Total Event Analysis from REDUCE-IT Showcases a Substantial Reduction in the Burden of Ischemic Events, Experts Debate Possible Mechanisms of Action of Icosapent Ethyl Presented at ACC 2019, New Orleans, Los Angeles

The total event analysis from the REDUCE-IT trial, presented at ACC 2019 showed that among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, icosapent ethyl substantially reduced the burden of first, subsequent, and total ischemic events. The results are exciting as this is one of the first non-LDL targeted trials to demonstrate a cardiovascular benefit, and is likely to be featured in future guidelines.

The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dL (median baseline of 216 mg/dL) and LDL-cholesterol >40 and ≤100 mg/dL (median baseline of 75 mg/dL), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Inclusion criteria comprised of the following: age >45 years with established CV disease or age >50 years with diabetes and ≥1 additional risk factor, fasting TG level from 150-499 mg/dl, Low-density lipoprotein (LDL) cholesterol level from 41 and 100 mg/dl and on a stable dose of statin for ≥4 weeks. In time-to-first-event analyses that were published in the New England Journal of Medicine, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. According to this analysis, the primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary endpoint were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). However, lead author Dr. Deepak Bhatt, Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital, believed that these patients were at risk for not only first but also subsequent ischemic events. Therefore, as a pre-specified statistical method, Bhatt and his colleagues aimed to determine differences in total events using negative binomial regression. They also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint-frailty analysis.

The results were staggering. In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762-second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 versus 89 per 1000 patient years for icosapent ethyl versus placebo, respectively; RR 0.70, 95% CI 0.62-0.78, P<0.0001). Icosapent ethyl also reduced each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 versus 44 per 1000 patient years for icosapent ethyl versus placebo, respectively, RR 0.72, 95% CI 0.63-0.82, P<0.0001). Clearly, the results of analyses using varied statistical models presented for REDUCE-IT (median follow-up of 4.9 years) demonstrate one thing, that icosapent ethyl 4 grams daily significantly reduced the rate of total primary endpoint events (RR 0.70, 95% CI 0.62-0.78, P<0.0001), each primary endpoint component, including cardiovascular death, and total key secondary endpoint events in statin-treated patients with elevated triglycerides and established cardiovascular disease or diabetes at risk for not only first but also subsequent ischemic events.

In an accompanying editorial titled ‘FISHing for the Miracle of Eicosapentaenoic Acid’ written by John J.P. Kastelein, M.D., Ph.D., and Erik S.G. Stroes, M.D., Ph.D. from the Academic Medical Center, University of Amsterdam, the authors speculate about the mechanism of action. While fish oils were known to reduce levels of proinflammatory eicosanoids and increase production of anti-inflammatory mediators, in REDUCE-IT, icosapent ethyl reduced C-reaction protein levels. “Extrapolating from the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), we estimated that the observed reduction in C-reactive protein level (0.65 mg per liter) from baseline would be likely to account for only an additional 5% lower risk of ischemic events,” they noted. Other potential mechanisms of action of icosapent ethyl include its effects on inflammation and on the development, progression, and rupture of the arterial plaque, as well as an antiarrhythmic effect. The observation of 30% fewer sudden cardiac deaths in the icosapent ethyl group in a tertiary analysis may provide support for the latter effect. However, according to them, these effects, even when combined, could not fully explain the results of REDUCE-IT. Echoing these sentiments in an interview at ACC, lead author Dr. Bhatt stated, “ I think even though we focus on the drug initially as a triglyceride-lowering drug, indeed its been approved by the FDA for use in patients with triglycerides of ≥500. Our goal in REDUCE-IT was to look at its effect on ischemic events, not triglycerides. The drug certainly reduces triglycerides by a significant amount. But it’s likely that it also has other effects, anti-inflammatory effects. Prior work has shown cell membrane stabilizing effects that might amount for significant reduction in sudden cardiac death and cardiac arrest. So, I think it’s one of the situations to use the word of pleiotropy- i.e. it reduces triglycerides but there are probably other effects at play as well.”

Highlighting the importance of the present findings, Dr. Bhatt emphasized, “In concert, icosapent ethyl really leads to a significant reduction in ischemic events, if anything, we underappreciated it with the initial analysis and now, we can get a sense of the full totality of the contribution of the drug in the reduction of the atherosclerotic burden. It’s good for patients obviously, but it also has implications in terms of effectiveness. Reducing events like cardiovascular death, that’s pretty intuitive, that’s a good thing from a healthcare economics perspective, even reducing coronary artery revascularization and hospitalization for UA is important as there’s a lot of economic cost to those. I think both from a patient perspective and a cost-effectiveness perspective, it’ll do a lot for patient care.” Referring to the next step, he added, “Having said that, we do have a biomarker analysis to answer the question more scientifically to what the mechanism of benefit might be. We also have formal cost-effective analyses that have been started. So there’s a lot more to come from REDUCE-IT trial.”

Dr. Christopher Cannon, Education Director, Cardiovascular Innovation, Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School, also expressed his excitement, stating how impressed he was by the practicality of the findings. He commented, “The total event analyses from the REDUCE-IT trial were very impressive. They reported a 25% first event reduction, which was highly significant, but as is amazing to me, they found that beyond that, there is almost double the number of second, third and fourth events. So, another 45% of the total number of events, which is twice as much benefit as we knew the last time we heard about the trial. To see the benefit over time is very reassuring that this is a real finding and one that can impact the course of a given patient. So what’s exciting for me is that it’s been all about LDL(lower is better), but then they got everyone to just about 70 and then look at the triglycerides. If triglycerides are ≥135, then you have a second intervention to add to the therapy to get these robust benefits, so it is very practical.” Expressing their optimism on the study results, Kastelein, M.D., Ph.D., and Erik S.G. Stroes concluded, “After a parade of failed cardiovascular outcome trials of fish oils, REDUCE-IT has shown a substantial benefit with respect to major adverse cardiovascular events. More data are needed to confirm these effects and to inform an understanding of the mechanism of action, the uniqueness of the compound tested, and the potential influence of mineral oil as the comparator. However, the finding that the risks of several cardiovascular outcomes were significantly and consistently lower with icosapent ethyl than with placebo make us hopeful that the use of icosapent ethyl can substantially improve cardiovascular health in patients with statin-controlled LDL cholesterol levels who have elevated triglyceride levels.”

To view the interview with Dr. Deepak Bhatt, click here.

To view the slides presented at ACC 2019, click here.