Potential effects of icosapent ethyl on cardiovascular outcomes in cigarette smokers: REDUCE-IT smoking

AIMS: Cigarette smoking is among the most well-established risk factors for adverse cardiovascular outcomes. We sought to determine whether icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid with antiatherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking. METHODS AND RESULTS: Reduction of Cardiovascular Events with Icosapent Ethyl Trial (REDUCE-IT) was a multinational, double-blind trial that randomized 8179 statin-treated patients with elevated triglycerides and CV risk to IPE or placebo, with a median follow-up period of 4.9 years. Icosapent ethyl reduced the primary composite endpoint [CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or hospitalization for unstable angina] by 25% (P < 0.0001). In the current analyses, the effect of IPE was evaluated in REDUCE-IT using post hoc analyses based on smoking history. Groups were classified as current smokers (n = 1241), former smokers (n = 3672), and never smokers (n = 3264). Compared with placebo, IPE use in combined current and former smokers (n = 4913) was associated with significant reductions in time to the primary composite endpoint {hazard ratio: 0.77 [95% confidence interval (CI): 0.68–0.87]; P < 0.0001} and in total events [rate ratio: 0.71 (95% CI: 0.61–0.82); P < 0.0001]. These benefits remained significant when subdivided into current and former smokers (P = 0.04, P = 0.005), with reductions in the key secondary composite endpoint (P < 0.0001) and in the individual components of CV death or non-fatal MI (P = 0.04, P = 0.01) and fatal or non-fatal MI (P = 0.009, P = 0.01), respectively. Benefits were consistent and significant in non-smokers as well. Overall, there were similar estimated rates of first occurrences of primary CVD endpoints in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%). CONCLUSION: In REDUCE-IT, IPE treatment was associated with a reduced risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may attenuate CV hazards attributable to smoking.