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Background and aims: Whether a single cardiac troponin measurement can safely rule-out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters.Methods: In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12 and >12 hours from symptom onset. The limit of detection (2 ng/L), rule-out (5 ng/L) and sex-specific 99th centile (16 ng/L women, 34 ng/L men) thresholds were compared. Results: In 41,103 consecutive patients (60 [17] years, 46% women), 12,595 (31%) presented within 3 hours and 3,728 (9%) had myocardial infarction. In those presenting ≤3 hours, a threshold of 2 ng/L had greater sensitivity and negative predictive value (99.4% [95% confidence interval 99.2-99.5%] and 99.7% [99.6-99.8%]) compared to 5 ng/L (96.5% [96.2-96.8%] and 99.3% [99.1- 99.4%]). In those presenting ≥3 hours, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% [70.6-72.2%] and 92.5% [92.0-93.0%], respectively. Findings were consistent in an external validation cohort of 7,088 patients.Conclusions: In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.

Background. In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays.Methods. In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1,688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients.Results. Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92-0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy.Conclusion. We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care.

Background: The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. Methods: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups ( Results: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients Conclusions: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population.

Importance: Type 2 myocardial infarction occurs owing to multiple factors associated with myocardial oxygen supply-demand imbalance, which may confer different risks of adverse outcomes.\ud \ud Objective: To evaluate the prevalence and outcomes of different factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction.\ud \ud Design, Setting, and Participants: In this secondary analysis of a stepped-wedge, cluster randomized clinical trial conducted at 10 secondary and tertiary care hospitals in Scotland, 6096 patients with an adjudicated diagnosis of type 1 or type 2 myocardial infarction from June 10, 2013, to March 3, 2016, were identified, and the findings were reported on August 28, 2018. The trial enrolled consecutive patients with suspected acute coronary syndrome. The diagnosis of myocardial infarction was adjudicated according to the Fourth Universal Definition of Myocardial Infarction and the primary factor associated with oxygen supply-demand imbalance in type 2 myocardial infarction was defined. This secondary analysis was not prespecified. Statistical analysis was performed from July 7 to 30, 2020.\ud \ud Intervention: Implementation of a high-sensitivity cardiac troponin I assay.\ud \ud Main Outcomes and Measures: All-cause death at 1 year according to the factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction.\ud \ud Results: Of 6096 patients (2602 women [43%]; median age, 70 years [IQR, 58-80 years]), 4981 patients had type 1 myocardial infarction, and 1115 patients had type 2 myocardial infarction. The most common factor associated with oxygen supply-demand imbalance was tachyarrhythmia (616 of 1115 [55%]), followed by hypoxemia (219 of 1115 [20%]), anemia (95 of 1115 [9%]), hypotension (89 of 1115 [8%]), severe hypertension (61 of 1115 [5%]), and coronary mechanisms (35 of 1115 [3%]). At 1 year, all-cause mortality occurred for 15% of patients (720 of 4981) with type 1 myocardial infarction and 23% of patients (285 of 1115) with type 2 myocardial infarction. Compared with patients with type 1 myocardial infarction, those with type 2 myocardial infarction owing to hypoxemia (adjusted odds ratio [aOR], 2.35; 95% CI, 1.72-3.18) and anemia (aOR, 1.83; 95% CI, 1.14-2.88) were at greatest risk of death, whereas those with type 2 myocardial infarction owing to tachyarrhythmia (aOR, 0.83; 95% CI, 0.65-1.06) or coronary mechanisms (aOR, 1.07; 95% CI, 0.17-3.86) were at similar risk of death as patients with type 1 myocardial infarction.\ud \ud Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, mortality after type 2 myocardial infarction was associated with the underlying etiologic factor associated with oxygen supply-demand imbalance. Most type 2 myocardial infarctions were associated with tachyarrhythmia, with better prognosis, whereas hypoxemia and anemia accounted for one-third of cases, with double the mortality of type 1 myocardial infarction. These differential outcomes should be considered by clinicians when determining which cases need to be managed if patient outcomes are to improve.\ud \ud Trial Registration: ClinicalTrials.gov Identifier: NCT01852123.

ObjectivesTo evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics.DesignIndividual patient level data meta-analysis and modelling study.SettingFourteen studies from 13 countries, including randomised controlled trials and prospective observational studies.ParticipantsIndividual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated.Main outcome measureAdjudicated diagnosis of acute heart failure.ResultsOverall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged 75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure.ConclusionsIn an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach.Study registrationPROSPERO CRD42019159407.

Additional file 1: eTable 1. Virology, laboratory tests at presentation with suspected COVID-19. eTable 2. Baseline characteristics of patients stratified according to whether the diagnosis of COVID-19 was confirmed or probable. eTable 3. Virology, laboratory tests at presentation stratified according to whether the diagnosis of COVID-19 was confirmed or probable. eTable 4. Use of serial testing in patients with suspected COVID-19. eTable 5. Diagnostic performance of the index and serial combined nasal and throat swab for the secondary outcome of a diagnosis of confirmed COVID-19 on serial testing. eFigure 1. Stack plot of the number of RT-PCR tests performed stratified according to whether the test was positive (red) or negative (blue). eFigure 2. Heat map of RT-PCR testing in patients with confirmed COVID-19 stratified according to whether the index test was negative (a) or positive (b). eFigure 3. Sensitivity of serial testing using the combined nasal and throat swab for the primary (confirmed and probable COVID-19) and secondary (confirmed COVID-19) outcome in patients who were tested at least four times. eFigure 4. Negative predictive value of serial testing using the combined nasal and throat swab for the primary (confirmed and probable COVID-19) and secondary (confirmed COVID-19) outcome in patients who were tested at least four times. eFigure 5. Forest plot of the (a) sensitivity and (b) negative predictive value of the index combined nasal and throat swab for a diagnosis of confirmed COVID-19 stratified by subgroups.