Troponin in early presenters to rule out myocardial infarction.

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 AND RESULTS: 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 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, 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 with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, 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 7088 patients. CONCLUSION: 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.

Influence of Age on the Diagnosis of Myocardial Infarction.

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 (<50, 50-74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. 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 <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5-82.9), 80.6% (95% CI, 79.2-82.1), and 81.6% (95% CI, 79.8-83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1-98.5) to 95.5% (95% CI, 95.2-95.8), and 82.6% (95% CI, 81.9-83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%-91.9%] versus 82.6% [95% CI, 81.9%-83.4%]) and positive predictive value (59.3% [57.0%-61.5%] versus 51.5% [49.9%-53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%-57.9%] versus 81.6% [79.8%-83.3%]. 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.

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.

Risk factors for type 1 and type 2 myocardial infarction.

AIMS: Whilst the risk factors for type 1 myocardial infarction due to atherosclerotic plaque rupture and thrombosis are established, our understanding of the factors that predispose to type 2 myocardial infarction during acute illness is still emerging. Our aim was to evaluate and compare the risk factors for type 1 and type 2 myocardial infarction. METHODS AND RESULTS: We conducted a secondary analysis of a multi-centre randomized trial population of 48 282 consecutive patients attending hospital with suspected acute coronary syndrome. The diagnosis of myocardial infarction during the index presentation and all subsequent reattendances was adjudicated according to the Universal Definition of Myocardial Infarction. Cox regression was used to identify predictors of future type 1 and type 2 myocardial infarction during a 1-year follow-up period. Within 1 year, 1331 patients had a subsequent myocardial infarction, with 924 and 407 adjudicated as type 1 and type 2 myocardial infarction, respectively. Risk factors for type 1 and type 2 myocardial infarction were similar, with age, hyperlipidaemia, diabetes, abnormal renal function, and known coronary disease predictors for both (P < 0.05 for all). Whilst women accounted for a greater proportion of patients with type 2 as compared to type 1 myocardial infarction, after adjustment for other risk factors, sex was not a predictor of type 2 myocardial events [adjusted hazard ratio (aHR) 0.82, 95% confidence interval (CI) 0.66-1.01]. The strongest predictor of type 2 myocardial infarction was a prior history of type 2 events (aHR 6.18, 95% CI 4.70-8.12). CONCLUSIONS: Risk factors for coronary disease that are associated with type 1 myocardial infarction are also important predictors of type 2 events during acute illness. Treatment of these risk factors may reduce future risk of both type 1 and type 2 myocardial infarction.

Cardiac Troponin Thresholds and Kinetics to Differentiate Myocardial Injury and Myocardial Infarction.

BACKGROUND: Although the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It is unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. METHODS: In a secondary analysis of a multicenter randomized controlled trial, we identified 46 092 consecutive patients presenting with suspected acute coronary syndrome without ST-segment-elevation myocardial infarction. High-sensitivity cardiac troponin I concentrations at presentation and on serial testing were compared between patients with myocardial injury and infarction. The positive predictive value and specificity were determined at the sex-specific 99th percentile upper reference limit and rule-in thresholds of 64 ng/L and 5-fold of the upper reference limit for a diagnosis of type 1 myocardial infarction. RESULTS: Troponin was above the 99th percentile in 8188 patients (18%). The diagnosis was type 1 or type 2 myocardial infarction in 50% and 14% and acute or chronic myocardial injury in 20% and 16%, respectively. Troponin concentrations were similar at presentation in type 1 (median [25th-75th percentile] 91 [30-493] ng/L) and type 2 (50 [22-147] ng/L) myocardial infarction and in acute (50 [26-134] ng/L) and chronic (51 [31-130] ng/L) myocardial injury. The 99th percentile and rule-in thresholds of 64 ng/L and 5-fold upper reference limit gave a positive predictive value of 57% (95% CI, 56%-58%), 59% (58%-61%), and 62% (60%-64%) and a specificity of 96% (96%-96%), 96% (96%-96%), and 98% (97%-98%), respectively. The absolute, relative, and rate of change in troponin concentration were highest in patients with type 1 myocardial infarction (P<0.001 for all). Discrimination improved when troponin concentration and change in troponin were combined compared with troponin concentration at presentation alone (area under the curve, 0.661 [0.642-0.680] versus 0.613 [0.594-0.633]). CONCLUSIONS: Although we observed important differences in the kinetics, cardiac troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction in practice and should not guide management decisions in isolation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01852123.

High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial.

