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Background: Testing for high-sensitivity cardiac troponin (hs-cTn) may assist triage and clinical decision-making in patients presenting to the emergency department with symptoms of acute coronary syndrome; however, this could result in the misclassification of risk because of analytical variation or laboratory error. We sought to evaluate a new laboratory-based risk-stratification tool that incorporates tests for hs-cTn, glucose level and estimated glomerular filtration rate to identify patients at risk of myocardial infarction or death when presenting to the emergency department., Methods: We constructed the clinical chemistry score (CCS) (range 0-5 points) and validated it as a predictor of 30-day myocardial infarction (MI) or death using data from 4 cohort studies involving patients who presented to the emergency department with symptoms suggestive of acute coronary syndrome. We calculated diagnostic parameters for the CCS score separately using high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT)., Results: For the combined cohorts ( n = 4245), 17.1% of participants had an MI or died within 30 days. A CCS score of 0 points best identified low-risk participants: the hs-cTnI CCS had a sensitivity of 100% (95% confidence interval [CI] 99.5%-100%), with 8.9% (95% CI 8.1%-9.8%) of the population classified as being at low risk of MI or death within 30 days; the hs-cTnT CCS had a sensitivity of 99.9% (95% CI 99.2%-100%), with 10.5% (95% CI 9.6%-11.4%) of the population classified as being at low risk. The CCS had better sensitivity than hs-cTn alone (hs-cTnI < 5 ng/L: 96.6%, 95% CI 95.0%-97.8%; hs-cTnT < 6 ng/L: 98.2%, 95% CI 97.0%-99.0%). A CCS score of 5 points best identified patients at high risk (hs-cTnI CCS: specificity 96.6%, 95% CI 96.0%-97.2%; 11.2% [95% CI 10.3%-12.2%] of the population classified as being at high risk; hs-cTnT CCS: specificity 94.0%, 95% CI 93.1%-94.7%; 13.1% [95% CI 12.1%-14.1%] of the population classified as being at high risk) compared with using the overall 99th percentiles for the hs-cTn assays (specificity of hs-cTnI 93.2%, 95% CI 92.3-94.0; specificity of hs-cTnT 73.8%, 95% CI 72.3-75.2)., Interpretation: The CCS score at the chosen cut-offs was more sensitive and specific than hs-cTn alone for risk stratification of patients presenting to the emergency department with suspected acute coronary syndrome. Study registration : ClinicalTrials.gov, nos. NCT01994577; NCT02355457., Competing Interests: Competing interests: Peter Kavsak has received research grants from the Canadian Institutes of Health Research (CIHR), Abbott Laboratories, Abbott Point of Care, Beckman Coulter, Randox Laboratories, Roche Diagnostics and Siemens Healthcare Diagnostics. He has received consultant or advisor fees, or honoraria from Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division of Canada, Beckman Coulter, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics and Ortho Clinical Diagnostics. In addition, he has a pending patent application filed by McMaster University on a laboratory score for risk stratification in patients with possible cardiac injury. Johannes Neumann has received research grants from the German Heart Foundation/German Foundation of Heart Research and from Else Kröner Fresenius Stiftung. Louise Cullen has received grants from Abbott Diagnostics, Roche and Alere, and personal fees for education and consulting from Abbott Diagnostics, Siemens, Beckman Coulter and Alere. Martin Than has received grants and personal fees in the form of speaker fees or funding for education from Abbott, Alere, Beckman Coulter and Roche. Colleen Shortt is employed by Abbott Diagnostics. Jaimi Greenslade has received research grants that were provided to his institution from Roche and Abbott, as well as a research grant from Emergency Medicine Foundation to support data collection for this study. John Pickering has received nonfinancial support from Abbott Diagnostics and Roche Diagnostics outside the submitted work. Dirk Westermann has received speaker fees from Bayer, Boehringer Ingelheim, Berlin-Chemie, AstraZeneca, BIOTRONIK and Novartis, outside the submitted work. William Parsonage has received research grants from Abbott Laboratories and Roche during the conduct of the study, and fees for being an advisory board member and nonfinancial support from Abbott Laboratories, outside the submitted work. P.J. Devereaux reports grants from Abbott Diagnostics, Boehringer Ingelheim, Covidien, Octopharma, Philips Healthcare, Roche Diagnostics and Stryker, outside the submitted work. Richard Troughton has received research grants from the Health Research Council of New Zealand, Roche Diagnostics and Merck, as well as consulting fees from Merck. Stefan Blankenberg has received honoraria from Abbott Diagnostics, Siemens, Thermo Fisher Scientific and Roche Diagnostics, outside the submitted work. Andrew Worster has received a research grant from CIHR. In addition, he has a pending patent application filed by McMaster University on a laboratory score for risk stratification for patients with possible cardiac injury. No other competing interests were declared., (© 2018 Joule Inc. or its licensors.)

