proposed. These include different pharmacological effects of the formulation used in each trial (a carboxylic acid formulation in STRENGTH versus an EPA ethyl ester in REDUCE-IT); potential differences in the biological effects of EPA and DHA; as well as confounding due to the effects of the comparator (neutral corn oil in STRENGTH versus mineral oil in REDUCE-IT). Irrespective of ongoing controversy, however, it is important to note that the REDUCE-IT trial results do provide support for the concept of targeting elevated triglycerides in statin-treated patients to reduce residual cardiovascular risk.

References 1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
2. 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;324:2268-80.
3. Sharma G, Martin SS, Blumenthal RS. Effects of omega-3 fatty acids on major adverse cardiovascular events: what matters most: the drug, the dose, or the placebo? JAMA 2020;324:2262-4.
Key words omega-3 fatty acids; residual cardiovascular risk; STRENGTH; REDUCE-IT