Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses

Abstract

Background: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations.

Methods: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

Results: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005).

Conclusions: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Keywords: eicosapentaenoic acid; icosapent ethyl; myocardial revascularization; prevention & control.

Figures

Figure 1.

Kaplan-Meier curve of time to coronary revascularization from randomization: intention-to-treat population. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. ARR is based on the observed rates of events of 9.2% for icosapent ethyl and 13.3% for placebo. ARR indicates absolute risk reduction; HR, hazard ratio; NNT, number needed to treat; No. at risk, number of patients at risk; and RRR, relative risk reduction.

Figure 2.

Time to coronary revascularization from date of randomization by 1-month increments: intention-to-treat population. This figure was constructed by estimating the hazard ratio and 95% CI of the coronary revascularization end point repeatedly with a stratified Cox proportional hazards model (ie, stratified by the 3 randomization factors of REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial): geographic region, cardiovascular risk stratum, and ezetimibe use) by censoring time-to-event data from 30 days until 6 years, with a gap of 30 days between each model. All hazard ratios and the upper and lower limits of 95% CI over the time from 30 days to 6 years were plotted accordingly.

Figure 3.

Kaplan-Meier curves: intention-to-treat population. Kaplan-Meier curves of the time from randomization to elective (A), urgent (B), and emergent (C) coronary revascularization. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. Time to elective coronary revascularization ARR is based on the observed event rates of 4.7% for icosapent ethyl and 6.8% for placebo. Time to urgent coronary revascularization ARR is based on the observed rates of 4.4% for icosapent ethyl and 6.6% for placebo. Time to emergent coronary revascularization ARR is based on the observed event rates of 1.0% for icosapent ethyl and 1.6% for placebo. ARR indicates absolute risk reduction; HR, hazard ratio; NNT, number needed to treat; No. at risk, number of patients at risk; and RRR, relative risk reduction.

Figure 4.

Kaplan-Meier curves: intention-to-treat population. Kaplan-Meier curves of time from randomization to percutaneous coronary intervention (A) or coronary artery bypass graft surgery (B). The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. Time to percutaneous coronary intervention ARR is based on the observed event rates of 7.7% for icosapent ethyl and 10.9% for placebo. Time to coronary artery bypass graft ARR is based on the observed event rates of 1.9% for icosapent ethyl and 3.0% for placebo. ARR indicates absolute risk reduction; HR, hazard ratio; NNT, number needed to treat; No. at risk, number of patients at risk; and RRR, relative risk reduction.

Figure 5.

Distribution of first and subsequent coronary revascularization events in the reduced data set for patients randomly assigned 1:1 to icosapent ethyl vs placebo. Hazard ratios (HRs) and 95% CIs for between-group comparisons were generated using Li-Lagakos–modified Wei-Lin-Weissfeld method for first and second event categories. Rate ratio (RR) and 95% CI for group comparisons used a negative binomial model for additional events beyond first and second occurrences, that is, third event or more and overall treatment comparison. Analyses are based on reduced data set accounting for statistical handling of multiple end points occurring in a single calendar day by counting as a single event.