REDUCE-IT: High-Dose EPA Also Reduces Subsequent Events

March 29, 2019

NEW ORLEANS — A new analysis of the REDUCE-IT trial has shown that in addition to a large reduction in first ischemic events, the high dose purified form of eicosapentaenoic acid (EPA), icosapent ethyl (Vascepa, Amarin), was also associated with reductions in subsequent and total events.

The REDUCE-IT trial — first reported with great fanfare in November — showed a highly statistically significant 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina with the high-dose omega-3 oil product in patients with raised triglycerides who had cardiovascular disease or diabetes and one additional risk factor, and were already treated with statins.

The current analysis focusing on total events, including first and subsequent events, was presented by lead investigator Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, at the recent American College of Cardiology 68th Annual Scientific Session (ACC) 2019. The study was  published online March 22 in the Journal of the American College of Cardiology (JACC).

"Looking only at first events is a traditional statistical way of doing clinical trials, but from the perspective of patients or healthcare economics, we lose a large part of the pie by ignoring subsequent events," Bhatt said.

Dr Deepak Bhatt

He reported that in addition to the 25% reduction in first ischemic events, icosapent ethyl was associated with a 32% reduction in second events, a 31% reduction in third events, and a 48% reduction in fourth or subsequent events, with total events being reduced by 30% vs placebo.

"These results suggest that if 1000 REDUCE-IT-type patients took icosapent ethyl for 5 years, this would prevent 12 cardiovascular deaths, 42 MIs, 14 strokes, 76 coronary revascularizations and 16 hospitalizations for unstable angina — in total, 159 important ischemic events," Bhatt noted.    

Commenting on these latest results at a press conference, ACC spokesperson Eileen Handberg, PhD, research professor of medicine at the University of Florida in Gainesville, applauded Bhatt and his colleagues for this analysis.  

"We generally don’t see what happens to subsequent events in clinical trials. This analysis has shown that it is possible to impact the subsequent events as well as first events and that is what patients care about.

"If we can continue to reduce this risk it is extremely important. I think this type of analysis should be done in all clinical trials," Handberg said. 

But during the discussion at the session on late-breaking clinical trials, Donald M. Lloyd-Jones, MD, from Northwestern University's Feinberg School of Medicine in Chicago, Illinois, pointed out that subsequent events may not be as reliable an endpoint as first events in randomized trials.

"Once an event has occurred, we lose the balance brought about by randomization, as patients may receive different treatments after having an event, making it more difficult to attribute any difference on subsequent events to the study drug," Lloyd-Jones explained.  

Bhatt acknowledged this as a "legitimate point" but responded: "If the analysis of the time to first-event results were weak, then one would worry about doing total events analysis. But in this case the statistics on the primary endpoint of time to first event were so strong that I think we can be reassured on other analyses such as this one."

He added: "In the context of anti-atherosclerotic medicines, I think looking at total events gives a better sense of what is going on in real life, and patients care just as much about subsequent events as they do about first events." 

Event Reduction Regardless of Triglycerides

Bhatt also presented an analysis showing that total events were reduced with icosapent ethyl throughout the range of baseline triglycerides. 

"The drug was associated with significant reductions in events in all three tertiles of triglycerides, with the highest tertlile showing a particularly large 40% reduction in risk," he reported.

"As we move up the triglyceride tertiles the rates of events go up, but what is regarded as high triglyceride levels is a matter of debate as risk of events is pretty high even in the lowest tertile in this study," Bhatt added. "This leads us to appreciate the large burden of ischemic events that statin patients have at triglyceride levels of 100 mg/dL or above and the potential role of icosapent ethyl in reducing this risk."

The REDUCE-IT trial randomly assigned 8179 statin-treated patients with triglycerides ≥135 and < 500 mg/dL, LDL cholesterol > 40 and ≤100 mg/dL, and a history of atherosclerosis (71% of patients) or diabetes (29% of patients) to icosapent ethyl 4 g/day or placebo.

Results of the current analysis show that after a median follow-up of 4.9 years, 1606 (55.2%) first primary endpoint events and 1303 (44.8%) subsequent primary endpoint events occurred, including 762 second events, and 541 third or more events.

Overall, icosapent ethyl reduced total primary endpoint events (61 vs 89 per 1000 patient years for icosapent ethyl vs placebo, respectively; rate ratio [RR], 0.70; 95% confidence interval [CI] 0.62 - 0.78; P < .0001).

In the JACC paper, the authors point out that the REDUCE-IT patients represent a population at high risk for ischemic events, as suggested by the annualized placebo primary endpoint event rate (5.74%).

The researchers add: "Given the broad inclusion criteria and relatively few exclusion criteria, these results are likely generalizable to a large proportion of at-risk statin-treated patients with atherosclerosis or diabetes."

REDUCE-IT was funded by Amarin Pharma.  Bhatt reports receiving research funding from Amarin. Handberg and Lloyd-Jones have disclosed no relevant financial relationships.

American College of Cardiology 68th Annual Scientific Session (ACC) 2019: Late Breaker IV session. Presented March 18, 2019.

J Am Coll Cardiol. Published online March 22, 2019. Abstract

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