Background: Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) assays have been shown to provide similar analytical precision despite substantially shorter turnaround times compared with laboratory-based hs-cTn assays. We applied the previously developed machine learning based personalised Artificial Intelligence in Suspected Myocardial Infarction Study (ARTEMIS) algorithm, which can predict the individual probability of myocardial infarction, with a single POC hs-cTn measurement, and compared its diagnostic performance with standard-of-care pathways for rapid rule-out of myocardial infarction., Methods: We retrospectively analysed pooled data from consecutive patients of two prospective observational cohorts in geographically distinct regions (the Safe Emergency Department Discharge Rate cohort from the USA and the Suspected Acute Myocardial Infarction in Emergency cohort from Australia) who presented to the emergency department with suspected myocardial infarction. Patients with ST-segment elevation myocardial infarction were excluded. Safety and efficacy of direct rule-out of myocardial infarction by the ARTEMIS algorithm (at a pre-specified probability threshold of <0·5%) were compared with the European Society of Cardiology (ESC)-recommended and the American College of Cardiology (ACC)-recommended 0 h pathways using a single POC high-sensitivity cardiac troponin I (hs-cTnI) measurement (Siemens Atellica VTLi as investigational assay). The primary diagnostic outcome was an adjudicated index diagnosis of type 1 or type 2 myocardial infarction according to the Fourth Universal Definition of Myocardial Infarction. The safety outcome was a composite of incident myocardial infarction and cardiovascular death (follow-up events) at 30 days. Additional analyses were performed for type I myocardial infarction only (secondary diagnostic outcome), and for each cohort separately. Subgroup analyses were performed for age (<65 years vs ≥65 years), sex, symptom onset (≤3 h vs >3 h), estimated glomerular filtration rate (<60 mL/min per 1·73 m 2 vs ≥60 mL/min per 1·73 m 2 ), and absence or presence of arterial hypertension, diabetes, a history of coronary artery disease, myocardial infarction, or heart failure, smoking, and ischaemic electrocardiogram signs., Findings: Among 2560 patients (1075 [42%] women, median age 58 years [IQR 48·0-69·0]), prevalence of myocardial infarction was 6·5% (166/2560). The ARTEMIS-POC algorithm classified 899 patients (35·1%) as suitable for rapid rule-out with a negative predictive value of 99·96% (95% CI 99·64-99·96) and a sensitivity of 99·68% (97·21-99·70). For type I myocardial infarction only, negative predictive value and sensitivity were both 100%. Proportions of missed index myocardial infarction (0·05% [0·04-0·42]) and follow-up events at 30 days (0·07% [95% CI 0·06-0·59]) were low. While maintaining high safety, the ARTEMIS-POC algorithm identified more than twice as many patients as eligible for direct rule-out compared with guideline-recommended ESC 0 h (15·2%) and ACC 0 h (13·8%) pathways. Superior efficacy persisted across all clinically relevant subgroups., Interpretation: The patient-tailored, medical decision support ARTEMIS-POC algorithm applied with a single POC hs-cTnI measurement allows for very rapid, safe, and more efficient direct rule-out of myocardial infarction than guideline-recommended pathways. It has the potential to expedite the safe discharge of low-risk patients from the emergency department including early presenters with symptom onset less than 3 h at the time of admission and might open new opportunities for the triage of patients with suspected myocardial infarction even in ambulatory, preclinical, or geographically isolated care settings., Funding: The German Center for Cardiovascular Research (DZHK)., Competing Interests: Declaration of interests BT is supported by a grant from the German Foundation of Heart Research and Werner Otto Stiftung; is the co-recipient of a grant from the Ernst und Berta Grimmke-Stiftung (unrelated to this project); and has received travel grants from the German Center for Cardiovascular Research (DZHK). BT is the local representative of the partner sites Hamburg/Kiel/Luebeck in the Use and Access Committee of the DZHK Heart Bank. JHG reports fellowship funding from Advance Queensland and payment by the Emergency Medicine Foundation to her institution. WAP reports that his institution receives consulting fees from Siemens Healthineers. WAP reports acitivities at the Board (executive and horonary treasurer) of the Cardiac Society of Australia and New Zealand. LC reports non-salaried grant support and provision of assays through her institution from Abbott Diagnostics, Abbott Point-of-Care (POC), Radiometer Pacific, Roche Diagnostics, Siemens Healthineers, and Beckman Coulter. LC also reports consulting fees from Siemens Healthineers, Beckman Coulter, Quidel/Ortho, and payment or honoraria from Abbott Diagnostics, Roche Diagnostics, and Glycardial. Both WAP and LC report research funding and provision of assays by Siemens Healthineers. FSA reports doing advisory board or consultant activities for Mindray, Wefen, and Abbott Vascular, and non-salaried grant support through the Hennepin Healthcare Research Institute from Abbott Diagnostics, Abbott POC, Roche Diagnostics, Siemens Healthineers, Beckman Coulter, Quidel/Ortho, Becton Dickinson, and Sysmex, and fees for serving as Associate Editor for Clinical Chemistry. AZ is a Board member of the Basel Biometric Society. AZ and SB are listed as co-inventors of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication Number WO2022043229A1). AZ is scientific director and CEO of Cardio-CARE, SB is scientific advisor of Cardio-CARE, HS was a biostatistician at Cardio-CARE, and EDC is a biostatistician at Cardio-CARE, a 100% non-profit daughter company of the Kühne Foundation. Cardio-CARE is a shareholder of ART-EMIS Hamburg. SB receives consulting fees from Thermo Fisher, and payment or honoraria from Abbott Diagnostics, Amarin, AMGEN, AstraZeneca, Bayer, Bristol Meyers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, LumiraDx, Novartis, Roche Diagnostics, and Thermo Fisher. SB is a member of the advisory board of Thermo Fisher. SB and AZ were co-founders of ARTEMIS in 2022. Both sold their shares in 2023 and have no personal financial or legal relationship to ARTEMIS. KS declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)