Diagnostic Performance of High-Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite US Cohort
Abstract
Background:
European data support the use of low high-sensitivity troponin (hs-cTn) measurements or a 0/1-hour (0/1-h) algorithm for myocardial infarction to exclude major adverse cardiac events (MACEs) among patients in the emergency department with possible acute coronary syndrome. However, modest US data exist to validate these strategies. This study evaluated the diagnostic performance of an initial hs-cTnT measure below the limit of quantification (LOQ: 6 ng/L), a 0/1-h algorithm, and their combination with history, ECG, age, risk factors, and initial troponin (HEART) scores for excluding MACE in a multisite US cohort.
Methods:
A prospective cohort study was conducted at 8 US sites, enrolling adult patients in the emergency department with symptoms suggestive of acute coronary syndrome and without ST-elevation on ECG. Baseline and 1-hour blood samples were collected, and hs-cTnT (Roche; Basel, Switzerland) was measured. Treating providers blinded to hs-cTnT results prospectively calculated HEART scores. MACE (cardiac death, myocardial infarction, and coronary revascularization) at 30 days was adjudicated. The proportion of patients with initial hs-cTnT measures below the LOQ and risk according to a 0/1-h algorithm was determined. The negative predictive value (NPV) was calculated for both strategies when used alone or with a HEART score.
Results:
Among 1462 participants with initial hs-cTnT measures, 46.4% (678 of 1462) were women and 37.1% (542 of 1462) were Black with an age of 57.6±12.9 (mean±SD) years. MACEs at 30 days occurred in 14.4% (210 of 1462) of participants. Initial hs-cTnT measures below the LOQ occurred in 32.8% (479 of 1462), yielding an NPV of 98.3% (95% CI, 96.7–99.3) for 30-day MACEs. A low-risk HEART score with an initial hs-cTnT below the LOQ occurred in 20.1% (294 of 1462), yielding an NPV of 99.0% (95% CI, 97.0–99.8) for 30-day MACEs. A 0/1-h algorithm was complete in 1430 patients, ruling out 57.8% (826 of 1430) with an NPV of 97.2% (95% CI, 95.9–98.2) for 30-day MACEs. Adding a low HEART score to the 0/1-h algorithm ruled out 30.8% (441 of 1430) with an NPV of 98.4% (95% CI, 96.8–99.4) for 30-day MACEs.
Conclusions:
In a prospective multisite US cohort, an initial hs-cTnT below the LOQ combined with a low-risk HEART score has a 99% NPV for 30-day MACEs. The 0/1-h hs-cTnT algorithm did not achieve an NPV >99% for 30-day MACEs when used alone or with a HEART score.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02984436.
Clinical Perspective
What Is New?
•
In the largest prospective multisite US study of high-sensitivity cardiac troponin T (hs-cTnT) strategies to date, an initial hs-cTnT below the level of quantification (<6 ng/L) was associated with a negative predictive value (NPV) of 98.3% (95% CI, 96.7–99.3) for 30-day major adverse cardiac events.
•
A 0/1-hour algorithm ruled out 57.8% of patients with an NPV of 97.2% (95% CI, 95.9–98.2) for 30-day major adverse cardiac events.
•
The addition of a low-risk history, ECG, age, risk factors, and troponin (HEART) score to an initial hs-cTnT below the level of quantification and the 0/1-hour algorithm improved NPV for 30-day major adverse cardiac events to 99.0% (95% CI, 97.0–99.8) and 98.4% (95% CI, 96.8–99.4), respectively.
What Are the Clinical Implications?
•
When used without a risk score, an initial hs-cTnT measure below the level of quantification or a 0/1-hour algorithm may have insufficient sensitivity and NPV to exclude 30-day major adverse cardiac events in US patients in an emergency department.
•
The addition of a low-risk HEART score to an initial hs-cTnT measure below the level of quantification and a 0/1-hour algorithm, improves sensitivity and NPV for cardiac events but rules out fewer patients.
•
In total, our results suggest that adding a risk score to hs-cTnT strategies increases their safety.
Among patients presenting to the emergency department (ED) with symptoms concerning for acute coronary syndrome (ACS), clinicians rely on cardiac troponin (cTn) measures to diagnose and exclude myocardial infarction (MI) and injury.1–3 High-sensitivity cTn (hs-cTn) T and I assays, which have recently been approved for use in the United States, can quantify lower cTn concentrations with greater precision than prior cTnT or cTnI assays.4 Although hs-cTn assays have been used in Europe, Canada, and the Asia-Pacific region for many years and are well studied there, prospective data on their performance in US populations remain limited.5,6
Two important hs-cTn risk stratification strategies have emerged from international data: use of an initial very low hs-cTnT measure (below the limit of quantification [LOQ]) and use of an algorithm with an initial and 1-hour hs-cTnT measure (0/1-h algorithm), which is currently recommended by the European Society of Cardiology.7–11 Some US hospitals that have transitioned to hs-cTn have integrated these strategies into their risk stratification algorithms for patients with possible ACS.12 In addition, most of these algorithms also incorporate electrocardiographic data and risk scores such as the history, ECG, age, risk factors, and initial troponin (HEART) score into their clinical decision making. Recent analyses of the HIGH US (High-Sensitivity Cardiac Troponin I in the United States) cohort suggested that single low hs-cTn measures and a 0/1-h algorithm using a Siemens hs-cTnI assay are safe strategies for excluding MI in a US population of patients with possible ACS.6,13,14 However, multisite US data for these strategies using hs-cTnT assay are lacking.15–18 In addition, few studies have evaluated the utility of adding clinical variables such as electrocardiographic ischemia and HEART score to hs-cTn strategies.19 Furthermore, although the ability of hs-cTnT assays to detect MI during patients’ index ED encounters has been established, their ability to detect downstream major adverse cardiac events (MACEs) such as cardiac death, MI, and revascularization is less clear.
