1. IRIS Post-hoc Analysis Background IRIS compared the safety and efficacy of early ICD implantation with medical treatment alone in 898 patients at high risk for SCD after MI Primary analysis showed significantly fewer deaths due to SCD in the ICD group compared with medical therapy alone; this was offset by an increase in non-SCD, resulting in a neutral effect on total mortality after 72 months Objective of Post-hoc Analysis Elucidate predictors and mechanisms that contributed to the observed increase in non-sudden cardiac death (SCD) in the implantable cardiac defibrillator (ICD) group

2. IRIS Post-hoc Analysis Key Post-hoc Findings Mortality risk patterns were consistent across 30 subgroups, with early ICD associated with decreased risk of SCD and increased risk of non-SCD in each subgroup (except for 91 patients with STEMI who did not undergo reperfusion) Independent of ICD use, five factors predicted total mortality: older age, left main or three-vessel disease, QRS ≥120 ms, NYHA class 3 or 4 heart failure, and ejection fraction <35% Use of an ACE inhibitor or ARB and administration of clopidogrel were associated with lower mortality risk Right ventricular pacing was associated with increased total mortality due to an elevated risk of non-SCD Periods of appropriate or inappropriate shocks were associated with a particularly high risk of total mortality due to increased non-SCD

3. IRIS Post-hoc Analysis Summary SCD is reduced by the ICD in the first 2 years The risk of non–SCD is higher in the ICD group than in controls throughout the study, the difference being most prominent at 3 years of follow up In multivariate analysis, the IRIS overall result is identical in 30 interaction tests for subgroup effects, except the one without reperfusion ICD intervention is associated with an increased risk of death due to elevated non-SCD: identified periods at risk are those with both appropriate and inappropriate shocks, and those with increased right ventricular pacing