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. METHODS: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 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 <5 ng/L at presentation. During a previous validation phase, myocardial infarction was ruled out when troponin concentrations were <99th percentile at 6 to 12 hours after symptom onset. The coprimary outcome was length of stay (efficacy) and myocardial infarction or cardiac death after discharge at 30 days (safety). Patients were followed for 1 year to evaluate safety and other secondary outcomes. RESULTS: We enrolled 31 492 patients (59±17 years of age [mean±SD]; 45% women) with troponin concentrations <99th percentile at presentation. Length of stay was reduced from 10.1±4.1 to 6.8±3.9 hours (adjusted geometric mean ratio, 0.78 [95% CI, 0.73-0.83]; P<0.001) after implementation and the proportion of patients discharged increased from 50% to 71% (adjusted odds ratio, 1.59 [95% CI, 1.45-1.75]). Noninferiority was not demonstrated for the 30-day safety outcome (upper limit of 1-sided 95% CI for adjusted risk difference, 0.70% [noninferiority margin 0.50%]; P=0.068), but the observed differences favored the early rule-out pathway (0.4% [57/14 700] versus 0.3% [56/16 792]). At 1 year, the safety outcome occurred in 2.7% (396/14 700) and 1.8% (307/16 792) of patients before and after implementation (adjusted odds ratio, 1.02 [95% CI, 0.74-1.40]; P=0.894), and there were no differences in hospital reattendance or all-cause mortality. CONCLUSIONS: Implementation of an early rule-out pathway for myocardial infarction reduced length of stay and hospital admission. Although noninferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and health care providers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03005158.

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

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/1.73m2. 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 61 years; 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 revascularization (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.

Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

BACKGROUND: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. METHODS: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. RESULTS: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. CONCLUSIONS: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).

Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction.

AIMS: The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. METHODS AND RESULTS: In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong's test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82-0.85] and 0.85 (95% CI 0.81-0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70-0.77) and 0.73 (95% CI 0.66-0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P < 0.001 and P = 0.008, respectively). CONCLUSION: The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01852123.

High-Sensitivity Cardiac Troponin and the Universal Definition of Myocardial Infarction.

BACKGROUND: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood. METHODS: In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories. RESULTS: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12-6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33-3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82-1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes. CONCLUSIONS: Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Type 2 Myocardial Infarction: Evolving Approaches to Diagnosis and Risk-Stratification.

BACKGROUND: Type 2 myocardial infarction (T2MI) is frequently encountered in clinical practice and associated with adverse outcomes. CONTENT: T2MI occurs most frequently due to noncoronary etiologies that alter myocardial oxygen supply and/or demand. The diagnosis of T2MI is often confused with acute nonischemic myocardial injury, in part because of difficulties in delineating the nature of symptoms and misunderstandings about disease categorization. The use of objective features of myocardial ischemia using electrocardiographic (ECG) or imaging abnormalities may facilitate more precise T2MI diagnosis. High-sensitivity cardiac troponin (hs-cTn) assays allow rapid MI diagnosis and risk stratification, yet neither maximum nor delta values facilitate differentiation of T2MI from T1MI. Several investigational biomarkers have been evaluated for T2MI, but none have robust data. There is interest in evaluating risk profiles among patients with T2MI. Clinically, the magnitude of maximum and delta cTn values as well as the presence and magnitude of ischemia on ECG or imaging is used to indicate disease severity. Scoring systems such as GRACE, TIMI, and TARRACO have been evaluated, but all have limited to modest performance, with substantial variation in time intervals used for risk-assessment and endpoints used. SUMMARY: The diagnosis of T2MI requires biomarker evidence of acute myocardial injury and clear clinical evidence of acute myocardial ischemia without atherothrombosis. T2MIs are most often caused by noncoronary etiologies that alter myocardial oxygen supply and/or demand. They are increasingly encountered in clinical practice and associated with poor short- and long-term outcomes. Clinicians require novel biomarker or imaging approaches to facilitate diagnosis and risk-stratification.

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19.

BACKGROUND: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain. METHODS: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results. RESULTS: We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53-80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1-3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing. CONCLUSIONS: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.

Assessment and Treatment of Patients With Type 2 Myocardial Infarction and Acute Nonischemic Myocardial Injury.

Although coronary thrombus overlying a disrupted atherosclerotic plaque has long been considered the hallmark and the primary therapeutic target for acute myocardial infarction (MI), multiple other mechanisms are now known to cause or contribute to MI. It is further recognized that an MI is just one of many types of acute myocardial injury. The Fourth Universal Definition of Myocardial Infarction provides a taxonomy for acute myocardial injury, including 5 subtypes of MI and nonischemic myocardial injury. The diagnosis of MI is reserved for patients with myocardial ischemia as the cause of myocardial injury, whether attributable to acute atherothrombosis (type 1 MI) or supply/demand mismatch without acute atherothrombosis (type 2 MI). Myocardial injury in the absence of ischemia is categorized as acute or chronic nonischemic myocardial injury. However, optimal evaluation and treatment strategies for these etiologically distinct diagnoses have yet to be defined. Herein, we review the epidemiology, risk factor associations, and diagnostic tools that may assist in differentiating between nonischemic myocardial injury, type 1 MI, and type 2 MI. We identify limitations, review new research, and propose a framework for the diagnostic and therapeutic approach for patients who have suspected MI or other causes of myocardial injury.

