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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: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI)., Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain., Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016)., Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization., Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies., Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died., Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies., Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome., Primary Funding Source: Emergency Care Foundation.

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/)

Background: We aimed to evaluate the efficacy and safety of using high-sensitivity cardiac troponin T (hs-cTnT) within an accelerated diagnostic protocol (ADP) in patients presenting with symptoms suggestive of acute myocardial infarction (AMI) for rapid rule-out of AMI., Methods: In two independent large multicenter studies, levels of hs-cTnT at presentation and at 2 h were combined with the Thrombolysis In Myocardial Infarction (TIMI) risk score and ECG findings. The ADP defined patients with normal levels of hs-cTnT at presentation and 2 h, a TIMI score ≤1, and normal ECG findings as candidates for rapid rule-out of AMI and rapid discharge. Major adverse cardiac events (MACEs) occurring within 30-days were centrally adjudicated by two independent cardiologists., Results: In the derivation cohort, among 1085 consecutive patients 198 patients (18.2%) had a MACE. The ADP classified 374 patients (34.5%) as low-risk. None of these patients had a MACE at 30 days, resulting in a negative predictive value (NPV) of 100% (95% CI, 99.0-100%) and a sensitivity of 100% (95% CI, 98.2%-100%). In the validation cohort, among 1590 consecutive patients 231 patients (14.5%) had a MACE. The ADP classified 641 patients (40.3%) as low-risk. 6 of these patients had a MACE at 30 days, resulting in a NPV of 99.1% (95% CI, 98.0-99.6%) and a sensitivity of 97.4% (95% CI, 94.5-98.8%)., Conclusions: The ADP including hs-cTnT allows early identification 35 to 40% of patients to be at extremely low risk of MACE and therefore ideal candidates for outpatient management., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: High sensitivity assays for cardiac troponin (cTn) have reduced time to diagnosis of myocardial infarction (MI) but at costs to diagnostic specificity. We hypothesised that measurement of an upstream open reading frame peptide (uORF) from the human cTnT gene (TnTuORF) might improve cTn specificity in MI patients., Methods: A novel immunoassay to TnTuORF was developed and used to document circulating concentrations in normal healthy volunteers (n=150); assess potential trans-organ secretion in patients undergoing cardiac catheterisation (n=16); characterise temporal TnTuORF concentrations during ST-elevation MI (STEMI, n=4) and assess the potential of TnTuORF to assist the diagnosis and prognosis of MI in patients presenting with chest pain suspicious of ACS (n=502). Plasma immunoreactive TnTuORF was characterised on reverse phase and size exclusion HPLC., Results: In normal volunteers and suspected acute coronary syndrome (ACS) patients, TnTuORF had no relationship with TnI or TnT. Trans-organ venous sampling suggested TnTuORF secretion is not exclusively cardiac based. In STEMI patients, TnTuORF concentrations decreased for up to 12h after onset. In suspected ACS patients, TnTuORF could not diagnose MI (ROC AUC=0.446, P=0.117) but could diagnose cardiac disorders other than MI (AUC=0.79, P<0.001)., Conclusion: This is the first evidence for a circulating uORF peptide. TnTuORF does not appear to aid the diagnosis of MI but further studies to assess its potential in cardiovascular disease are required., (Copyright © 2015 Elsevier Ireland Ltd. 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.)

Objective: To investigate whether a high-sensitivity troponin assay, shown to improve early detection of acute myocardial infarction (AMI), permits accelerated rule-in/rule-out of AMI., Methods: Patients who presented to the emergency department within 4 h of the onset of chest pain suggestive of acute coronary syndrome were prospectively recruited from November 2007 to April 2010. Blood samples were taken at 0, 1, 2 and 12-24 h after presentation and were analysed for clinically applied troponin I and for high-sensitivity troponin T (hsTnT). The dynamic change in hsTnT levels between time points was measured. The primary outcome was admission diagnosis of AMI., Results: Of the 385 patients recruited, 82 (21.3%) had AMI. The sensitivity of hsTnT by 2 h was 95.1% (88.7-98.1%), specificity 75.6% (73.8-76.5%), positive predictive value 53.8% (50.2-55.5%) and negative predictive value 98.3% (96.0-99.3%). The sensitivity was not statistically different between peak values at 2 h and 24 h. Adding ECG results reduced the false negative rate to 1.2%. The additional application of ≥20% delta criterion over the 2 h period for 0-2 h samples increased specificity to 92.4% (90.2-94.3%) but reduced sensitivity to 56.1% (48.0-63.2%)., Conclusion: hsTnT taken at 0 and 2 h after presentation, together with ECG results, could identify patients suitable for early stress testing with a false negative rate for AMI of 1.2%. Further trials of such an approach are warranted. The specificity of hsTnT for diagnosing AMI could be improved by the use of a delta of ≥20%, but at the cost of major reductions in sensitivity.

Objectives: The purpose of this study was to determine whether a new accelerated diagnostic protocol (ADP) for possible cardiac chest pain could identify low-risk patients suitable for early discharge (with follow-up shortly after discharge)., Background: Patients presenting with possible acute coronary syndrome (ACS), who have a low short-term risk of adverse cardiac events may be suitable for early discharge and shorter hospital stays., Methods: This prospective observational study tested an ADP that included pre-test probability scoring by the Thrombolysis In Myocardial Infarction (TIMI) score, electrocardiography, and 0 + 2 h values of laboratory troponin I as the sole biomarker. Patients presenting with chest pain due to suspected ACS were included. The primary endpoint was major adverse cardiac event (MACE) within 30 days., Results: Of 1,975 patients, 302 (15.3%) had a MACE. The ADP classified 392 patients (20%) as low risk. One (0.25%) of these patients had a MACE, giving the ADP a sensitivity of 99.7% (95% confidence interval [CI]: 98.1% to 99.9%), negative predictive value of 99.7% (95% CI: 98.6% to 100.0%), specificity of 23.4% (95% CI: 21.4% to 25.4%), and positive predictive value of 19.0% (95% CI: 17.2% to 21.0%). Many ADP negative patients had further investigations (74.1%), and therapeutic (18.3%) or procedural (2.0%) interventions during the initial hospital attendance and/or 30-day follow-up., Conclusions: Using the ADP, a large group of patients was successfully identified as at low short-term risk of a MACE and therefore suitable for rapid discharge from the emergency department with early follow-up. This approach could decrease the observation period required for some patients with chest pain. (An observational study of the diagnostic utility of an accelerated diagnostic protocol using contemporary central laboratory cardiac troponin in the assessment of patients presenting to two Australasian hospitals with chest pain of possible cardiac origin; ACTRN12611001069943)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)