Principal Findings:

The primary CV outcome of CV death, nonfatal myocardial infarction (MI), stroke, coronary revascularization, or unstable angina, for IPE vs. placebo, was 17.2% vs. 22.0% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.68-0.83; p < 0.0001).

Secondary outcomes, for IPE vs. placebo:

• Change in TG levels at 1 year: -39.0 mg/dl vs. 4.5 mg/dl
• Change in LDL at 1 year: 2 mg/dl vs. 7 mg/dl
• CV death or MI: 9.6% vs.12.4%, p < 0.001
• All MI: 6.1% vs. 8.7%, p < 0.001
• Revascularization: 5.3% vs. 7.8%, p < 0.001
• All-cause mortality: 6.7% vs. 7.6%, p = 0.09
• Atrial fibrillation/flutter: 5.3% vs. 3.9%
• Serious adverse bleeding events: 2.7% vs. 2.1%, p = 0.06

Total and recurrent event analysis: 55.2% were first primary events. Total (first and subsequent) primary endpoint event rates were reduced to 61 from 89 per 1,000 patient-years for IPE vs. placebo, respectively (rate ratio [RR] 0.70, 95% CI 0.62-0.78, p < 0.0001). The first occurrence of a primary composite endpoint was reduced with IPE vs. placebo (HR 0.75, 95% CI 0.68-0.83, p < 0.0001), as was the second occurrence (HR 0.68, 95% CI 0.60-0.78, p < 0.0001). Similar effects were noted for key secondary endpoints.

USA subanalysis (n = 3,146 [38.5%]): Primary endpoint, for IPE vs. placebo: 18.2% vs. 24.7%, p = 0.0001); CV death: 4.7% vs. 6.7%, p = 0.007; MI: 6.7% vs. 8.8%, p = 0.01; stroke: 2.6% vs. 4.1%, p = 0.02; all-cause mortality: 7.2% vs. 9.8%, p = 0.004. Safety endpoints were similar to the overall cohort.

Cost-effectiveness analysis: The assumed cost of IPE = $4.16/day. The quality-adjusted life-years for IPE and placebo during the trial period were 3.34 and 3.27 and lifetime were 11.61 and 11.35, respectively. IPE was cost-saving in the majority of simulations. Overall, IPE appeared to be cost-dominant compared with placebo.

Eicosapentaenoic acid (EPA) levels and CV outcomes: Benefit of IPE vs. placebo was maintained across baseline EPA level tertiles (<20, 20-34, >34 mcg/ml) for primary and key secondary endpoint; p for interaction = 0.91. Median baseline EPA level 26.1, increased by ~400% at 1 year and was sustained out to 5 years in the IPE arm (p < 0.0001), while it remained more or less unchanged in the placebo arm. On-treatment EPA levels via IPE correlated with the primary endpoint, key secondary endpoint, and most other CV endpoints. Benefits noted were beyond those that could be explained by degree of TG or other biomarker changes such as LDL cholesterol, HDL, or hs-CRP.

Impact on revascularization: A total of 920 patients underwent coronary revascularization during the trial. Time to coronary revascularization was significantly lower with IPE compared with placebo (11.4% vs. 16.7%, HR 0.66, 95% CI 0.58-0.76, p < 0.0001: number needed to treat [NNT] = 24). Emergent or urgent revascularization: 5.3% vs. 7.8% (p < 0.0001); similar benefit for percutaneous coronary intervention and coronary artery bypass grafting.

Diabetes subset (n = 4,787): Median glycated hemoglobin (HbA1c), 7.0%. Primary endpoint for IPE vs. placebo: 22.2% vs. 29.2% (p < 0.0001). Effect is consistent among patients with and without established CVD at baseline. Key secondary composite endpoint (CV death/MI/stroke): 15.3% vs. 21.2% (p < 0.0001). Time to first and total events similarly lower with IPE. All-cause mortality: 7.5% vs. 8.4% (p = 0.15); CV death/MI: 10.2% vs. 13.5% (p < 0.0001); urgent/emergent revascularization: 5.7% vs. 7.2% (p = 0.02); stroke: 2.6% vs. 3.8% (p = 0.009); atrial fibrillation/flutter: 3.5% vs. 2.2% (p = 0.01). No significant changes in HbA1c or glucose.

Need for revascularization procedures: First coronary revascularization for IPE vs. placebo: 9.2% vs. 13.3% (p < 0.0001), NNT = 24. PCI: 7.7% vs. 10.9% (p < 0.001), CABG: 1.9% vs. 3.0% (p = 0.0005). Reductions were noted in both elective and urgent/emergent revascularizations. Results were consistent across tertiles of TG levels (p for interaction = 0.07). Total revascularizations were similarly reduced with IPE vs. placebo.

Patients with prior MI (n = 3,693): Primary endpoint for IPE vs. placebo: 20.2% vs. 26.1%, HR 0.74 (0.65-0.85); p = 0.00001; CV death or MI: 11.5% vs. 15.6%, p = 0.0002; fatal or nonfatal MI: 7.9% vs. 11.6%, p = 0.00009; all-cause mortality: 7.3% vs. 8.9%, p = 0.05; CV death: 4.5% vs. 6.4%, p = 0.01 (reductions noted in sudden cardiac death and cardiac arrest). Results similar by prior revascularization status.

Comparison of investigator-reported and adjudicated endpoints: The Kappa statistic between Clinical Endpoint Committee (CEC)-adjudicated vs. site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. For the primary endpoint, event rates were similar by both methods: investigator-reported (23.4% vs. 30.6%, HR 0.74, p < 0.0001) and CEC-adjudicated (21.7% vs. 28.3%, HR 0.75, p < 0.0001) for IPE vs. placebo, respectively.

Effect across eGFR categories: 22.2% had eGFR <60 at baseline (patients with GFR <30 or on renal replacement therapy were excluded from the trial). Effect of IPE vs. placebo for the primary endpoint was consistent across GFR categories; <60: 27.2% vs. 35.6%, p = 0.0002; 60-<90: 21.4% vs. 27.5%, p = 0.001; ≥90: 17.2% vs. 23.2%, p = 0.003; p for interaction = 0.41. Similar results were noted for the key secondary composite endpoint (p for interaction = 0.77), for CV death, and for the safety endpoints of atrial fibrillation/flutter and serious bleeding.

Reduction in MI: Overall MI incidence for IPE vs. placebo: 8.6% vs. 12.0% (p < 0.0001); ST-segment elevation MI (STEMI): 2.7% vs. 3.9% (p = 0.0008); NSTEMI: 5.9% vs. 7.8% (p = 0.001); fatal or nonfatal MI: 6.1% vs. 8.7% (p < 0.0001). At least one bleeding event among STEMI patients: 19.4% vs. 14.5% (p = 0.41).