High-Sensitivity Troponin and the Application of Risk Stratification Thresholds in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: Guidelines acknowledge the emerging role of high-sensitivity cardiac troponin (hs-cTnl) for risk stratification and the early rule-out of myocardial infarction, but multiple thresholds have been described. We evaluate the safety and effectiveness of risk stratification thresholds in patients with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome (n=48 282) were enrolled in a multicenter trial across 10 hospitals in Scotland. In a prespecified secondary and observational analysis, we compared the performance of the limit of detection (<2 ng/L) and an optimized risk stratification threshold (<5 ng/L) using the Abbott high-sensitivity troponin I assay. Patients with myocardial injury at presentation, with ≤2 hours of symptoms or with ST-segment elevation myocardial infarction were excluded. The negative predictive value was determined in all patients and in subgroups for a primary outcome of myocardial infarction or cardiac death within 30 days. The secondary outcome was myocardial infarction or cardiac death at 12 months, with risk modeled using logistic regression adjusted for age and sex. RESULTS: In total, 32 837 consecutive patients (61±17 years, 47% female) were included, of whom 23 260 (71%) and 12,716 (39%) had hs-cTnl concentrations of <5 ng/L and <2 ng/L at presentation. The negative predictive value for the primary outcome was 99.8% (95% CI, 99.7%-99.8%) and 99.9% (95% CI, 99.8%-99.9%) in those with hs-cTnl concentrations of <5 ng/L and <2 ng/L, respectively. At both thresholds, the negative predictive value was consistent in men and women and across all age groups, although the proportion of patients identified as low risk fell with increasing age. Compared with patients with hs-cTnl concentrations of ≥5 ng/L but <99th centile, the risk of myocardial infarction or cardiac death at 12 months was 77% lower in those <5 ng/L (5.3% vs 0.7%; adjusted odds ratio, 0.23 [95% CI, 0.19-0.28]) and 80% lower in those <2 ng/L (5.3% vs 0.3%; adjusted odds ratio, 0.20 [95% CI, 0.14-0.29]). CONCLUSIONS: Use of risk stratification thresholds for hs-cTnl identify patients with suspected acute coronary syndrome and at least 2 hours of symptoms as low risk at presentation irrespective of age and sex. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Exploring Patient Experience of Chest Pain Before and After Implementation of an Early Rule-Out Pathway for Myocardial Infarction: A Qualitative Study.

STUDY OBJECTIVE: High-sensitivity cardiac troponin assays enable myocardial infarction to be excluded in the emergency department (ED). As part of a prospective clinical trial, we explore how introducing an early rule-out pathway may affect patient experience of chest pain. METHODS: In a qualitative study, participants presenting to the ED with suspected acute coronary syndrome, and for whom the diagnosis of myocardial infarction was excluded, were interviewed before (n=23) or after (n=26) implementation of an early rule-out pathway. Preimplementation, diagnosis of myocardial infarction was excluded on serial troponin testing requiring admission to the hospital. Postimplementation, diagnosis could be excluded in the ED, enabling direct patient discharge. Semistructured interviews exploring the patients' illness experience were conducted approximately 1 week postdischarge, transcribed verbatim, and analyzed thematically. Themes emerging pre- and postimplementation are described. RESULTS: Common themes emerged across both pathways: participants commonly sought health care advice before presenting to the ED; a discordance may exist between the objective interpretation of troponin results by clinicians and the patients' experience of illness; and pretest information, trust in the clinician, and active listening may enhance reassurance gained from negative test results. Other themes related to the care pathway were that routine care procedures appeared to be a source of frustration for participants requiring hospital admission, and patients assessed with the early rule-out pathway appeared less likely to appraise their future health status. CONCLUSION: The early rule-out of myocardial infarction may be enhanced by recognition of patient out-of-hospital experience and improved communication surrounding reassurance and future cardiovascular health goals.

Long-Term Outcomes in Patients With Type 2 Myocardial Infarction and Myocardial Injury.

