Major adverse cardiac events in patients with indeterminate high-sensitivity troponin testing and chest pain: a systematic review

Abstract Objectives Contemporary high-sensitivity cardiac troponin (hs-cTn) assays can detect very low levels of myocardial injury, leading many emergency department (ED) chest pain patients to exceed the 99th-percentile upper reference limit, despite low risk for myocardial infarction. This systematic review aimed to synthesize evidence quantifying the risk of MACE among ED patients with a single troponin concentration measurement above the 99th percentile reference limit but below diagnostic cutoffs for myocardial infarction. Methods Electronic searches of MEDLINE, Cochrane Reviews, CINAHL and EMBASE (2002–2025) were conducted. Studies were included if outcomes for patients with indeterminate single hs-Tn measurements were reported or extractable. Patients with ECG findings suggestive of ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) were excluded. Two reviewers independently screened abstracts and extracted data. MACE was defined as acute myocardial infarction (MI), stroke, and cardiovascular mortality 30 days after index ED visit. Results The search strategy yielded 709 potentially relevant citations. Eight studies were included: one randomized controlled trial, three prospective cohort, and four retrospective cohort studies. The incidence of MACE ranged from 0.3 to 14.8%. 46,066 of 129,060 eligible patients (40%) had a second test after an indeterminate result. Risk of bias was high for most observational studies, primarily due to information and incorporation bias, and randomized controlled trials had some concern for bias in the selection of the reported results, randomization process, and intended intervention. Conclusions It remains unknown whether patients with an indeterminate hs-Tn result and no serial testing are at increased risk for MACE. More than half of such patients did not receive serial testing. The study demonstrates inconsistent approaches for managing indeterminate troponin results, underscoring the need for physicians to interpret indeterminate values cautiously and consider clinical assessment in low-risk chest pain patients.