Icosapent ethyl following acute coronary syndrome: the REDUCE-IT trial

,


Introduction
The REDUCE-IT [Reduction of Cardiovascular Events With Icosapent Ethyl (IPE)-Intervention Trial] trial showed robust reductions in ischaemic events with IPE vs. placebo, including reduced cardiovascular (CV) death, albeit with increased rates of bleeding, and of atrial fibrillation (AF). 1 These observations were confirmed in patients with prior myocardial infarction (MI). 2 Patients with recent (<12 months) acute coronary syndrome (ACS) are at very high risk of future CV events (including arrhythmias) for which they usually receive intensive antithrombotic therapy, which might increase bleeding risk with IPE.The benefit and safety of IPE in this specific patient subgroup are largely unknown and were explored in the present post hoc analysis of the original trial database.

Methods
REDUCE-IT was a double-blind, placebo-controlled trial that randomized 8179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides, and with either established CV disease or with diabetes and at least one additional risk factor, to either 4 g IPE or placebo. 1 The trial methods and results have previously been published. 1,3The primary outcome was a composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina.The key secondary outcome was a composite of CV death, non-fatal MI, or non-fatal stroke.
Recent ACS (n = 840) was defined as MI or unstable angina within 12 months before randomization.In subsequent analyses, this group was compared with patients experiencing ACS ≥12 months before randomization (n = 3651).Time-to-first event was analysed by Kaplan-Meier analysis and compared using the log-rank test.Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a Cox proportional hazards model computed to determine the risk of primary and secondary outcomes according to the use of IPE vs. placebo in two-sided analyses.The model was stratified by the three randomization factors of CV risk category (established CV disease or diabetes plus risk factors), geographic region, and baseline ezetimibe use.Time-to-subsequent events was analysed using the Wei, Lin, and Weissfeld model to estimate HR and 95% CI for treatment effects.Total events were analysed by negative-binomial regression model to estimate rate ratio (RR) and 95% CI for treatment effects.Absolute risk reduction (ARR) was calculated as difference of event incidence rates between IPE and placebo.Statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc.).
In contrast, among recent ACS patients, the proportion of patients with at least one treatment-emergent adverse event (TEAE) did not differ between treatment arms (78.8% for IPE vs. 76.7% for placebo, Fisher's exact P = .51),nor did total bleeding or bleeding-related Figure 1 (A) First and subsequent events for the primary composite outcome in patients with recent ACS. (B) Cumulative incidence curves of the primary composite outcome in patients with recent ACS serious adverse events (6.9% vs. 8.1%, Fisher's exact P = .60and 1.6% vs. 3.2%, Fisher's exact P = .17,respectively).Among recent ACS patients who were on DAPT at study entry (n = 584), the percentage with at least one treatment-emergent bleeding adverse event was 7.7% in the IPE arm and 9.4% with placebo (Fisher's exact P = .46).No haemorrhagic strokes occurred in either arm.Similar to the overall trial, among recent ACS patients, TEAEs of AF or flutter were higher in the IPE arm than with placebo (7.4% vs. 2.9%, Fisher's exact P = .005),as was the safety endpoint of hospitalizations for AF or flutter (4.8% vs. 1.7%, log-rank P = .01).

Discussion
In REDUCE-IT patients with recent ACS (<12 months before randomization), IPE dramatically reduced ischaemic CV events compared with placebo, apparently more dramatically than in the overall trial (ARR of 9.3%, NNT of 11 vs. ARR 4.8%, NNT of 21). 1 This benefit accrued without increased bleeding, even in patients receiving DAPT.5][6][7][8] On the other hand, the risk of AF or flutter was increased with IPE, as previously reported in REDUCE-IT 1,2 and in other trials of omega 3 fatty acids, 9,10 but with no increased risk of stroke.Given the post hoc nature of this analysis and the lack of adjustment for multiplicity, these results should be interpreted with caution and require further confirmation.However, these findings reaffirm the importance of targeting high-risk patients to achieve substantial benefit and the importance of targeting patients with elevated triglycerides early after ACS (within 12 months after the index event).

Conclusion
In this post hoc subgroup analysis of REDUCE-IT, IPE dramatically reduced the risk of ischaemic events in high-risk, statin-treated patients with recent ACS (<12 months), without excess bleeding.This supports initiation of IPE in REDUCE-IT-eligible patients as soon as possible after ACS.