A new fish oil medication (omega-3 carboxylic acids [CA]) did not reduce the risk of cardiac events as compared to placebo in those patients with existing heart disease or who were at high risk of heart disease due to other medical conditions, according to results from the STRENGTH trial presented Sunday at the American Heart Association (AHA) Scientific Session 2020 virtual conference.
Michael Lincoff, MD, of Cleveland Clinic, presented the results of the study, which were simultaneously published online in JAMA.
Considerable research efforts have been expended on the potential for omega-3 fatty acids to lower cardiovascular risk. Previous observational studies have demonstrated that dietary consumption of either fatty fish or omega-3 fatty acids can lower prospective risk of cardiovascular events.
Furthermore, additional studies have suggested that red blood cell concentrations of either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are inversely correlated with cardiovascular risk. Finally, biomarker studies have demonstrated that omega-3 fatty acids exert favorable effects on lipoprotein metabolism and inflammatory, oxidative, thrombotic and arrhythmogenic factors implicated in cardiovascular disease.
All that being said, it remains uncertain whether omega-3 fatty acids reduce cardiovascular risk or prevent heart disease in the general population.
A CA formulation of EPA and DHA (omega-3 CA, brand name Epanova) has been previously documented to have favorable effects on lipid and inflammatory markers. It is administered as a free fatty acid not requiring hydrolysis by pancreatic lipase during intestinal absorption, eliminating the need for co-administration with a high-fat diet and resulting in greater bioavailability compared with standard omega-3 ethyl ester formulations.
The investigators assessed the effects of omega-3 CA on cardiovascular outcomes.
The STRENGTH trial was a double-blind, randomized, multicenter, international trial comparing omega-3 CA (4 gm daily, n=6,539) with a matching corn oil placebo (n=6,539) in statin-treated participants with high cardiovascular risk, hypertriglyceridemia (triglyceride levels ≥180 mg/dL and <500 mg/dL) and low levels of high-density lipoprotein cholesterol (HDL-C <42 mg/dL for men or <47 mg/dL for women).
The primary efficacy measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization and hospitalization for unstable angina. Changes in lipid and inflammatory biomarkers, as well as safety and tolerability were evaluated.
The study began in 2014 and was stopped slightly early, in January 2020, after an independent Data and Safety Monitoring Board recommended for futility because preliminary results of the study deemed it unlikely to prove the benefit of omega-3 CA medication.
Over a median follow-up time of about 3 years, 1,580 patients experienced at least one cardiac event. There were no significant differences in the number of patients experiencing cardiac events between the two treatment groups. Additionally, atrial fibrillation occurred more frequently among patients taking the omega-3 CA medication than in those receiving the control corn oil.
The neutral results of the omega-3 CA medication in STRENGTH are in contrast with the favorable results of icosapent ethyl shown in the REDUCE-IT trial, first presented at the AHA Scientific Sessions 2018 and published in The New England Journal of Medicine in January 2019, showed that the risk of ischemic events, including cardiovascular-related death, was significantly lower among those who received 2 grams of icosapent ethyl twice daily than among those who received placebo. Icosapent ethyl is a highly purified EPA omega-3 acid in ethyl ester form.
One question Lincoff raised regarding the diverging results between STRENGTH and REDUCE-IT was the nature of the placebo in each trial. He said that mineral oil, the placebo in REDUCE-IT, raised that study’s patients’ triglyceride levels by a mean of 2.2%, low-density lipoprotein cholesterol (LDL-C) levels by a mean of 10.2%, apolipoprotein B (Apo-B) by 7.8% and high-sensitivity C-reactive protein (hsCRP) by 32%. By contrast, the corn oil placebo in STRENGTH lowered this study’s patients’ triglyceride levels by a mean of 0.9%, LDL-C by 1.1%, Apo-B by 1.0% and hsCRP by 6.3%.
During a news briefing announcing the results, Alberico Catapano, PhD, of the University of Milano, Italy, said “the jury is still out” as to whether mineral oil might produce more negative effects than corn oil.
“Some data seems to suggest yes, some data seems to suggest no,” he said.
Given these data, Lincoff asked whether the unfavorable effects of the mineral oil placebo led to an exaggerated demonstration of efficacy in the REDUCE-IT trial.
“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,” Lincoff said in a news release announcing the STRENGTH study results.
“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,” he said
The STRENGTH trial was funded by AstraZeneca, manufacturer of the omega-3 CA.