Objective

To evaluate the benefit and safety of icosapent ethyl in patients with a recent ACS.

Study design

Post hoc analysis of REDUCE-IT, a randomized, double-blind, placebo-controlled trial. 

Study population 

REDUCE-IT included 8179 statin-treated patients with controlled low-density lipoprotein cholesterol (LDL-C) levels and moderately elevated triglycerides (TGs), and with either established cardiovascular disease or with diabetes and at least one additional risk factor. This post hoc analysis included 840 patients (median age 59.5 years, 76.9% male, 36.9% with diabetes) with a recent ACS, defined as a myocardial infarction (MI) or unstable angina within 12 months before randomization.  Almost all patients (99.9%) were on statin treatment, and 805 (95.8%) received antiplatelet therapy.  The median time between the index ACS and randomization was similar in patients in the icosapent ethyl and placebo groups (5.5 vs. 5.6 months). 

Main study variable

Primary outcome: The primary efficacy outcome of REDUCE-IT was a composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was a composite of first cardiovascular death, non-fatal MI, or non-fatal stroke.

Methods

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 determined using a Cox proportional hazards model. Time-to-subsequent events was analysed using the Wei, Lin, and Weissfeld model to estimate HR and 95% CI for treatment effects.

Results

Treatment with icosapent ethyl was associated with 37% reduction in the incidence of first primary endpoint and 36% reduction in total primary events (Table 1). The absolute risk reduction (ARR) in the first primary outcome with icosapent ethyl was 9.3% (number needed to treat [NNT] 11, 95% CI 7–28). The benefit from icosapent ethyl was less in 3651 patients with an ACS ≥12 months before randomization, with 22.0% relative risk reduction (HR 0.78; 95% CI 0.68–0.90) and ARR 4.7% (NNT 21).

Table 1. Effect of icosapent ethyl on primary events in ACS patients in REDUCE-IT

Treatment with icosapent ethyl also reduced first key secondary composite events by 36% (HR 0.64; 95% CI 0.44–0.92, p=0.01) and total key secondary events by 28% (relative risk 0.72; 95% CI 0.47–1.09), although this latter result was not statistically significant. 

In patients with a recent ACS, the incidence of treatment-emergent adverse events did not differ between the two treatment groups (78.8% for icosapent ethyl vs. 76.7% for placebo). Additionally, there was no difference in the incidence of total bleeding events (6.9% vs. 8.1%, respectively) or bleeding-related serious adverse events (1.6% vs. 3.2%). 

Author conclusions

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