STRENGTH Trial Fails to Show Cardiovascular Benefit with Omega-3 CA Use

A. Michael Lincoff, MD

A study presented at the American Heart Association (AHA) Scientific Sessions 2020 is adding new twist to the story of EPA and DHA in cardiovascular care, results of the STRENGTH trial indicate omega-3 carboxylic acid (CA) does not decrease risk of major adverse cardiovascular events compared to placebo.

One of the most anticipated studies in recent memory due to the success of REDUCE-IT and EPA-based icosapent ethyl (Vascepa), the STRENGTH trial indicates treatment with 4 grams of omega-3 CA (Epanova) daily was not associated with a reduction in major adverse cardiovascular events but did increase a patient’s risk for atrial fibrillation and adverse events.

“Many people continue to take fish oil supplements to prevent heart disease. However, the fish oil medication we tested in the STRENGTH trial was not effective for that purpose,” said lead investigator A. Michael Lincoff, MD, vice chairman for Research of the Department of Cardiovascular Medicine and an interventional cardiologist in the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, in a statement from the AHA.

Few nutritional supplements have captivated the attention of the public and medical community in the same manner as fish oil and omega-3 supplements. While dozens of studies and trials have been performed to understand potential benefits, STRENGTH was placed under a microscope after Amarin’s icosapent ethyl brought excitement around these agents to a fever pitch at AHA 2018.

Designed as a phase 3 study, STRENGTH began in 2014 and enrolled 13,078 adult patients from 675 centers in 22 countries. Although the trial was event-driven by design, it was stopped in January 2020 after preliminary analysis indicated it was unlikely use of omega-3 CA would result in cardiovascular benefit. The original design called for a minimum of 1600 events. The primary end point of the trial was a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

With patients randomized in a 1:1 ratio, investigators created cohorts of 6539 patients who received either omega-3 CA or a matching corn oil placebo.For inclusion in the study, patients needed to be statin-treated with high cardiovascular risk, have hypertriglyceridemia, and have low levels of HDL cholesterol. At the time when the study was terminated based on the recommendation of an independent Data and Safety Monitoring Board, a total of 1384 patients had experienced a primary end point event.

For the study’s primary end point, omega-3 CA was not associated with a reduction in events (HR, 0.99; 95% CI, 0.90-1.09; P=.84). Additionally, analysis of time to atrial fibrillation among with an event revealed a 69% increase in risk of atrial fibrillation (HR, 1.69; 95% CI, 1.29-2.21).

Investigators also noted omega-3 CA appeared to have an impact on lipids. Specifically, omega-3 CA was associated with mean reduction in triglycerides of -19% and a 20% reduction in hsCRP from baseline to follow-up. Results also suggested omega-3 CA was associated with a mean increase of 268.8% in plasma EPA and a mean increase of 298.6% in RBC EPA from baseline to follow-up.

In his summary, Lincoff noted the mineral oil used in REDUCE-IT contributed to increases in LDL cholesterol, ApoB, or hsCRP, and this effect was not seen with the corn oil placebo used in STRENGTH. Lincoff also pointed out the increased risk of atrial fibrillation seen in STRENGTH and other omega-3 trials contributes to uncertainty surrounding net benefit or harm with the absence of omega-3 fatty acid preparation.

“We believe the questions surrounding the benefit versus risk of fish oil will remain unanswered unless another trial using a neutral placebo such as corn oil is able to definitively show cardiovascular benefits for an omega-3 fatty acid medication,” Lincoff added.

This study, “STRENGTH Trial: Cardiovascular Outcomes With Omega-3 Carboxylic Acids (Epanova) In Patients With High Vascular Risk And Atherogenic Dyslipidemia,” was presented at AHA 2020.