REDUCE-IT Subanalysis: Icosapent Ethyl Reduces Total and Recurrent CV Events

Looking beyond first events matters to patients and also warrants attention from a broader health economics perspective, the lead investigator says.

REDUCE-IT Subanalysis: Icosapent Ethyl Reduces Total and Recurrent CV Events

NEW ORLEANS, LA—A recurrent event analysis of the REDUCE-IT trial demonstrates that icosapent ethyl (Vascepa; Amarin), a prescription omega-3 fatty acid formulation, reduces total cardiovascular events by 30% in a cohort of statin-treated patients with high triglyceride levels and either established cardiovascular disease or diabetes plus risk factors. Additionally, first, second, third, and fourth or more events were also reduced substantially.

“In the context especially of anti-atherosclerotic medicines, looking at total events provides a better sense of what actually is going on in real life,” said Deepak L Bhatt, MD, MPH (Brigham and Women’s Hospital, Boston, MA), who presented the findings this week in a late-breaking trial session at the American College of Cardiology (ACC) 2019 Scientific Session. “From a patient’s perspective, they don't really think time to first event, they care about that second and third or fourth event, especially if it's a fatal event.”

As reported by TCTMD and published in the New England Journal of Medicine (NEJM), REDUCE-IT showed the success of icosapent ethyl in reducing the first occurrence of both MACE (CV death, MI, stroke, coronary revascularization, or unstable angina) and a key secondary composite endpoint of CV death, MI, or stroke over a median follow-up of 4.9 years in more than 8,000 international patients who were at least 45 years old and had established CVD (secondary prevention cohort) or who were at least 50 years old and had diabetes and at least one additional CVD risk factor (primary prevention cohort).

In a panel discussion following Bhatt’s presentation, Lynne Braun, PhD, CNP (Rush University Medical Center, Chicago, IL), called the findings of this secondary analysis, which were simultaneously published in the Journal of the American College of Cardiology, “as impressive as the first results.”

The findings confirm that icosapent ethyl “should be strongly considered to reduce residual risk in patients with elevated triglycerides receiving statin therapy,” Bhatt and colleagues write.

Total Event Results

Of the total 2,909 adjudicated MACE events from the full data set, 55% were deemed to be first events. Fatal or nonfatal MIs made up the largest proportion of first events (33%), while coronary revascularizations made up the majority of subsequent events (60%).

Compared with patients in the placebo arm, those treated with icosapent ethyl had 25% fewer first events (HR 0.75; 95% CI 0.68-0.83), 32% fewer second events (HR 0.68; 95% CI 0.60-0.78), 31% fewer third events (HR 0.69; 95% CI 0.59-0.82); and 48% fewer fourth or more events (RR 0.52; 95% CI 0.38-0.70). This summed up to 30% fewer total events with the study drug over the 4.9-year follow-up (RR 0.70; 95% CI 0.62-0.78).

While drug adherence in both cohorts waned over time, there appeared to be a sustained treatment effect on total events. Icosapent ethyl was also associated with a reduction of total secondary endpoint events (RR 0.72; 95% CI 0.63-0.82).

All findings were upheld in a variety of statistical analyses, including one in which patients were stratified by baseline triglycerides.

“Analysis of first recurrent and total events demonstrates the large burden of ischemic events in statin-treated patients with baseline triglycerides greater than approximately 100 mg/dL and the potential role of icosapent ethyl in reducing this residual risk,” Bhatt concluded. “For every 1,000 patients treated with icosapent ethyl for 5 years, 12 cardiovascular deaths would be averted, 42 fatal or nonfatal heart attacks would be averted, 14 fatal or nonfatal strokes would be averted, 76 coronary revascularizations would be avoided, and 16 hospitalizations for unstable angina would be avoided, for a total of 159 ischemic events that could be prevented.”