This study was designed to address these evidence gaps and to determine whether aspects of hs-cTnT use are uniquely American. Thus, this study aimed to prospectively evaluate the diagnostic performance (safety and efficacy) of the Roche hs-cTnT assay for the detection of 30-day MACEs and the composite of cardiac death or MI at 30 days using an initial hs-cTnT below the LOQ and a 0/1-h algorithm with or without the inclusion of important clinical variables: interpretation of the ECG and the HEART score.
Methods
Study Design and Oversight
This is a prospective observational cohort study of patients in the ED with acute chest pain or other symptoms suggestive of ACS enrolled at 8 US EDs from January 25, 2017, to September 6, 2018 (University of Florida, Gainesville; Wake Forest University, Winston-Salem, NC; Henry Ford Health System, Detroit, MI; University of Maryland St. Joseph Medical Center, Towson; University of Maryland Medical Center, Baltimore; University of Maryland Baltimore Washington Medical Center, Glen Burnie; University of California-Davis, Sacramento; and University of Utah, Salt Lake City). Before the study start, ethics approval was obtained from all relevant institutional review boards, and the study was registered at ClinicalTrials.gov (Unique identifier: NCT02984436). The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization guidelines for good clinical practice, and the Code of Federal Regulations 21, Part 50. The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Study Setting and Population
Patients ≥21 years of age presenting to the ED with chest discomfort or other symptoms consistent with possible ACS were prospectively enrolled. Possible ACS was defined by the ED provider ordering serial troponins. Exclusion criteria included ST-segment elevation MI at ED presentation, systolic blood pressure <90 mm Hg, a life expectancy of <90 days, a noncardiac illness requiring admission, lack of capacity to provide consent, inability to be contacted for follow-up, non–English speaking, pregnancy, and prior enrollment in the current study. To be included in this analysis, patients meeting the above criteria were required to be enrolled within 1 hour of the site’s first clinical blood draw and to have a second standard-of-care cTn measurement within the next 2 to 12 hours.
Study Procedures
After written informed consent was obtained, serial blood samples were collected from study participants for hs-cTnT analysis at baseline (<1 hour from first clinical sample) and 1, 2, and 3 hours later plus or minus 30 minutes. Treating providers were blinded to hs-cTnT results. Thus, the care of participants was determined by the local standard of care, based in part on their local contemporary cTn results. Each patient had an ECG performed as part of routine clinical care that was interpreted prospectively by the treating ED provider and recorded on the STOP-CP (High Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification) treating provider case report form. ECGs were defined as ischemic if they had new T-wave inversions or ST-segment depressions >1 mm in at least 2 contiguous leads. In addition, HEART score data were collected prospectively from the treating ED provider. For this analysis, the history, ECG, age, and risk factor (HEAR) components of the HEART score from the treating provider were used in combination with the hs-cTnT value. Consistent with prior studies, a score of 0 to 3 was considered low risk, and scores ≥4 were not low risk.20–22
Blood samples for hs-cTnT measurement were collected in lithium heparin and EDTA tubes. After collection, samples were centrifuged for 10 to 15 minutes and maintained in storage at –70° C. hs-cTnT concentrations were measured by a central laboratory (University of Maryland School of Medicine, Baltimore) by personnel blinded to the time of collection and other patient information and using the troponin T high-sensitivity assay on the cobas e 601 analyzer. The assay is an electrochemiluminescence sandwich immunoassay that uses both ruthenium-labeled and biotin-labeled antibodies to form a sandwich complex with cTnT. It has a measuring range of 3 to 10 000 ng/L and a LOQ of 6 ng/L. Although the limit of blank for the hs-cTnT used in this analysis has been reported to be 3 ng/L, results less than the LOQ are not reported in the United States, per US Food and Drug Administration specification. The assay has an overall 99th percentile upper reference limit of 19 ng/L in the United States with a coefficient of variation of <10%.23 No changes occurred in the manufacturing or specifications of this assay during the duration of this study.
Outcomes
The primary outcome for this study was MACEs (cardiac death, MI, and coronary revascularization) at 30 days inclusive of index-visit events. Secondary outcomes included the composite of cardiac death or MI and individual components of the MACE outcomes at index visit and 30 days. Thirty-day phone follow-up calls and medical record reviews were completed on all participants to identify MACE outcomes. Patients with a clinical diagnosis of MI, an elevated local contemporary cTn, or death during the follow-up period were adjudicated by expert reviewers (M.H.i.V., M.M., J.P.S., J.M.). Adjudicators classified deaths as cardiac or noncardiac. Cardiac death was defined according to the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes).24 Death resulting from stroke was not considered a cardiac death. In cases when the cause of death could not be determined, the death was considered cardiovascular. To determine MI, adjudicators used the Fourth Universal Definition of MI: rise or fall of troponin with at least 1 value above the 99th percentile of the upper reference limit with at least 1 of the following: (1) symptoms of ischemia, (2) electrocardiographic changes indicative of new ischemia, (3) development of pathological Q waves on the ECG, or (4) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.3 Coronary revascularization was defined as coronary artery bypass grafting or angioplasty with or without stent placement. Adjudicators had access to all clinical data, including the local clinical contemporary troponin assay results, but were blinded to hs-cTnT results. Any discrepancies between adjudicators were resolved through review by the third adjudicator.
