BACKGROUND: In the era of high-sensitivity troponin assays, overdiagnosis of acute coronary syndrome (ACS) has become increasingly common, overriding underdiagnosis and carrying a burden of healthcare issues. This study aimed to assess the incidence, predictors, and sex differences in ACS overdiagnosis among patients presenting with chest pain (CP) to the emergency department (ED). METHODS: Consecutive CP patients presenting at the ED were included. Patients with other causes of CP, non-suspicious for ACS, were excluded. Six-month ACS rate was assessed in discharged patients. In ACS hospitalized patients, clinical records were analyzed to evaluate true-ACS incidence. Patients inappropriately hospitalized for ACS (ACS-overdiagnosis, false-positives) were compared to correctly discharged (true-negatives) and actual ACS patients (true-positives and false-negatives). RESULTS: From 7040 CP patients, a random sample of 1025 was included. ACS was initially diagnosed in 237 (23.1 %) patients who were hospitalized, while 788 (76.9 %) were discharged from the ED. ACS misdiagnosis occurred in 30 (2.9 %) patients: 8 (1 %) discharged patients experienced ACS at follow-up (false-negatives) while 22 (9.3 %) hospitalized for ACS were considered not to have ACS (ACS-overdiagnosis). True incident ACS at 6 months was 223 (21.8 %). Independent predictors of ACS overdiagnosis were electrocardiographic alterations, troponin T >
99° percentile, and male sex, while women were older with lower pre-test likelihood of ACS according to ED physicians, with a higher rate of early discharge but similar outcomes. CONCLUSIONS: ACS overdiagnosis is more frequent than underdiagnosis, carrying potential issues for the healthcare system. Patients with ACS overdiagnosis were more commonly men with elevated high-sensitivity troponin, often indistinguishable from true-ACS patients according to standard care.