REDUCE-IT Substudy: Higher EPA, Not Lower TGs Associated with Reduced CV Events

March 31, 2020

ACC.20/WCC. Increased blood levels of eicosapentaenoic acid and not reduced triglycerices may explain reduction in cardiovascular events and death seen in REDUCT-IT study.

The markedly reduced rates of cardiovascular (CV) events and death among patients taking the prescription fish oil icosapent ethyl seen in the landmark REDUCE-IT trial may be associated with higher serum levels of the omega-3 fatty acid eicosapentaenoic acid (EPA) and not a decrease in triglyceride levels, according to findings from a REDUCE-IT substudy presented during ACC.20/WCC.

“A major missing piece of the puzzle, and what many clinicians want to know, is how icosapent ethyl actually works to produce such dramatic cardiovascular risk lowering,” said Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and lead author of the current study in an ACC press release. “On-treatment EPA levels achieved via the drug strongly correlated with lower rates of cardiovascular events, heart attack, stroke, coronary revascularization procedures, unstable angina, sudden cardiac arrest, new heart failure, or death for any reason.”

The REDUCE-IT trial, published in Janauary 2019, found that when compared with placebo, icosapent ethyl 4 grams daily led to a reduced combined rate of first and subsequent nonfatal myocardial infarction (MI), stroke, cardiovascular death, coronary revascularization or hospitalizations for unstable angina by 25% and 30%, respectively, over the median of 4.9 years of follow-up. The study included 8,179 patients at 473 sites in 11 countries who had elevated cardiovascular risk and were already taking statins, antiplatelet therapy, and hypertension medications.

In the REDUCE-IT EPA analysis, Bhatt et al found that regardless of initial serum EPA levels prior to randomization, patients derived a similar and large degree of cardiovascular benefit. The researchers note that baseline EPA levels were not available for about 14% of patients, but the baseline characteristics and outcomes between those with and without missing data were similar.

CV events decrease with higher EPA levels

The researchers then examined achieved EPA levels on the drug compared with placebo, grouping patients by tertiles ranging from the lowest to highest levels of EPA and averaged across visits. Achieved EPA within the icosapent ethyl group was strongly associated with cardiovascular events, and each of the tertiles showed a significant relative risk reduction in cardiovascular events.

Looking at on-treatment EPA levels from lowest to highest, they found significant associations with all measured cardiovascular outcomes. “The higher the EPA level in their blood, the lower the rates of the different cardiovascular events, cardiovascular deaths and even total mortality,” said Bhatt.

Results of the analysis showed that overall, the drug significantly increased serum EPA levels by 386% from baseline to one-year compared with placebo. Levels of docosahexaenoic acid (DHA) decreased by 2.9%, which Bhatt says suggests the cardiovascular benefits are clearly from EPA and not DHA.

Other CV events reduced, too

The relationship between on-treatment EPA and other cardiovascular outcomes was also examined. Patients with the highest on-treatment EPA levels experienced a significant reduction in hospitalizations for new heart failure with the drug vs. placebo (no significant reduction in heart failure was seen in the main trial). In addition, there were significant associations between on-treatment EPA levels and lower risks of sudden cardiac death and cardiac arrest. Analyses are underway looking at the association with bleeding and atrial fibrillation.

The researchers caution that the results only apply to the specific icosapent ethyl formulation of EPA, and that EPA within blood can distribute differentially, possibly resulting in differential downstream tissue distribution.

“Changes in triglycerides levels and other cardiovascular risk markers, including LDL, HDL, apoB and CRP, appear to be responsible for a significantly lesser portion of the overall observed benefit,” Bhatt says. “I think this finding is going to usher in a whole new era of cardiovascular therapies. We are, in a sense, where we were with statins when the first one came out.”