Statistical Analysis
All study data were collected by individual sites and managed in Research Electronic Data Capture version 9.1.1.25 Statistical analyses were performed with R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics, including means, SDs, frequencies, and percent, appropriate for measurement level were used to examine distribution of values and to identify missing and extreme values for verification. hs-cTnT strategies evaluated included an initial hs-cTnT below the LOQ and a 0/1-h algorithm with or without the inclusion of interpretation of the ECG and HEART score. To evaluate test performance of these strategies and cut points, measures of efficacy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by the construction of 2×2 contingency tables.26 Consistent with prior studies, an NPV ≥99% was considered sufficient for the clinical use of a rule-out strategy.27,28 Efficacy was defined as the proportion of the cohort who would be ruled out by a cut point or algorithm, which is consistent with prior hs-cTn studies.29–31 Their 95% CIs were calculated by the Clopper-Pearson exact method with the GenBinomApps package.32
Next, the cohort was stratified into early presenters (patients presenting within <3 hours of symptoms) and late presenters (presenting ≥3 hours of symptoms) and test performance of hs-cTnT strategy, including or excluding clinical variables of ischemic or nonischemic ECG and treating provider HEART score calculation. The bayesian logistic regression was performed to impute the missing values and to study the effect of loss to follow-up with the mice.impute.logreg function in R package mice. Missing follow-up data were imputed from demographic variables and troponin results. The imputation procedure was repeated 25 times, and results were averaged among the 25 imputed data sets.
Four sensitivity analyses were conducted. First, to assess whether test performance differed when patients were adjudicated on the basis of hs-cTnT measures, patients were readjudicated for MACE outcomes using hs-cTnT results with the adjudicators blinded to the local contemporary troponin assay measures. Second, test performance was evaluated after outcomes for patients lost to follow-up were imputed (n=25 data sets) using multiple imputation based on patients’ demographics, cardiovascular risk factors, and hs-cTnT results. Third, test performance was evaluated after including only type 1 MI, rather than both type 1 and 2 MIs, in the MACE and cardiac death and MI composite outcomes. Last, we tested whether performance differed if patients with an uncertain cause of death were classified as having noncardiovascular deaths.
Results
A total of 1583 patients with symptoms suggestive of ACS were enrolled, of whom 1462 were eligible for analysis (Figure 1). Of these, 46.4% (678 of 1462) were women and 37.1% (542 of 1462) were Black. The average age was 57.6±12.9 years (mean±SD). Additional characteristics of the STOP CP cohort are summarized in Table 1. Samples for hs-cTnT measurement were collected at 0 hours in 99.9% (1460 of 1462) and at 1 hour in 97.9% (1432 of 1462) of participants. The median time from ED arrival to baseline study blood draw was 82 minutes (interquartile range, 63–106 minutes). Follow-up at 30 days was complete in 96.2% of patients (1406 of 1462), with 3.8% (56 of 1462) lost to follow-up. MACEs at 30 days occurred in 14.4% (210 of 1462). This included 0.6% (9 of 1462) with cardiac death, 12.7% (185 of 1462) with MI, and 1.6% (24 of 1462) with coronary revascularization without MI. MACEs at the index visit occurred in 12.4% (181 of 1462), with index cardiac deaths in 0.1% (2 of 1462), MI in 11.6% (169 of 1462), and revascularization without MI in 0.8% (11 of 1462). After the index visit (during the 30-day follow-up period), MACEs occurred in 3.1% (46 of 1462), with 0.5% (7 of 1462) having cardiac death, 1.8% (26 of 1462) with MI, and 1.0% (14 of 1462) with revascularization without MI.
Patient characteristics | With MACEs (n=210) | Without MACEs (n=1252) | Total (n=1462) |
---|---|---|---|
Age, mean±SD, y | 61.4±12.1 | 57.0±12.9 | 57.6±12.9 |
Sex, n (%) | |||
Female | 66 (31.4) | 612 (48.9) | 678 (46.4) |
Race, n (%) | |||
American Indian/Alaska Native | 4 (2.0) | 20 (1.6) | 24 (1.6) |
Asian | 2 (1.0) | 10 (0.8) | 12 (0.8) |
Native Hawaiian | 0 (0.0) | 2 (0.2) | 2 (0.1) |
Black or African American | 64 (30.5) | 478 (38.2) | 542 (37.1) |
White | 135 (64.3) | 704 (56.2) | 839 (57.4) |
Other | 5 (2.4) | 38 (3.0) | 43 (2.9) |
Ethnicity, n (%) | |||
Hispanic or Latino | 6 (2.9) | 55 (4.4) | 61 (4.2) |
Not Hispanic or Latino | 199 (94.8) | 1187 (94.8) | 1386 (94.8) |
Unknown | 5 (2.4) | 10 (0.8) | 15 (1.0) |
Risk factors, n (%) | |||
Current or history of smoking | 117 (55.7) | 689 (55) | 806 (55.1) |
Current or history of cocaine use | 30 (14.3) | 141 (11.3) | 171 (11.7) |
Hypertension | 161 (76.7) | 809 (64.6) | 970 (66.3) |
Hyperlipidemia | 125 (59.5) | 567 (45.3) | 692 (47.3) |
Diabetes | 84 (40.0) | 347 (27.7) | 431 (29.5) |
Family history of coronary disease | 102 (48.6) | 572 (45.7) | 674 (46.1) |
BMI >30 kg/m2 | 96 (45.7) | 658 (52.6) | 754 (51.6) |
Prior coronary disease | 114 (54.3) | 359 (28.7) | 473 (32.4) |
Prior MI | 82 (39.0) | 236 (18.8) | 318 (21.8) |
Prior PCI | 65 (31.0) | 181 (14.5) | 246 (16.8) |
Prior CABG* | 39 (18.6) | 66 (5.3) | 105 (7.2) |
Prior cerebral vascular accident | 25 (11.9) | 133 (10.6) | 158 (10.8) |
Prior peripheral vascular disease | 21 (10.0) | 69 (5.5) | 90 (6.2) |
Prior end-stage renal disease | 19 (9.0) | 54 (4.3) | 73 (5.0) |
Prior congestive heart failure | 68 (32.4) | 238 (19.0) | 306 (20.9) |
Chest pain at ED arrival, n (%)* | 124 (59.3) | 889 (71.0) | 1013 (69.6) |
Chest pain onset, n (%)* | |||
≤3 h from arrival (early) | 79 (37.8) | 437 (35.1) | 516 (35.5) |
>3 h from arrival (late) | 130 (62.2) | 808 (64.9) | 938 (64.5) |
ECG at arrival, n (%) | |||
Ischemic ECG | 26 (12.4) | 65 (5.2) | 91 (6.2) |
Nonischemic ECG | 184 (87.6) | 1187 (94.8) | 1371 (93.8) |
HEART score, median (IQR) | 6 (5–7) | 4 (3–5) | 4 (3–5) |
Time from arrival to initial sample, median (IQR), min | 78 (62–97) | 82 (63–107) | 82 (63–105) |
Initial study hs-cTnT sample, median (IQR), ng/L | 44.6 (22.4–104.7) | 7.88 (4.61–15.4) | 9.22 (4.91–21.2) |
Creatinine at index visit, median (IQR), mg/dL | 1.01 (0.84–1.42) | 0.90 (0.76–1.11) | 0.92 (0.77–1.13) |
BMI indicates body mass index; CABG, coronary artery bypass graft; ED, emergency department; HEART, history, ECG, age, risk factors, and troponin; hs-cTnT, high-sensitivity cardiac troponin T; IQR, interquartile range; MACE, major adverse cardiac event; MI, myocardial infarction; PCI, percutaneous coronary intervention; and STOP CP, High Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification.
