The new occlusive/non-occlusive MI paradigm to remedy the failure of high risk non-ST elevation MI criteria in the real world - insights from the DIFOCCULT-3 trial

Abstract Background The current ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) paradigm fails to identify many patients with acute coronary occlusion (ACO), delaying treatment and worsening outcomes. The new occlusive MI (OMI) and non-occlusive MI (NOMI) paradigm aims to overcome these limitations by focusing on the presence of ACO rather than rigid ECG thresholds. It integrates clinical judgement, subtle ECG changes, AI assistance, biomarkers, and imaging when necessary. Although guidelines add 'high-risk NSTEMI' criteria to capture missed occlusions, these are inconsistently applied, and often inadequate in the real world. Purpose We compared OMI diagnosis with high-risk NSTEMI criteria regarding acute coronary occlusion detection and diagnostic accuracy in patients not meeting conventional STEMI cutoffs. Methods The DIFOCCULT-3 study (NCT06570759) is a multicenter, modified cluster-randomized study comparing the OMI/NOMI and STEMI/NSTEMI paradigms. A total of 6,007 adult patients presenting with suspected MI were enrolled. Interventional cardiologists were assigned in a 1:1 ratio to either paradigm, and patients were treated according to the team on duty. On OMI/NOMI days, physicians actively sought ACO using clinical gestalt, AI-assisted ECG, and bedside echocardiography. The current study, as a subgroup analysis, included patients without diagnostic ST-segment elevation in the DIFOCCULT-3 cohort. To account for the dynamic nature of ACO that might spontaneously reperfuse at the time of angiogram, an adjudicated endpoint was used, defined as TIMI 0–1 flow or TIMI 2 with culprit features (90% stenosis, thrombus, ulceration, or staining) in patients with significant troponin elevation. Diagnostic metrics were compared using chi-square testing. Results A total of 4089 patients were analyzed. Among 1894 NSTEMI patients in the STEMI/NSTEMI arm, only 148 (7.8%) were reported to meet high-risk NSTEMI criteria. In the OMI/NOMI arm, among 2195 patients without diagnostic ST elevation, 1115 (46.2%) were reclassified as requiring acute intervention based on OMI diagnosis. Among those with angiographically confirmed ACO but without diagnostic ST elevation, high-risk NSTEMI criteria identified only 7.1% (98/1287), whereas the OMI paradigm detected 63.7% (811/1274) (P 0.001). For ACO detection, high-risk NSTEMI showed 7.1% sensitivity and 96.4% specificity, compared with 63.7% and 79.9% for OMI/NOMI, respectively (P 0.001). Overall diagnostic accuracy was 70% with OMI/NOMI versus 45% with high-risk NSTEMI criteria (P 0.001). Conclusion In real-world practice, guideline-defined high-risk NSTEMI criteria are highly insensitive for detecting ACO and fail to compensate for the limitations of the current STEMI/NSTEMI paradigm. The OMI/NOMI paradigm markedly improves identification of patients requiring urgent invasive management and offers a more accurate, physiology-based approach to MI triage.