Effects of icosapent ethyl according to baseline residual risk in patients with atherosclerotic cardiovascular disease: results from REDUCE-IT

Abstract

Aims: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline cardiovascular disease (CVD) risk in patients with atherosclerotic cardiovascular disease (ASCVD).

Methods and results: Participants from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with ASCVD were included (n = 5785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the European Society of Cardiology (ESC) guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models, including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs. 489 patients in the icosapent ethyl vs. placebo group [95% confidence interval (CI)]; hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), and 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96), respectively (P for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%), respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%), respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina.

Conclusion: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk.

Keywords: Atherosclerotic cardiovascular disease; Eicosapentaenoic acid; Icosapent ethyl; Residual risk; Secondary prevention; Triglycerides.

Graphical Abstract

Figure 1

Calibration of the SMART2 and SMART-REACH risk models across CVD risk quartiles. Mean predicted (by the SMART2 risk score) vs. observed 5-year risk of 3-point MACE (A), and mean predicted (by the SMART-REACH model) vs. observed 5-year survival free of 3-point MACE (B) across CVD risk quartiles. Error bars represent 95% confidence intervals. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Figure 2

Relative treatment effects of icosapent ethyl across CVD risk quartiles. Relative treatment effects of icosapent ethyl on the risk of 3-point MACE (A) and 5-point MACE (B) in the CVD risk quartiles. The P-value is for the interaction between baseline risk and the relative treatment effect of icosapent ethyl. The grey dotted line denotes the overall trial hazard ratio. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Figure 3

Absolute treatment effects of icosapent ethyl on 3-point MACE across CVD quartiles. Kaplan-Meier curves of the cumulative incidence of 3-point MACE in participants randomized to icosapent ethyl and placebo within each CVD risk quartile. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Figure 4

Absolute treatment effects of icosapent ethyl on 5-point MACE across CVD risk quartiles. Kaplan-Meier curves of the cumulative incidence of 5-point MACE in participants randomized to icosapent ethyl and placebo within each CVD risk quartile. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Figure 5

Lifetime benefit from icosapent ethyl across CVD risk quartiles. Average predicted survival free of 3-point MACE on placebo and on icosapent ethyl within each CVD risk quartile. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Figure 6

Continuous relation between baseline risk and the effects of icosapent ethyl. The continuous relation between baseline 5-year risk of 3-point MACE and the relative and absolute treatment effects of icosapent ethyl on the risk of 3-point MACE, derived from restricted cubic spline functions. The dotted lines denote 95% confidence intervals. The histogram shows the distribution of baseline risk in the study population Abbreviation: MACE, major adverse cardiovascular events.