*
Missing responses for prior CABG (n=1), chest pain at ED arrival (n=6), and chest pain onset (n=8).

Diagnostic Performance of LOQ
Diagnostic performance of the initial hs-cTnT measures below the LOQ (<6 ng/L) is presented in Table 2. Initial hs-cTnT measures below the LOQ occurred in 32.8% (95% CI, 30.4–35.3) of the cohort. Among these patients, 0 had cardiac death, 5 had MI, and 3 had revascularization without MI during the 30-day follow-up. Thus, the NPV of an initial hs-cTnT measure below the LOQ was 98.3% (95% CI, 96.7–99.3) for MACEs at 30 days with a sensitivity of 96.2% (95% CI, 92.6–98.3). For cardiac death and MI at 30 days, the NPV was 99.0% (95% CI, 97.6–99.7) and sensitivity was 97.4% (95% CI, 94.0–99.1). For index-visit MI, the NPV was 99.2% (95% CI, 97.9–99.8) and sensitivity was 97.6% (95% CI, 94.1–99.4). The characteristics of the 8 patients with an initial hs-cTnT below the LOQ who experienced MACEs are summarized in Table I in the Data Supplement.
Risk stratification strategy | Sensitivity (95% CI), % | Specificity (95% CI), % | PPV (95% CI), % | NPV (95% CI), % | Efficacy (95% CI), % |
---|---|---|---|---|---|
30-d MACEs | |||||
hs-cTnT <6 ng/L | 96.2 (92.6–98.3) | 37.7 (35.0–40.4) | 20.6 (18.1–23.3) | 98.3 (96.7–99.3) | 32.8 (30.4–35.3) |
hs-cTnT <6 ng/L and nonischemic ECG | 96.2 (92.6–98.3) | 36.6 (34.0–39.4) | 20.3 (17.9–23.0) | 98.3 (96.6–99.3) | 31.9 (29.5–34.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 98.6 (95.9–99.7) | 37.4 (34.7–40.2) | 20.5 (18.0–23.2) | 99.0 (97.0–99.8) | 20.1 (18.1–22.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 98.6 (95.9–99.7) | 36.5 (33.8–39.2) | 20.3 (17.8–22.9) | 99.0 (97.0–99.8) | 20.1 (18.0–22.2) |
30-d Cardiac death and MI | |||||
hs-cTnT <6 ng/L | 97.4 (94.0–99.1) | 37.3 (34.7–40.0) | 18.9 (16.5–21.4) | 99.0 (97.6–99.7) | 32.8 (30.4–35.3) |
hs-cTnT <6 ng/L and nonischemic ECG | 97.4 (94.0–99.1) | 36.3 (33.6–39.0) | 18.6 (16.2–21.2) | 98.9 (97.5–99.7) | 31.9 (29.5–34.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 99.5 (97.1–100.0) | 37.1 (34.4–39.8) | 18.8 (16.4–21.4) | 99.7 (98.1–100.0) | 20.1 (18.1–22.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 99.5 (97.1–100.0) | 36.1 (33.5–38.9) | 18.6 (16.2–21.1) | 99.7 (98.1–100.0) | 20.1 (18.0–22.2) |
Index-visit MI | |||||
hs-cTnT <6 ng/L | 97.6 (94.1–99.4) | 36.8 (34.2–39.5) | 16.8 (14.5–19.3) | 99.2 (97.9–99.8) | 32.8 (30.4–35.3) |
hs-cTnT <6 ng/L and nonischemic ECG | 97.6 (94.1–99.4) | 35.8 (33.2–38.5) | 16.6 (14.3–19.1) | 99.1 (97.8–99.8) | 31.9 (29.5–34.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 99.4 (96.7–100.0) | 36.6 (33.9–39.3) | 16.8 (14.5–19.3) | 99.7 (98.1–100.0) | 20.1 (18.1–22.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 99.4 (96.7–100.0) | 35.6 (33.0–38.3) | 16.6 (14.3–19.0) | 99.7 (98.1–100.0) | 20.1 (18.0–22.2) |
HEART indicates history, ECG, age, risk factors, and troponin; hs-cTnT, high-sensitivity cardiac troponin T; LOQ, limit of quantification; MACE, major adverse cardiac event; MI, myocardial infarction; NPV, negative predictive value; and PPV, positive predictive value.
