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The omega-3 fatty acid eicosapentaenoic acid (EPA) was crucial to the mechanism by which icosapent ethyl (Vascepa) conferred cardiovascular (CV) benefits in REDUCE-IT, an analysis of the trial showed.

People entered the trial with a baseline median EPA concentration of 26.1 µg/mL. On-treatment daily average EPA increased to 135.2 µg/mL among icosapent ethyl users and 27.7 µg/mL in the placebo group, the between-group absolute difference of 103.8 µg/mL being significant (P<0.0001), according to Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital in Boston.

Icosapent ethyl's 25% reduction in the primary endpoint -- time from randomization to the first occurrence of composite of CV death, MI, stroke, coronary revascularization, and unstable angina requiring hospitalization -- was found to correlate strongly with EPA concentration over the course of the trial (HR 1.03, 95% CI 0.91-1.16), Bhatt told the audience at the .

CV risk reduction corresponded to a lesser degree with other biomarkers such as triglycerides, LDL cholesterol, and hsCRP levels over the roughly 5-year follow-up of REDUCE-IT.

"These benefits were beyond what can be explained by the degree of triglyceride or other biomarker changes," Bhatt said. "The lion's share of benefit from this drug was in fact due to achieved EPA levels."

A proprietary prescription fish oil product containing pure EPA, icosapent ethyl was shown in the REDUCE-IT trial to work for primary and secondary prevention in people with established CV disease (or diabetes and other risk factors) who had elevated triglyceride levels despite at least 4 weeks of statin use. However, the exact mechanism underlying the benefit wasn't clear.

The trial had more than 8,000 patients randomized to icosapent ethyl 4 g/day or placebo.

In the present study, REDUCE-IT data showed that on-treatment EPA levels via icosapent ethyl correlated strongly with other endpoints, such as CV death, MI, stroke, coronary revascularization, unstable angina, sudden cardiac death, cardiac arrest, new heart failure, and all-cause mortality, according to Bhatt.

"These data provide a mechanistic underpinning for the large risk reductions seen in multiple endpoints with icosapent ethyl in REDUCE-IT," he concluded.

But the finding of reduced heart failure with the drug needs further exploration, commented Eugene Yang, MD, of the University of Washington School of Medicine in Bellevue, during an ACC press conference. He added that the relationship between EPA level and major bleeding also requires further examination.

On-treatment dose-response analyses of the HR for bleeding, serious bleeding, and atrial fibrillation/flutter are not yet available from REDUCE-IT.

Investigators observed that baseline serum EPA concentration had no effect on the CV event rates. However, 14% of trial participants did not have baseline EPA levels taken, Bhatt acknowledged.

Discussant Gregory Schwartz, MD, of Denver Veterans Affairs Medical Center and University of Colorado Medicine, asked Bhatt to compare the EPA bump achieved with icosapent ethyl versus other sources during the ACC late-breaking trial session.

"You can't achieve these EPA levels naturally even if one is eating multiple servings of fish a day," Bhatt replied. "You would need to take 20, 30 [fish oil] supplement pills ... It's not a way I would recommend to achieve this level of EPA."

One year after the release of the REDUCE-IT study, icosapent ethyl was granted FDA approval for the indication of CV risk reduction.

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