Background: The new European Society of Cardiology guidelines to rule-in and rule-out acute myocardial infarction (AMI) in the emergency department include a rapid assessment algorithm based on high-sensitivity cardiac troponin and sampling at 0 and 1 hour. Emergency department physicians require high sensitivity to confidently rule-out AMI, whereas cardiologists aim to minimize false-positive results., Methods: High-sensitivity troponin I and T assays were used to measure troponin concentrations in patients presenting with chest-pain symptoms and being investigated for possible acute coronary syndrome at hospitals in New Zealand, Australia, and Canada. AMI outcomes were independently adjudicated by at least 2 physicians. The European Society of Cardiology algorithm performance with each assay was assessed by the sensitivity and proportion with AMI ruled out and the positive predictive value and proportion ruled-in., Results: There were 2222 patients with serial high-sensitivity troponin T and high-sensitivity troponin I measurements. The high-sensitivity troponin T algorithm ruled out 1425 (64.1%) with a sensitivity of 97.1% (95% confidence interval [CI], 94.0%-98.8%) and ruled-in 292 (13.1%) with a positive predictive value of 63.4% (95% CI, 57.5%-68.9%).The high-sensitivity troponin I algorithm ruled out 1205 (54.2%) with a sensitivity of 98.8% (95% CI, 96.4%-99.7%)) and ruled-in 310 (14.0%) with a positive predictive value of 68.1% (95% CI, 62.6%-73.2%)., Conclusions: The sensitivity of the European Society of Cardiology rapid assessment 0-/1-hour algorithm to rule-out AMI with high-sensitivity troponin may be insufficient for some emergency department physicians to confidently send patients home. These algorithms may prove useful to identify patients requiring expedited management. However, the positive predictive value was modest for both algorithms., (© 2016 American Heart Association, Inc.)

Objective: To validate the National Institute for Health and Care Excellence (NICE) recommended algorithms for high-sensitivity troponin (hsTn) assays in adults presenting with chest pain., Methods: International post hoc analysis of three prospective, observational studies from tertiary hospital emergency departments. The primary endpoint was cardiac death or acute myocardial infarction (AMI) within 24 hours of presentation, and the secondary endpoint was major adverse cardiac events (MACE) at 30 days., Results: 15% of patients were diagnosed with non-ST elevation myocardial infarction (MI) on admission. The hsTnI algorithm classified 2506/3128 (80.1%) of patients as 'ruled out' with 50 (2.0%) missed MI. 943/3128 (30.1%) of patients had a troponin I level below the limit of detection on admission with 2 (0.2%) missed MI. For the hsTnT algorithm, 1794/3374 (53.1%) of patients were 'ruled out' with 7 (0.4%) missed MI. 490/3374 (14.5%) of patients had a troponin T below the limit of blank on admission with no MI. MACE at 30 days occurred in 10.7% and 8.5% of patients 'ruled out' defined by the hsTnI and hsTnT algorithms, respectively., Conclusions: The NICE algorithms could identify patients with low probability of AMI within 2 hours; however, neither strategy performed as predicted by the NICE diagnostic guidance model. Additionally, the rate of MACE at 30 days was sufficiently high that the algorithms should only be used as one component of a more extensive model of risk stratification., Trial Registration Number: ACTRN12611001069943, NCT00470587; post-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Importance: Low concentrations of high-sensitivity cardiac troponin I determined on presentation to the emergency department (ED) have been shown to have an excellent negative predictive value (NPV) for the identification of acute myocardial infarction. The sensitivity, and therefore clinical applicability, of such testing strategies is unknown., Objective: To