Additional diagnostic test characteristics of an initial hs-cTnT measure below the LOQ with and without clinical variables are summarized in Table 2. The addition of a nonischemic ECG to an initial hs-cTnT below the LOQ had an efficacy of 31.9% (95% CI, 29.5–34.4) with an NPV of 98.3% (95% CI, 96.6–99.3) and 98.9% (95% CI, 97.5–99.7) for 30-day MACEs and 30-day cardiac death or MI, respectively. For index-visit MI, the NPV was 99.1% (95% CI, 97.8–99.8) and sensitivity was 97.6% (95% CI, 94.1–99.4). A HEART score of 0 to 3 with an initial hs-cTnT below the LOQ had an efficacy of 20.1% (95% CI, 18.1–22.3) with an NPV of 99.0% (95% CI, 97.0–99.8) for 30-day MACEs and 99.7% (95% CI, 98.1–100.0) for 30-day cardiac death or MI. For index-visit MI, the NPV was 99.7% (95% CI, 98.1–100.0) and sensitivity was 99.4% (95% CI, 96.7–100.0). An initial hs-cTnT below the LOQ combined with both a nonischemic ECG and HEART score of 0 to 3 had an efficacy of 20.1% (95% CI, 18.0–22.2) with an NPV of 99.0% (95% CI, 97.0–99.8) and 99.7% (95% CI, 98.1–100.0) for 30-day MACEs and 30-day cardiac death or MI, respectively. For index-visit MI, the NPV was 99.7% (95% CI, 98.1–100.0) and sensitivity was 99.4% (95% CI, 96.7–100.0).
Diagnostic Performance of the 0/1-h Algorithm
Diagnostic performance of the hs-cTnT 0/1-h algorithm is presented in Table 3 and Figure 2. Among 1430 patients with 0- and 1-hour hs-cTnT measurements, 57.8% (826 of 1430) had values in the rule-out range, 29.0% (414 of 1430) had values in the observation zone, and 13.3% (190 of 1430) had values in the rule-in range. The rule-out range had an NPV of 97.2% (95% CI, 95.9–98.2) and a sensitivity of 88.7% (95% CI, 83.5–92.7) for 30-day MACEs. For 30-day cardiac death or MI, the rule-out range had an NPV of 98.4% (95% CI, 97.3–99.2) and a sensitivity of 92.9% (95% CI, 88.2–96.2). Index-visit MI occurred in 1.0% (8 of 826) of patients in the rule-out range with an NPV of 99.0% (95% CI, 98.1–99.6) and a sensitivity of 95.1% (95% CI, 90.6–97.9).
Risk stratification strategy | Sensitivity (95% CI) | Specificity (95% CI) | PPV (95% CI) | NPV (95% CI) | Efficacy (95% CI) |
---|---|---|---|---|---|
30-d MACEs | |||||
0/1-h | 88.7 (83.5–92.7) | 93.6 (92.0–94.9) | 58.4 (51.1–65.5) | 97.2 (95.9–98.2) | 57.8 (55.2–60.3) |
0/1-h and nonischemic ECG | 88.7 (83.5–92.7) | 89.0 (87.1–90.7) | 47.3 (41.0–53.6) | 97.1 (95.7–98.2) | 55.7 (53.1–58.3) |
0/1-h and HEART score 0–3 | 96.6 (93.0–98.6) | 88.9 (87.0–90.6) | 48.7 (42.5–54.9) | 98.4 (96.8–99.4) | 30.8 (28.5–33.3) |
0/1-h and HEART score 0–3 and nonischemic ECG | 96.6 (93.0–98.6) | 85.5 (83.4–87.4) | 42.6 (37.0–48.3) | 98.4 (96.7–99.4) | 30.7 (28.3–33.2) |
30-d Cardiac death and MI | |||||
0/1-h | 92.9 (88.2–96.2) | 93.7 (92.2–95.0) | 58.4 (51.1–65.5) | 98.4 (97.3–99.2) | 57.8 (55.2–60.3) |
0/1-h and nonischemic ECG | 92.9 (88.2–96.2) | 89.0 (87.1–90.7) | 46.5 (40.3–52.8) | 98.4 (97.2–99.1) | 55.7 (53.1–58.3) |
0/1-h and HEART score 0–3 | 98.4 (95.3–99.7) | 88.9 (87.1–90.6) | 47.9 (41.8–54.1) | 99.3 (98.0–99.9) | 30.8 (28.5–33.3) |
0/1-h and HEART score 0–3 and nonischemic ECG | 98.4 (95.3–99.7) | 85.5 (83.4–87.4) | 41.6 (36.1–47.3) | 99.3 (98.0–99.9) | 30.7 (28.3–33.2) |
Index-visit MI | |||||
0/1-h | 95.1 (90.6–97.9) | 93.3 (91.8–94.6) | 55.3 (47.9–62.5) | 99.0 (98.1–99.6) | 57.8 (55.2–60.3) |
0/1-h and nonischemic ECG | 95.1 (90.6–97.9) | 88.6 (86.7–90.3) | 43.8 (37.6–50.1) | 99.0 (98.0–99.6) | 55.7 (53.1–58.3) |
0/1-h and HEART score 0–3 | 98.8 (95.7–99.9) | 88.5 (86.7–90.2) | 45.3 (39.2–51.5) | 99.5 (98.4–99.9) | 30.8 (28.5–33.3) |
0/1-h and HEART score 0–3 and nonischemic ECG | 98.8 (95.7–99.9) | 85.2 (83.1–87.1) | 39.4 (33.9–5.0) | 99.5 (98.4–99.9) | 30.7 (28.3–33.2) |
HEART indicates history, ECG, age, risk factors, and troponin; hs-cTnT, high-sensitivity cardiac troponin T; MACE, major adverse cardiac event; MI, myocardial infarction; NPV, negative predictive value; PPV, positive predictive value; and 0/1-h, initial and 1-hour hs-cTnT measure.

