Study design and participants

The details of the REDUCE-IT design have been previously published (22). Briefly, patients were randomized in a double-blind manner to icosapent ethyl 4 g/day (2 g twice daily with meals) or placebo (Online Figures 1 and 2). Approximately 1,612 events were projected necessary for 90% power to detect a 15% relative risk reduction after accounting for 2 protocol pre-specified interim analyses (final 2-sided alpha level = 0.0437). This resulted in a target patient population of approximately 7,990 patients. Among all randomized patients, 70.7% were enrolled on the basis of secondary prevention and 29.3% for primary prevention. Patients were randomized to 1 of 2 treatment arms in a 1:1 ratio using a computer-generated randomization schema. Study medication and placebo capsules were similar in size and appearance to maintain blinding. Randomization was stratified according to cardiovascular risk cohort (secondary or primary prevention), use of ezetimibe (yes/no), and by geographical region (Westernized, Eastern European, and Asia Pacific countries). There were 473 sites in 11 countries randomizing and following patients from 2011 to 2018. The protocol was submitted to and approved by appropriate health authorities, ethics committees, and institutional review boards. Trial completion occurred after achieving the approximate number of pre-specified necessary events.

To be eligible, patients were required to be either ≥45 years of age with established cardiovascular disease (secondary prevention stratum) or ≥50 years of age with type 2 or 1 diabetes mellitus requiring treatment with medication, and to have at least 1 additional cardiovascular risk factor (primary prevention stratum) (20,22).

Patients had fasting triglycerides of ≥135 and <500 mg/dl and LDL-C >40 and ≤100 mg/dl. The initial version of the protocol permitted a 10% variance in the lower qualifying triglyceride level of ≥150 mg/dl; therefore, patients with triglycerides ≥135 mg/dl were randomized. After approximately 60% of the patients were enrolled, an amendment increased the lower limit of permissible triglyceride levels to 200 mg/dl with no variability allowance. The study included 841 (10.3%) patients with baseline triglyceride levels <150 mg/dl. Patients were required to be on stable statin therapy for ≥4 weeks with well-controlled LDL-C to investigate the potential benefit of icosapent ethyl 4 g/day beyond the current standard of care. Additional inclusion and exclusion criteria published previously (22) are provided in the Online Appendix.

After randomization, follow-up visits continued at 4 and 12 months and annually thereafter in this event-driven trial until approximately 1,612 primary efficacy endpoint events occurred, after which patients made a final end-of-study visit.

The original projected annual primary endpoint event rate for the REDUCE-IT placebo group was 5.9%; this was derived prior to study initiation (and therefore, prior to the 2 interim analyses conducted by the data monitoring committee) and was based on data available from cardiovascular outcome trials with similar high-risk statin-treated patients and reported endpoint components similar to the primary endpoint in REDUCE-IT (23–29). The observed annualized primary endpoint event rate for placebo patients in REDUCE-IT was 5.74%, which is consistent with historical cardiovascular outcome studies, including those published since the design of REDUCE-IT, with comparable patient populations and expanded or hard major adverse cardiovascular events (MACE) (4,8,9,30–44).

For the present pre-specified analysis, the primary outcome was the total of first plus subsequent ischemic events consisting of the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Protocol Amendment 2 (July 2016) designated the composite of hard MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) as the “key secondary endpoint” per suggestions from the Food and Drug Administration and with REDUCE-IT Steering Committee concordance. Exploratory analyses of the total of first and subsequent events were also performed for the key secondary composite endpoint.

Baseline characteristics were compared between treatment groups using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous variables. The analysis of total cardiovascular events was pre-specified in the study protocol. There are several methods for analyzing first and subsequent (recurrent) event data. As a pre-specified statistical method, we used the negative binomial regression model to calculate rates and rate ratios for total cardiovascular events, which accounts for the variability in each patient’s risk of events (45–47). As pre-specified supportive analyses, we used the modified Wei-Lin-Weissfeld method (Li and Lagakos modification) to calculate hazard ratios for the time to the first, second, or third event (48,49). An additional pre-specified analysis, the Andersen-Gill model using a Cox proportional-hazard with the counting-process formulation, was performed to model the total events (50,51). In addition, to account for informative censoring due to cardiovascular death, we calculated the hazard ratio for total nonfatal events using a joint frailty model (52). The joint frailty model simultaneously estimates hazard functions for nonfatal and fatal cardiovascular events and takes into account the fact that patients who are prone to have nonfatal events have an elevated risk of cardiovascular death. Our application of the joint frailty model used a gamma distribution for the frailty term.

To improve the performance and validity of our statistical models, a bundling approach was used, whereby nonfatal events occurring on the same day as a cardiovascular death were excluded, and at most, 1 nonfatal event was counted on any given day (e.g., for coronary revascularization occurring after an MI that eventually resulted in the patient’s death, only the death would be included). Statistical analyses using the full adjudicated endpoint events dataset without exclusions for this bundling approach are also included in the Online Appendix.

All efficacy analyses were conducted in accordance with the intention-to-treat principle. All tests were based on a 2-sided nominal significance level of 5% with no adjustments for multiple comparisons, consistent with pre-specified plans for such endpoints. All statistical analyses were conducted using SAS version 9.4 software (Cary, North Carolina). All analyses of first, subsequent, and total events were independently generated and validated by Drs. Gregson and Pocock.