BACKGROUND: Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. METHODS: We identified consecutive patients (n=2122) with elevated cardiac troponin I concentrations (≥0.05 µg/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the universal definition of myocardial infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (eg, nonfatal myocardial infarction or cardiovascular death) and noncardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models. RESULTS: The adjudicated index diagnosis was type 1 or 2 myocardial infarction or myocardial injury in 1171 (55.2%), 429 (20.2%), and 522 (24.6%) patients, respectively. At 5 years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were because of noncardiovascular causes (hazard ratio, 2.32; 95% confidence interval, 1.92-2.81 versus type 1 myocardial infarction). Despite this finding, the observed crude major adverse cardiovascular event rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for covariates (hazard ratio, 0.82; 95% confidence interval, 0.69-0.96). Coronary heart disease was an independent predictor of major adverse cardiovascular events in those with type 2 myocardial infarction or myocardial injury (hazard ratio, 1.71; 95% confidence interval, 1.31-2.24). CONCLUSIONS: Despite an excess in noncardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of major adverse cardiovascular events as those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risk.

High-Sensitivity Cardiac Troponin I and Clinical Risk Scores in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: High-sensitivity cardiac troponin assays can help to identify patients who are at low risk of myocardial infarction in the emergency department. We aimed to determine whether the addition of clinical risk scores would improve the safety of early rule-out pathways for myocardial infarction. METHODS: In 1935 patients with suspected acute coronary syndrome, we evaluated the safety and efficacy of 2 rule-out pathways alone or in conjunction with low-risk TIMI (Thrombolysis In Myocardial Infarction) (0 or 1), GRACE (Global Registry of Acute Coronary Events) (≤108), EDACS (Emergency Department Assessment of Chest Pain Score) (<16), or HEART (History, ECG, Age, Risk factors, Troponin) (≤3) scores. The European Society of Cardiology 3-hour pathway uses a single diagnostic threshold (99th percentile), whereas the High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway applies different thresholds to rule out (<5 ng/L) and rule in (>99th percentile) myocardial infarction. RESULTS: Myocardial infarction or cardiac death during the index presentation or at 30 days occurred in 14.3% of patients (276/1935). The European Society of Cardiology pathway ruled out 70%, with 27 missed events giving a negative predictive value of 97.9% (95% CI, 97.1-98.6). The addition of a HEART score ≤3 reduced the proportion ruled out by the European Society of Cardiology pathway to 25% but improved the negative predictive value to 99.7% (95% CI, 99.0-100; P<0.001). The High-STEACS pathway ruled out 65%, with 3 missed events for a negative predictive value of 99.7% (95% CI, 99.4-99.9). No risk score improved the negative predictive value of the High-STEACS pathways, but all reduced the proportion ruled out (24% to 47%; P<0.001 for all). CONCLUSIONS: Clinical risk scores significantly improved the safety of the European Society of Cardiology 3-hour pathway, which relies on a single cardiac troponin threshold at the 99th percentile to rule in and rule out myocardial infarction. Where lower thresholds are used to rule out myocardial infarction, as applied in the High-STEACS pathway, risk scores halve the proportion of patients ruled out without improving safety. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01852123.

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome.

BACKGROUND: High-sensitivity cardiac troponin testing may improve the risk stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment, and the effectiveness of testing in this group is uncertain. METHODS: In a prospective multicenter study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate <60mL/min/1.73m2). The negative predictive value and sensitivity of troponin concentrations below the risk stratification threshold (5 ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value and specificity at the 99th centile diagnostic threshold (16 ng/L in women, 34 ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year. RESULTS: Of 4726 patients identified, 904 (19%) had renal impairment. Troponin concentrations <5 ng/L at presentation identified 17% of patients with renal impairment as low risk for the primary outcome (negative predictive value, 98.4%; 95% confidence interval [CI], 96.0%-99.7%; sensitivity 98.9%; 95%CI, 97.5%-99.9%), in comparison with 56% without renal impairment (P<0.001) with similar performance (negative predictive value, 99.7%; 95% CI, 99.4%-99.9%; sensitivity 98.4%; 95% CI, 97.2%-99.4%). The positive predictive value and specificity at the 99th centile were lower in patients with renal impairment at 50.0% (95% CI, 45.2%-54.8%) and 70.9% (95% CI, 67.5%-74.2%), respectively, in comparison with 62.4% (95% CI, 58.8%-65.9%) and 92.1% (95% CI, 91.2%-93.0%) in those without. At 1 year, patients with troponin concentrations >99th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% versus 10%; adjusted hazard ratio, 2.19; 95% CI, 1.54-3.11). CONCLUSIONS: In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low risk and more as high risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had a 2-fold greater risk of a major cardiac event than those with normal renal function, and should be considered for further investigation and treatment. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: The British Heart Foundation.