determine the diagnostic performance of low concentrations of high-sensitivity cardiac troponin I in patients with suspected cardiac chest pain and an electrocardiogram showing no ischemia as an indicator of acute myocardial infarction., Design, Setting, and Participants: A pooled analysis of 5 international (Australia, New Zealand, and England) prospective, observational cohort studies with blinded outcome assessment and 30-day follow-up was conducted. A total of 3155 patients presenting with symptoms suggestive of cardiac ischemia were included in the analysis. Eligible patients had a nonischemic electrocardiogram determined and high-sensitivity troponin I measured at presentation. The lower limit of detection (1.2 ng/L) as well as cutoff concentrations rounded to the nearest integer for a high-sensitivity troponin I assay were used in the analysis. Recruitment was undertaken from November 1, 2007, to August 10, 2013., Main Outcomes and Measures: The primary outcome was fatal or nonfatal acute myocardial infarction occurring within 30 days of ED presentation, adjudicated with serial troponin testing. The secondary outcome was the proportion of patients potentially suitable for early discharge at each cutoff concentration., Results: Of the 3155 eligible patients, 1771 were male (56.1%), and mean (SD) age was 57.4 (13.3) years. Acute myocardial infarction developed in 291 individuals (9.2%). The 1.2-ng/L limit of detection gave a sensitivity of 99.0% (95% CI, 96.8%-99.7%) and an NPV of 99.5% (95% CI, 98.4%-99.9%). This cutoff level would allow for early discharge of 594 patients (18.8%). All higher rounded cutoff values had sensitivities less than 98.0%. Diagnostic performance of the limit of detection was maintained when patients were stratified by age, sex, risk factors, presence of coronary artery disease, and early presentation., Conclusions and Relevance: High-sensitivity troponin I concentrations determined at presentation to the ED that were below the limit of detection identified 18.8% of patients potentially suitable for discharge, with a high sensitivity for acute myocardial infarction. Rounded cutoff values above the limit of detection may not have the required sensitivity for clinical implementation.

Background: The early triage of patients toward rule-out and rule-in of acute myocardial infarction (AMI) is challenging. Therefore, we aimed to develop a 2-h algorithm that uses high-sensitivity cardiac troponin I (hs-cTnI)., Methods: We prospectively enrolled 1435 (derivation cohort) and 1194 (external validation cohort) patients presenting with suspected AMI to the emergency department. The final diagnosis was adjudicated by 2 independent cardiologists. hs-cTnI was measured at presentation and after 2 h in a blinded fashion. We derived and validated a diagnostic algorithm incorporating hs-cTnI values at presentation and absolute changes within the first 2 h., Results: AMI was the final diagnosis in 17% of patients in the derivation and 13% in the validation cohort. The 2-h algorithm developed in the derivation cohort classified 56% of patients as rule-out, 17% as rule-in, and 27% as observation. Resulting diagnostic sensitivity and negative predictive value (NPV) were 99.2% and 99.8% for rule-out; specificity and positive predictive value (PPV) were 95.2% and 75.8% for rule-in. Applying the 2-h algorithm in the external validation cohort, 60% of patients were classified as rule-out, 13% as rule-in, and 27% as observation. Diagnostic sensitivity and NPV were 98.7% and 99.7% for rule-out; specificity and PPV were 97.4% and 82.2% for rule-in. Thirty-day survival was 100% for rule-out patients in both cohorts., Conclusions: A simple algorithm incorporating hs-cTnI baseline values and absolute 2-h changes allowed a triage toward safe rule-out or accurate rule-in of AMI in the majority of patients., (© 2015 American Association for Clinical Chemistry.)

