Effects of icosapent ethyl on residual cardiovascular risk according to predicted baseline risk: results from REDUCE-IT

Abstract

Abstract Background Icosapent ethyl is recommended by the ESC CVD Prevention Guidelines as one of the intensified prevention strategies to be considered in patients with established CVD and a high residual risk.[1] Treatment effects of icosapent ethyl may vary between individual patients. This study aimed to determine the relative and absolute treatment effects of icosapent ethyl according to baseline CVD risk. Methods Participants from the REDUCE-IT trial with established CVD were included (n = 5,785).[2] Baseline 5-year risk of major adverse cardiovascular events (MACE), defined here as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was estimated using the ESC guideline-recommended SMART2 risk score.[3] Modification of the relative treatment effect of icosapent ethyl by baseline risk was assessed using a Cox proportional hazards model including a treatment-by-risk interaction. Next, relative treatment effects were derived stratified by quartiles of baseline risk. The observed 5-year absolute risk reduction (ARR) with icosapent ethyl within each risk quartile was assessed based on Kaplan-Meier estimates of the cumulative incidence of MACE. Results During a median follow-up of 4.8 years (interquartile range 3.2-5.3), 361 MACE events occurred in the icosapent ethyl group vs 489 in the placebo group (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.63-0.82). Mean predicted vs observed 5-year risk of MACE was 9.1% vs 10.2% in the first quartile (range 3.6-11.4%), 13.8% vs 14.6% in the second quartile (range 11.5-16.0%), 19.2% vs 19.5% in the third quartile (range 16.1-23.4%), and 33.4% vs 32.2% in the fourth quartile (range 23.5-83.0%). 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 = 0.06). The 5-year ARR (95% CI) with icosapent ethyl increased across risk quartiles, i.e. was 5.3% (1.8-8.7%), 5.6% (1.9-9.4%), 7.4% (3.0-11.8%), and 10.8% (5.3-16.2%) respectively (Figure). This translates to a number needed to treat (NNT; 95% CI) of 19 (11-54), 18 (11-52), 14 (8-34), and 9 (6-19). Conclusions Among CVD patients with elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE in individuals with a low, moderate, and high baseline risk. Absolute treatment benefits are largest for patients at the highest risk, as reflected by the twofold increase in ARR and decrease in NNT in the highest as compared to the lowest risk quartile.Icosapent ethyl effect in risk quartiles