In REDUCE-IT, the risk of the primary composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, assessed in a time-to-event analysis, was significantly lower, by 25%, among the patients who received 2 g of icosapent ethyl twice daily than among those who received placebo, corresponding to an absolute between-group difference of 4.8 percentage points in the rate of the end point and a number needed to treat of 21. The risk of the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis was also significantly lower, by 26%, in the icosapent ethyl group than in the placebo group, corresponding to an absolute between-group difference of 3.6 percentage points in the rate of the end point and a number needed to treat of 28. Prespecified hierarchical testing of other secondary end points revealed that the risks of a variety of fatal and nonfatal ischemic events were lower in the icosapent ethyl group than in the placebo group, including a 20% lower risk of cardiovascular death. The benefits were observed against a background of appropriate statin use among patients who had a median LDL cholesterol level of 75.0 mg per deciliter at baseline.

The overall rates of adverse events were similar in the trial groups. Serious adverse events related to bleeding occurred in more patients in the icosapent ethyl group than in the placebo group, although the overall rates were low; there were no fatal bleeding events in either group, and the rates of adjudicated hemorrhagic stroke, serious central nervous system bleeding, and serious gastrointestinal bleeding were not significantly higher in the icosapent ethyl group than in the placebo group. The rate of hospitalization for atrial fibrillation or flutter was significantly higher in the icosapent ethyl group than in the placebo group, although the rates were low. The rates of adverse events and serious adverse events leading to discontinuation of trial drug were similar in the two groups.

The results of REDUCE-IT stand apart from the negative findings of several contemporary trials of other agents that also lower triglyceride levels, including other n−3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors.10-13 It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA).12,13 Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n−3 fatty acids. JELIS, which compared a combination of statin therapy and pure EPA with statin therapy alone, showed that the risk of ischemic events was significantly lower in the group that received the combination treatment than in the group that received statin therapy alone.14 Although the dose of EPA administered in JELIS (1.8 g daily) was lower than the EPA-equivalent dose used in REDUCE-IT (4 g daily), it resulted in a plasma EPA level (170 μg per milliliter in a Japanese population) similar to that attained in a previous 12-week lipid study in which a total daily dose of 4 g of icosapent ethyl was used in a Western population (183 μg per milliliter)25,26 and similar to that attained in the current trial. However, unlike the current trial, JELIS included an open-label design without a placebo group, used a low-intensity statin, and was conducted in a single country; patients also had higher levels of LDL cholesterol at baseline (182 mg per deciliter [4.71 mmol per liter] before initiation of statin therapy) and lower baseline triglyceride values (151 mg per deciliter [1.70 mmol per liter]) than the patients in REDUCE-IT.

Metabolic data provide evidence that icosapent ethyl–based formulations do not raise LDL cholesterol levels, whereas DHA-based formulations do.27 The results of the current trial should not be generalized to other n−3 fatty acid preparations — in particular, dietary-supplement preparations of n−3 fatty acid mixtures, which are variable and unregulated and which have not been shown to have clinical benefit.

A triglyceride level of 150 mg per deciliter or higher was an initial inclusion criterion in REDUCE-IT (although the required level was subsequently changed to ≥200 mg per deciliter); however, owing to allowance for variability in these levels, 10.3% of enrolled patients had triglyceride levels lower than 150 mg per deciliter at baseline. The observed cardiovascular benefits were similar across baseline levels of triglycerides (<150, ≥150 to <200, and ≥200 mg per deciliter). In addition, the significantly lower risk of major adverse cardiovascular events with icosapent ethyl than with placebo appeared to occur irrespective of the attained triglyceride level at 1 year (≥150 or <150 mg per deciliter), which suggests that the cardiovascular risk reduction was not associated with attainment of a more normal triglyceride level. These observations suggest that at least some of the effect of icosapent ethyl that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels.28

Mechanisms responsible for the benefit of icosapent ethyl observed in REDUCE-IT are currently not known. The timing of the divergence of the Kaplan–Meier event curves suggests a delayed onset of benefit, which may reflect the time that is needed for a benefit from a reduction in triglyceride levels to be realized or may indicate that other mechanisms are involved. The modestly higher rate of bleeding events with icosapent ethyl suggests that there may be an antithrombotic mechanism of action. However, it is unlikely that an antithrombotic effect would reduce the rate of elective revascularization. Also, if the full explanation involved an antiplatelet or anticoagulant effect, one might expect a large increase in the rate of major bleeding events, which was not observed.29 It is possible that membrane-stabilizing effects could explain part of the benefit.20,21,30 Stabilization or regression of coronary plaque (or both) may also play a part.19,31 Our observation of lower rates of cardiac arrest and sudden cardiac death with icosapent ethyl than with placebo in the current trial might support that mechanism, although these findings should be viewed as exploratory. It is also possible that the difference in high-sensitivity C-reactive protein level observed in REDUCE-IT may contribute to the benefit; the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) showed a significant reduction in the risk of ischemic events with treatment targeted at inflammation.32-35 Blood samples obtained during REDUCE-IT have been banked for biomarker and genetic analyses that may provide more information regarding mechanisms of action.

Ongoing trials of moderate-to-high doses of pure EPA ethyl ester will provide further information on the effects of these agents.10,36 These trials include the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA (RESPECT-EPA; UMIN Clinical Trials Registry number, UMIN000012069), a secondary prevention outcomes trial involving statin-treated patients in Japan, and the Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy (EVAPORATE; ClinicalTrials.gov number, NCT02926027), which is examining changes in coronary plaque over 9 to 18 months.

Our trial has certain limitations. First, at the time the trial was designed, there was relatively little use of ezetimibe or data supporting its use.37 However, subgroup analyses do not suggest a differential benefit for patients taking ezetimibe. Similarly, proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors were not available for the majority of the patients in the trial.38 Second, if mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25% lower risk observed with icosapent ethyl, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL cholesterol level among the patients in the placebo group. Although JELIS was designed as an open-label study that did not use a mineral oil placebo, it showed a 19% lower risk of ischemic events with statin therapy plus EPA than with statin therapy alone.

In conclusion, among patients with elevated triglyceride levels who were receiving statin therapy, the risk of major ischemic events, including cardiovascular death, was significantly lower with 2 g of icosapent ethyl twice daily (total daily dose, 4 g) than with placebo.