The rule-in range yielded a PPV of 58.4% (95% CI, 51.1–65.5) and a specificity of 93.6% (95% CI, 92.0–94.9) for 30-day MACEs, whereas the PPV and specificity for 30-day cardiac death or MI were 58.4% (95% CI, 51.1–65.5) and 93.7% (95% CI, 92.2–95.0), respectively. Index-visit MI occurred in 55.3% (105 of 190) with a PPV and specificity of 55.3% (95% CI, 47.9–62.5) and 93.3% (95% CI, 91.8–94.6), respectively. However, for non–rule-out patients (the combination of the observation and rule-in zones), the PPV and specificity for 30-day MACEs were 29.8% (95% CI, 26.2–33.6) and 65.4% (95% CI, 62.7–68.1), respectively, whereas the PPV and specificity for 30-day cardiac death or MI were 28.2% (95% CI, 24.6–31.9) and 65.2% (95% CI, 62.5–67.8). Among the patients in the observation zone, 16.7% (69 of 414) had 30-day MACEs, 14.2% (59 of 414) had 30-day cardiac death or MI, and 12.3% (51 of 414) had index-visit MI. The 0/1-h algorithm results are summarized in Figure 2. True negatives and positives and false-negatives and -positives of the 0/1-h algorithm for 30-day MACEs are summarized in Table II in the Data Supplement.
The rule-out range of the 0/1-h algorithm combined with a nonischemic ECG occurred in 55.7% (797 of 1430) of patients. This combination yielded an NPV of 97.1% (95% CI, 95.7–98.2) and a sensitivity of 88.7% (95% CI, 83.5–92.7) for 30-day MACEs. For 30-day cardiac death or MI, the rule-out range had an NPV of 98.4% (95% CI, 97.2–99.1) and a sensitivity of 92.9% (95% CI, 88.2–96.2). For index-visit MI, the NPV was 99.0% (95% CI, 98.0–99.6) and sensitivity was 95.1% (95% CI, 90.6–97.9).
The addition of a low-risk HEART score to the rule-out range of the 0/1-h algorithm had an efficacy of 30.8% (441 of 1430). This combination yielded an NPV of 98.4% (95% CI, 96.8–99.4) and a sensitivity of 96.6% (95% CI, 93.0–98.6) for 30-day MACEs. For 30-day cardiac death or MI, the rule-out range with a low-risk HEART score had an NPV of 99.3% (95% CI, 98.0–99.9) and a sensitivity of 98.4% (95% CI, 95.3–99.7). For index-visit MI, the NPV was 99.5% (95% CI, 98.4–99.9) and sensitivity was 98.8% (95% CI, 95.7–99.9). Additional test characteristics for the 0/1-h algorithm with and without clinical variables are summarized in Table 3 and Figure 3.

Among the 1.6% (23 of 1430) of patients with 30-day MACEs who had hs-cTnT measures in the rule-out range of the 0/1-h algorithm, 1 patient had a cardiac-related death, 9 patients had an index-visit MI, 4 patients had 30-day MI, 6 patients had index revascularization without MI, 3 patients had revascularization during the 30-day follow-up, and 1 patient had revascularization events at index and within 30 days. Ten of the patients with missed MIs had type 2 MIs, whereas 3 patients had a type 1 MIs (1 of which developed into an ST-segment–elevation MI). All 23 patients had a nonischemic ECG, and 7 had a low-risk HEART score. The maximum absolute delta in the missed event group was 2 ng/L. The age range of these patients was 38 to 75 years; 26.1% (6 of 23) were Black; 4.3% (1 of 23) were Hispanic; 34.8% (8 of 23) were female; 52.2% (12 of 23) had a body mass index >30 kg/m2; and 39.1% (9 of 23) were early presenters. Characteristics of patients with MACEs who had hs-cTnT measures in the rule-out range are summarized in Table III in the Data Supplement.
Early and Late Presenters
Among 516 patients with chest pain onset <3 hours in the early presenter group, 15.3% (79 of 516) had MACEs. In this group, an initial hs-cTnT measure below the LOQ had an efficacy of 28.9% (95% CI, 25.0–33.0), an NPV of 98.6% (95% CI, 95.2–99.8), and a sensitivity of 97.5% (95% CI, 91.2–99.7) for 30-day MACEs. For 30-day cardiac death or MI, an initial hs-cTnT measure below the LOQ had an NPV of 98.6% (95% CI, 95.1–99.8) and a sensitivity of 97.3% (95% CI, 90.6–99.7). The initial hs-cTnT measure below the LOQ had an NPV of 99.3% (95% CI, 96.3–100.0) and a sensitivity of 98.4% (95% CI, 91.3–100.0) for index-visit MI. A HEART score of 0 to 3 with an initial hs-cTnT below the LOQ in early presenters had an efficacy of 20.5% (95% CI, 17.1–24.3) with an NPV of 100.0% (95% CI, 97.2–100.0) for 30-day MACEs and 100.0% (95% CI, 97.2–100.0) for 30-day cardiac death or MI. The combination of a low-risk HEART score and initial hs-cTnT below the LOQ in early presenters resulted in an NPV of 100.0% (95% CI, 97.2–100.0), and sensitivity was 100.0% (95% CI, 95.3–100.0) for index-visit MI.
In early presenters, the 0/1-h algorithm rule-out range had an NPV of 96.8% (95% CI, 93.9–98.5) and a sensitivity of 87.8% (95% CI, 78.2–94.3) for 30-day MACEs. For 30-day cardiac death or MI, the rule-out range had an NPV of 97.8% (95% CI, 95.3–99.2) and a sensitivity of 91.3% (95% CI, 82.0–96.7). For index-visit MI, the rule-out range had an NPV of 98.6% (95% CI, 96.3–99.6) and a sensitivity of 93.2% (95% CI, 83.5–98.1). The addition of a low-risk HEART score to the rule-out range of the 0/1-h algorithm in early presenters yielded an NPV of 98.2% (95% CI, 94.9–99.6) and a sensitivity of 95.9% (95% CI, 88.6–99.2) for 30-day MACEs. For 30-day cardiac death or MI, the rule-out range combined with a low-risk HEART score had an NPV of 98.8% (95% CI, 95.8–99.9) and a sensitivity of 97.1% (95% CI, 89.9–99.6). For index-visit MI, the NPV of the rule-out range combined with a low-risk HEART score was 99.4% (95% CI, 96.7–100.0), and the sensitivity was 98.3% (95% CI, 90.9–100.0). Additional diagnostic performance data among early and late presenters are presented in Tables 4 and 5 and Tables IV and V in the Data Supplement.