Objectives: International guidance recommends that early serial sampling of high sensitivity troponin be used to accurately identify acute myocardial infarction (AMI) in chest pain patients. The background evidence for this approach is limited. We evaluated whether on presentation and 4-hour high-sensitivity troponin I (hs-cTnI) could be used to accurately rule-out AMI., Design and Methods: hs-cTnI was measured on presentation and at 4-hours in adult patients attending an emergency department with possible acute coronary syndrome. We determined the sensitivity for AMI for at least one hs-cTnI above the 99th percentile for a healthy population or alone or in combination with new ischemic ECG changes. Both overall and sex-specific 99th percentiles were assessed. Patients with negative tests were designated low-risk., Results: 63 (17.1%) of 368 patients had AMI. The median (interquartile range) time from symptom onset to first blood sampling was 4.8h (2.8-8.6). The sensitivity of the presentation and 4h hs-cTnI using the overall 99th percentile was 92.1% (95% CI 82.4% to 97.4%) and negative predictive value 95.4% (92.3% to 97.4%) with 78.3% low-risk. Applying the sex-specific 99th percentile did not change the sensitivity. The addition of ECG did not change the sensitivity., Conclusion: Hs-cTnI >99th percentile thresholds measured on presentation and at 4-hours was not a safe strategy to rule-out AMI in this clinical setting irrespective of whether sex-specific 99th percentiles were used, or whether hs-cTnI was combined with ECG results., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aims: Assessment of patients with suspected non-ST elevation myocardial infarction (NSTEMI) is based on cardiac troponin (cTn) levels with the 99th percentile as cut-off. However, cardiovascular risk starts already at lower troponin concentrations. We therefore, aimed to investigate the utility of 2-hour algorithms using the high-sensitivity cardiac troponin I (hs-cTnI) 97.5th percentile as cut-off which corresponds to the standard URL for most biomarkers., Methods: Hs-cTnI was measured at presentation and 2h in 1624 chest pain patients. Diagnostic algorithms were developed applying hs-cTnI levels dichotomized at the 99th and 97.5th percentiles combined with hs-cTnI changes and/or ECG findings., Results: The prevalence of NSTEMI was 13.9%. The adjusted odds ratios for 1-year mortality were 2.7 (95% CI 1.4-5.1) for the 99th percentile and 3.1 (95% CI 1.6-5.9) for the 97.5th percentile. The best-performing 99th percentile-based algorithms provided a positive predictive value (PPV) of 86.3% and a negative predictive value (NPV) of 99.3%. Using 97.5th percentile-based algorithms to define NSTEMI resulted in few reclassifications and yielded similar diagnostic estimates (PPV 85.4%, NPV 99.4%)., Conclusion: The hs-cTnI 97.5th percentile integrated into 2-hour algorithms provided high diagnostic estimates and could, due to better prognostic properties serve as an alternative to the 99th percentile., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background and Aims: The use of high sensitivity troponin (hs-Tn) may enable early rule out of acute myocardial infarction (AMI) for patients presenting to the emergency department (ED) with chest pain. This study evaluated two approaches to the early rule out of AMI; a combination of a presentation hs-Tn <4ng/L and normal glucose at presentation (dual testing) and a presentation hs-Tn troponin below the limit of detection (LoD)., Methods: We utilised prospectively collected data on adult patients presenting with suspected ACS in two EDs in Australia and New Zealand. Blood samples were taken on presentation and tested for glucose and high sensitivity troponin I. The primary endpoint was index AMI and the secondary endpoint was 30-day acute coronary syndrome (ACS). Sensitivity, specificity, positive and negative predictive values were used to assess the diagnostic accuracy of the dual testing and LoD approaches., Results: Of the 1412 participants, 182 (12.9%) had index AMI. The LoD and the dual testing approach were 100% sensitive for index AMI. The specificity of the dual testing approach (25.2%) was slightly higher than that of the LoD (20.4%). Sensitivity for ACS was similar for the two approaches (96.5% for dual testing and 98.1% for the LoD)., Conclusions: The dual testing and LoD approach identified all patients with index AMI and could be used to reduce the proportion of patients requiring lengthy assessment and inpatient admission. Further investigation