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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.

BackgroundThe majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death.MethodsTARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months.DiscussionThis randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction.Trial registrationClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019.

Additional file 1: Supplementary Table 1. List of participating hospitals and sites.

Additional file 2.

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.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m . The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularisation (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.

Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early-rule out pathway is safe and effective for patients with suspected acute coronary syndrome.\ud \ud Methods: We performed a stepped-wedge cluster randomized controlled trial in the Emergency Departments of seven acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were

Background: High-sensitivity cardiac troponin assays enable the early risk stratification of patients with suspected acute coronary syndrome to identify those at low risk of myocardial infarction or cardiac death. We evaluated the performance of a novel high-sensitivity cardiac troponin I assay in early rule out pathways. Methods: In 1,920 patients with suspected acute coronary syndrome, cardiac troponin was measured using the Siemens Atellica high-sensitivity cardiac troponin I assay (99th centile: 34 ng/L women, 53 ng/L men). We evaluated three pathways which use either low risk-stratification thresholds of cardiac troponin (High-STEACS and the European Society of Cardiology (ESC) 1-hour pathway), or the 99th centile diagnostic threshold (ESC 3-hour pathway) to rule out myocardial infarction.Results: The primary outcome of myocardial infarction or cardiac death at 30-days occurred in 14.4% (277/1,920). The High-STEACS pathway ruled out 63% of patients (1,218/1,920), with 5 missed events for a negative predictive value (NPV) of 99.5% (95% confidence interval [CI], 99.1 to 99.8%). Similar performance was observed for the ESC 1-hour pathway with a NPV of 99.0% (97.6 to 99.8%). In contrast, the ESC 3-hour pathway ruled out 65% of patients (1,248/1,920), but missed 25 events for a NPV of 98.0% (97.1 to 98.7%). Conclusions: A novel high-sensitivity cardiac troponin I assay can safely identify patients at low risk of myocardial infarction or cardiac death. Diagnostic pathways that utilise low cardiac troponin concentrations for risk stratification miss fewer events than those that rely on the 99th centile to rule out myocardial infarction.

Background: \ud High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.\ud \ud Methods: \ud In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6–12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123.\ud \ud Findings: \ud Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620).\ud \ud Interpretation: \ud Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population.\ud \ud Funding: \ud The British Heart Foundation.

Supplemental Digital Content is available in the text., Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the optimal approach is uncertain. We compared the European Society of Cardiology rule-out pathway with a pathway that incorporates lower cardiac troponin concentrations to risk stratify patients. Methods: Patients with suspected acute coronary syndrome (n=1218) underwent high-sensitivity cardiac troponin I measurement at presentation and 3 and 6 or 12 hours. We compared the European Society of Cardiology pathway (