Cardiovascular Outcomes With Icosapent Ethyl by Baseline Low-Density Lipoprotein Cholesterol: A Secondary Analysis of the REDUCE-IT Randomized Trial

Abstract

Background: The efficacy of icosapent ethyl among patients with very well-controlled baseline low-density lipoprotein cholesterol (LDL-C) is unknown.

Methods: In this post hoc analysis of the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized clinical trial, statin-treated patients with high cardiovascular risk, elevated triglycerides (135-499 mg/dL), and baseline LDL-C of 41 to 100 mg/dL were included. Patients were randomized to icosapent ethyl (2 g twice daily) or placebo and then post hoc stratified by baseline LDL-C (<55 mg/dL versus ≥55 mg/dL). The primary composite end point included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.

Results: Among 8175 patients with baseline LDL-C data, 7117 (87.1%) had LDL-C ≥55 mg/dL and 1058 (12.9%) had LDL-C <55 mg/dL. In patients with LDL-C <55 mg/dL, the rate of the primary composite end point was lower in the icosapent ethyl group (16.2% versus 22.8%) than in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; absolute risk reduction, 6.6%; P=0.003). Among patients with LDL-C ≥55 mg/dL, a primary composite end point event occurred in a lower proportion of patients in the icosapent ethyl group (17.4% versus 21.9%) than in the placebo group (HR, 0.76 [95% CI, 0.69-0.85]; absolute risk reduction, 4.5%; P<0.0001). No significant interaction was observed between baseline LDL-C and treatment group (P for interaction=0.40). Findings were consistent among secondary cardiovascular end points and in sensitivity analyses.

Conclusions: Among statin-treated patients with elevated triglycerides and high cardiovascular risk, icosapent ethyl reduced the rate of cardiovascular end points irrespective of baseline LDL-C, including among eligible patients with optimal LDL-C control.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Keywords: cardiovascular outcomes; icosapent ethyl; low‐density lipoprotein cholesterol.

Figure 1. Kaplan–Meier plot of primary composite end point by baseline LDL‐C.

Presented are the Kaplan–Meier plots of the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina). Patients were randomized to icosapent ethyl (2 g twice daily) or placebo. Patients were stratified by baseline LDL‐C (<55 mg/dL and ≥55 mg/dL). Interaction P value for treatment effect by baseline LDL‐C group was 0.40. A, LDL‐C <55 mg/dL (N=1058). B, LDL‐C ≥55 mg/dL (N=7117). ARR indicates absolute risk reduction; LDL‐C, low‐density lipoprotein cholesterol; and NNT, number needed to treat.

Figure 2. Efficacy of icosapent ethyl by baseline LDL‐C.

Presented is the treatment hazard ratio of icosapent ethyl compared with placebo (y axis) for the primary composite end point by baseline LDL‐C (x axis). The primary composite end point included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. Baseline LDL‐C was evaluated continuously in this analysis using a natural cubic spline with knots placed at the 25th percentile, median, and 75th percentile of LDL‐C. A hazard ratio of <1 indicates benefit with icosapent ethyl. The x axis range covers the 1st to 99th percentile of LDL‐C values (35–133 mg/dL). HR indicates hazard ratio; and LDL‐C, low‐density lipoprotein cholesterol.

Figure 3. Kaplan–Meier plot of key secondary composite end point by baseline LDL‐C.

Presented are the Kaplan–Meier plots of the key secondary composite end point (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Patients were randomized to icosapent ethyl (2 g twice daily) or placebo. Patients were stratified by baseline LDL‐C (<55 mg/dL and ≥55 mg/dL). Interaction P value for treatment effect by baseline LDL‐C group was 0.11. ARR indicates absolute risk reduction; LDL‐C, low‐density lipoprotein cholesterol; and NNT, number needed to treat. A, LDL‐C <55 mg/dL (N=1058). B, LDL‐C ≥55 mg/dL (N=7117).

Figure 4. Forest plot of primary and secondary end points by baseline LDL‐C.

Presented is the forest plot of the primary and secondary end points. Patients were stratified by baseline LDL‐C (<55 mg/dL versus ≥55 mg/dL). Patients were randomized to icosapent ethyl (2 g twice daily) or placebo. The primary composite end point included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. A hazard ratio <1 indicates benefit with icosapent ethyl. ARR indicates absolute risk reduction; LDL‐C, low‐density lipoprotein cholesterol; and NNT, number needed to treat.