is still required to rule out unstable angina pectoris in patients identified as low risk., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objectives: Concentrations of troponin measured with high sensitivity troponin assays are raised in a number of emergency department (ED) patients; however many are not diagnosed with acute myocardial infarction (AMI). Clinical comparisons between the early use (2h after presentation) of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) assays for the diagnosis of AMI have not been reported., Design and Methods: Early (0 h and 2 h) hs-cTnT and hs-cTnI assay results in 1571 ED patients with potential acute coronary syndrome (ACS) without ST elevation on electrocardiograph (ECG) were evaluated. The primary outcome was diagnosis of index AMI adjudicated by cardiologists using the local cTnI assay results taken ≥6 h after presentation, ECGs and clinical information. Stored samples were later analysed with hs-cTnT and hs-cTnI assays., Results: The ROC analysis for AMI (204 patients; 13.0%) for hs-cTnT and hs-cTnI after 2h was 0.95 (95% CI: 0.94-0.97) and 0.98 (95% CI: 0.97-0.99) respectively. The sensitivity, specificity, PLR, and NLR of hs-cTnT and hs-cTnI for AMI after 2h were 94.1% (95% CI: 90.0-96.6) and 95.6% (95% CI: 91.8-97.7), 79.0% (95% CI: 76.8-81.1) and 92.5% (95% CI: 90.9-93.7), 4.48 (95% CI: 4.02-5.00) and 12.86 (95% CI: 10.51-15.31), and 0.07 (95% CI: 0.04-0.13) and 0.05 (95% CI:0.03-0.09) respectively., Conclusions: Exclusion of AMI 2h after presentation in emergency patients with possible ACS can be achieved using hs-cTnT or hs-cTnI assays. Significant differences in specificity of these assays are relevant and if using the hs-cTnT assay, further clinical assessment in a larger proportion of patients would be required., (Copyright © 2013 The Canadian Society of Clinical Chemists. All rights reserved.)

Objectives: The study objective was to validate a new high-sensitivity troponin I (hs-TnI) assay in a clinical protocol for assessing patients who present to the emergency department with chest pain., Background: Protocols using sensitive troponin assays can accelerate the rule out of acute myocardial infarction in patients with low-risk (suspected) acute coronary syndrome (ACS)., Methods: This study evaluated 2 prospective cohorts of patients in the emergency department with ACS in an accelerated diagnostic pathway integrating 0- and 2-h hs-TnI results, Thrombolysis In Myocardial Infarction (TIMI) risk scores, and electrocardiography. Strategies to identify low-risk patients incorporated TIMI risk scores= 0 or ≤ 1. The primary endpoint was a major adverse cardiac event (MACE) within 30 days., Results: In the primary cohort, 1,635 patients were recruited and had 30-day follow-up. A total of 247 patients (15.1%) had a MACE. The finding of no ischemic electrocardiogram and hs-TnI ≤ 26.2 ng/l with the TIMI = 0 and TIMI ≤ 1 pathways, respectively, classified 19.6% (n = 320) and 41.5% (n = 678) of these patients as low risk; 0% (n = 0) and 0.8% (n = 2) had a MACE, respectively. In the secondary cohort, 909 patients were recruited. A total of 156 patients (17.2%) had a MACE. The TIMI = 0 and TIMI ≤ 1 pathways classified 25.3% (n = 230) and 38.6% (n = 351), respectively, of these patients as low risk; 0% (n = 0) and 0.8% (n = 1) had a MACE, respectively. Sensitivity, specificity, and negative predictive value for TIMI = 0 in the primary cohort were 100% (95% confidence interval [CI]: 98.5% to 100%), 23.1% (95% CI: 20.9% to 25.3%), and 100% (95% CI: 98.8% to 100%), respectively. Sensitivity, specificity, and negative predictive value for TIMI ≤ 1 in the primary cohort were 99.2 (95% CI: 97.1 to 99.8), 48.7 (95% CI: 46.1 to 51.3), and 99.7 (95% CI: 98.9 to 99.9), respectively. Sensitivity, specificity, and negative value for TIMI ≤ 1 in the secondary cohort were 99.4% (95% CI: 96.5 to 100), 46.5% (95% CI: 42.9 to 50.1), and 99.7% (95% CI: 98.4 to 100), respectively., Conclusions: An early-discharge strategy using an hs-TnI assay and TIMI score ≤ 1 had similar safety as previously reported, with the potential to decrease the observation periods and admissions for approximately 40% of patients with suspected ACS. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study, NCT00470587; A 2 hr Accelerated Diagnostic Protocol to Assess patients with chest Pain symptoms using contemporary Troponins as the only biomarker [ADAPT]: a prospective observational validation study, ACTRN12611001069943)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)