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 anti-atherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking.
Methods and results: 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. IPE reduced the primary composite endpoint (CV death, nonfatal myocardial infarction [MI], nonfatal 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 upon 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% 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 nonfatal MI (P = 0.04, P = 0.01) and fatal or nonfatal MI (P = 0.009, P = 0.01), respectively. Benefits were consistent and significant in nonsmokers 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 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.
Keywords: REDUCE-IT; cardiovascular disease; cardiovascular risk factors; clinical trial; hypertriglyceridemia; icosapent ethyl; smoking.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.