Risk stratification strategy | Sensitivity (95% CI) | Specificity (95% CI) | PPV (95% CI) | NPV (95% CI) | Efficacy (95% CI) |
---|---|---|---|---|---|
30-d MACEs | |||||
hs-cTnT <6 ng/L | 97.5 (91.2–99.7) | 33.7 (29.3–38.4) | 21.2 (17.1–25.7) | 98.6 (95.2–99.8) | 28.9 (25.0–33.0) |
hs-cTnT <6 ng/L and nonischemic ECG | 97.5 (91.2–99.7) | 33.0 (28.6–37.7) | 21.0 (16.9–25.5) | 98.6 (95.1–99.8) | 28.3 (24.5–32.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 100.0 (96.3–100.0) | 33.5 (29.1–38.1) | 21.1 (17.0–25.6) | 100.0 (97.2–100.0) | 20.5 (17.1–24.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 100.0 (96.3–100.0) | 32.8 (28.4–37.4) | 20.9 (16.9–25.4) | 100.0 (97.2–100.0) | 20.3 (16.9–24.1) |
30-d Cardiac death and MI | |||||
hs-cTnT <6 ng/L | 97.3 (90.6–99.7) | 33.3 (28.9–38.0) | 19.8 (15.8–24.2) | 98.6 (95.1–99.8) | 28.9 (25.0–33.0) |
hs-cTnT <6 ng/L and nonischemic ECG | 97.3 (90.6–99.7) | 32.6 (28.3–37.3) | 19.6 (15.7–24.1) | 98.6 (95.1–99.8) | 28.3 (24.5–32.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 100.0 (96.0–100.0) | 33.1 (28.7–37.7) | 19.7 (15.8–24.2) | 100.0 (97.2–100.0) | 20.5 (17.1–24.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 100.0 (96.0–100.0) | 32.4 (28.1–37.0) | 19.6 (15.6–24.0) | 100.0 (97.2–100.0) | 20.3 (16.9–24.1) |
Index-visit MI | |||||
hs-cTnT <6 ng/L | 98.4 (91.3–100.0) | 32.7 (28.3–37.2) | 16.8 (13.1–21.0) | 99.3 (96.3–100.0) | 28.9 (25.0–33.0) |
hs-cTnT <6 ng/L and nonischemic ECG | 98.4 (91.3–100.0) | 32.0 (27.7–36.5) | 16.6 (13.0–20.8) | 99.3 (96.3–100.0) | 28.3 (24.5–32.4) |
hs-cTnT <6 ng/L and HEART score 0–3 | 100.0 (95.3–100.0) | 32.4 (28.1–37.0) | 16.7 (13.0–20.9) | 100.0 (97.2–100.0) | 20.5 (17.1–24.3) |
hs-cTnT <6 ng/L and HEART score 0–3 and nonischemic ECG | 100.0 (95.3–100.0) | 31.8 (27.5–36.3) | 16.6 (12.9–20.8) | 100.0 (97.2–100.0) | 20.3 (16.9–24.1) |
HEART indicates history, ECG, age, risk factors, and troponin; hs-cTnT, high-sensitivity cardiac troponin T; LOQ, limit of quantification; MACE, major adverse cardiac event; MI, myocardial infarction; NPV, negative predictive value; and PPV, positive predictive value.
Risk stratification strategy | Sensitivity (95% CI) | Specificity (95% CI) | PPV (95% CI) | NPV (95% CI) | Efficacy (95% CI) |
---|---|---|---|---|---|
30-d MACEs | |||||
0/1-h | 87.8 (78.2–94.3) | 93.0 (90.1–95.2) | 58.9 (46.8–70.3) | 96.8 (93.9–98.5) | 55.3 (50.8–59.7) |
0/1-h and nonischemic ECG | 87.8 (78.2–94.3) | 88.8 (85.4–91.6) | 48.4 (37.9–59.0) | 96.6 (93.7–98.4) | 53.3 (48.8–57.7) |
0/1-h and HEART score 0–3 | 95.9 (88.6–99.2) | 88.8 (85.4, 91.6) | 50.0 (39.6, 60.4) | 98.2 (94.9, 99.6) | 33.7 (29.6, 38.1) |
0/1-h and HEART score 0–3 and nonischemic ECG | 95.9 (88.6–99.2) | 85.7 (82.0–88.9) | 44.5 (35.1–54.3) | 98.2 (94.9–99.6) | 33.5 (29.4–37.9) |
30-d Cardiac death and MI | |||||
0/1-h | 91.3 (82.0–96.7) | 93.1 (90.2–95.3) | 58.9 (47.8–70.3) | 97.8 (95.3–99.2) | 55.3 (50.8–59.7) |
0/1-h and nonischemic ECG | 91.3 (82.0–96.7) | 88.9 (85.5–91.7) | 48.4 (37.9–59.0) | 97.8 (95.2–99.2) | 53.3 (48.8–57.7) |
0/1-h and HEART score 0–3 | 97.1 (89.9–99.6) | 88.9 (85.5–91.7) | 50.0 (39.6–60.4) | 98.8 (95.8–99.9) | 33.7 (29.6–38.1) |
0/1-h and HEART score 0–3 and nonischemic ECG | 97.1 (89.9–99.6) | 85.9 (82.2–89.0) | 44.5 (35.1–54.3) | 98.8 (95.8–99.9) | 33.5 (29.4–37.9) |
Index-visit MI | |||||
0/1-h | 93.2 (83.5–98.1) | 92.3 (89.4–94.6) | 53.4 (41.4–65.2) | 98.6 (96.3–99.6) | 55.3 (50.8–59.7) |
0/1-h and nonischemic ECG | 93.2 (83.5–98.1) | 88.2 (84.9–91.1) | 44.1 (33.8–54.8) | 98.5 (96.2–99.6) | 53.3 (48.8–57.7) |
0/1-h and HEART score 0–3 | 98.3 (90.9–100.0) | 88.2 (84.9–91.1) | 45.8 (35.6–56.3) | 99.4 (96.7–100.0) | 33.7 (29.6–38.1) |
0/1-h and HEART score 0–3 and nonischemic ECG | 98.3 (90.9–100.0) | 85.3 (81.6–88.5) | 40.9 (31.6–50.7) | 99.4 (96.7–100.0) | 33.5 (29.4–37.9) |
HEART indicates history, ECG, age, risk factors, and troponin; MACE, major adverse cardiac event; MI, myocardial infarction; NPV, negative predictive value; PPV, positive predictive value; and 0/1-h, initial and 1-hour high-sensitivity cardiac troponin measure.