Panel Discussion

Panelist Vera Bittner, MD (University of Alabama at Birmingham), said she “was struck by the very different distribution of events when you look at first events and subsequent events.” She asked whether all revascularizations that occurred were ischemia-driven as well as what the impact of icosapent ethyl was on the different subcomponents of the recurrent events.

“Similar to what we’ve done in ODYSSEY, we've done a joint frailty model here and saw a significant reduction in cardiovascular death as well as in nonfatal events,” Bhatt replied. “Each of the components of that primary endpoint was significantly reduced, both in the time-to-first-event analysis that was published in NEJM and now in the total events analysis as published in JACC. So whether it’s cardiovascular death, MI, stroke—that’s all-cause stroke—revascularization for coronary purposes, or hospitalization for unstable angina, each of those was significantly reduced.”

The revascularizations were both urgent and elective, and all were “significantly reduced,” he continued. “I’ll point out that all those data are from a blinded trial and the adjudication . . . was all done blinded. Of course, sometimes people say revascularization can be subjective in the eyes of the performing physician, but here those endpoints were all blindly adjudicated. So I think we can take those sorts of endpoints to the bank.”

Additionally, panelist Donald Lloyd-Jones, MD (Northwestern University, Chicago, IL), complimented the researchers on their statistical methods. “You're clearly using state-of-the-art approaches to really understand what's a difficult problem to tease out,” he said. “Once an event has occurred, obviously you lose the balance that is given to us by randomization because now patients have to be treated differently because they've had a first event. I'm wondering if you can comment on interpreting this because it becomes a little more difficult to ascribe the causation, if you will, to the study drug because now we’re getting very different treatments in the patients who had events.”

The research team took a “more conservative approach” to their statistical analyses for this analysis than the prespecified methodologies they had submitted to the US Food and Drug Administration in the original trial, and they were rewarded with a “very high degree of statistical assurance,” Bhatt explained. “In terms of total events and potential confounding by subsequent treatments, it's a legitimate point. That’s why we led with time-to-first-event analyses that were presented at AHA and published in the NEJM. That’s the most rigorous way to always evaluate data.”

In addition to being what patients care about, total events “really matter” from a health economic perspective, he observed. “I agree with you, if the time-to-first-event analyses were weak, that one must worry about doing total events analyses, but in this case,  I think we can be pretty reassured. It's not the situation, say, with antithrombotics and anticoagulants for A-fib where if you have a stroke then maybe the doctor will put you on certain open-label therapies or dual antiplatelet therapy trials where if you have an ischemic event, you'll go off the study drug and then go onto some open-label drug. Here that was less likely to occur given the type of drug we were studying.”

Looking forward, Bhatt and colleagues write that “ongoing analyses of multiple biomarkers collected in REDUCE-IT may provide additional insight into the biological mechanisms behind the large degree of relative and absolute risk reductions with icosapent ethyl seen in a variety of important ischemic events, including cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization.”

  • REDUCE-IT was sponsored by Amarin Pharma.
  • Bhatt reports receiving grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Roche, Eisai, Ethicon, Medtronic, Sanofi Aventis, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, Ironwood, Abbott, Regeneron, PhaseBio, Idorsia, Synaptic, and The Medicines Company; receiving unfunded research support from FlowCo, PLx Pharma, Novo Nordisk, Takeda, and Merck; serving on the advisory boards of Medscape Cardiology, Regado Biosciences, and Cardax; serving on the board of directors of the Boston VA Research Institute; being the deputy editor of Clinical Cardiology; being a site coinvestigator for Biotronik, Boston Scientific, Svelte, and St. Jude Medical (now Abbott); receiving honoraria from the American College of Cardiology (ACC); serving on clinical trial committees funded by Bayer and Boehringer Ingelheim; receiving personal fees from the Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, the Society of Cardiovascular Patient Care, HMP Global, the Harvard Clinical Research Institute (now Baim Institute for Clinical Research), the Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, and TobeSoft; and receiving nonfinancial support from the ACC, the American Heart Association, and the Society of Cardiovascular Patient Care.