Sensitivity Analyses
A sensitivity analysis using outcomes from readjudication of MACEs and cardiac death or MI using hs-cTnT values did not substantively change results (Tables VI and VII in the Data Supplement). Test performance for 30-day MACEs and cardiac death or MI, including only type 1 MI, is presented in Tables VIII and IX in the Data Supplement. In addition, a sensitivity analysis imputing events for patients lost to follow-up produced no substantive differences in results (Tables X and XI in the Data Supplement). Last, a sensitivity analysis for uncertain causes of death classified as noncardiovascular deaths produced no substantive differences in results (Tables XII and XIII in the Data Supplement).
Discussion
This multisite, prospective study of hs-cTnT strategies in US patients in the ED suggests that adding a HEART score to these strategies improves safety. When used alone, a single hs-cTnT measure below the LOQ had insufficient NPV and sensitivity to rule out 30-day MACEs. However, for 30-day cardiac death or MI, the NPV was 99.0%, but with a lower bound of the 95% CI extending to 97.6%, many clinicians may find this unacceptable. Furthermore, the addition of a low-risk HEART score to an initial hs-cTnT value below the LOQ increases the NPV for 30-day cardiovascular death and MI to 99.7%. The tradeoff with adding the HEART score to an initial hs-cTnT value below the LOQ is that efficacy is decreased from 32.8% to 20.1%.20,22
Prior studies demonstrated that very low initial hs-cTnT measures in patients with chest pain onset >3 hours were associated with a >99% NPV for MI.8,9,33 These studies used the limit of blank (3 ng/L) and limit of detection (5 ng/L) as cut points, which are concentrations less than the LOQ (Figure 1 in the Data Supplement). Unfortunately, as a result of concerns about measurement imprecision, the US Food and Drug Administration does not allow reporting of values below the LOQ,34 which makes extrapolating these data to the United States difficult. Among late presenters (those with chest pain onset >3 hours), use of the LOQ at arrival for the cutoff yielded a 98.2% NPV for 30-day MACEs. These results are consistent with the findings of a subanalysis of the TRAPID-AMI (High Sensitivity Cardiac Troponin T Assay for Rapid Rule-Out of Acute Myocardial Infarction) cohort and a Canadian study, which reported NPVs <99% for MACEs at the limit of detection and LOQ, respectively.9,35 Our sensitivity analysis of type 1 and 2 MIs (Tables VIII and IX in the Data Supplement) suggests that type 2 MIs are more frequently missed by low initial hs-cTnT measures. Given that the clinical significance of type 2 MIs varies and their treatment is based on the underlying cause, the importance of missing type 2 MI events is unclear. However, many studies suggest that type 2 MI events are prognostically important.36
The hs-cTnT 0/1-h algorithm, which is recommended by the European Society of Cardiology guidelines, has been well validated in Europe for the detection of index MI.8,12,37-40 In the original derivation and validation study by Reichlin et al,41 the 0/1-h algorithm ruled out 60% of patients with 100% sensitivity and NPV for MI. This was validated in separate rest-of-world cohorts, demonstrating a 99.1% to 100% NPV.15,37-39 On the basis of these data, several US EDs that were early adopters of hs-cTnT are currently using protocols based on a 0/1-h algorithm.12,40 Although a small number of patients in the TRAPID-AMI cohort were enrolled in the United States, our study represents the first large prospective multisite US examination of an hs-cTnT 0/1-h algorithm. Our results demonstrating that the hs-cTnT 0/1-h algorithm had an NPV of 99.0% for index-visit MI are similar to those in prior studies. This includes a recent analysis of the 0/1-h algorithm using a hs-cTnI assay in the HIGH US cohort.6
Although prior studies of the 0/1-h algorithm have focused largely on index MI as an outcome, studies of risk stratification algorithms designed to identify patients in he ED for early discharge (eg, the HEART Pathway or the Emergency Department Assessment of Chest Pain Score] accelerated diagnostic protocol) have focused on 30-day MACEs or the composite of 30-day cardiac death and MI as outcomes.42–46 Although there is some debate about the acceptable missed 30-day MACE rate and the importance of coronary revascularization outcomes, Than et al47 demonstrated that most ED providers find an NPV of <99% for 30-day MACEs to be unacceptable. In our study, the diagnostic performance of the 0/1-h algorithm for 30-day MACEs or 30-day cardiac death or MI NPV was <99%. Thus, for many ED providers, the hs-cTnT 0/1-h algorithm, when used alone, may not have a sufficient NPV to support early ED discharge. However, the addition of a low-risk HEART score to the rule-out range of the 0/1-h algorithm achieved improved NPV, with a 99.3% NPV for 30-day cardiac death or MI. Our results are similar to those of a study by Mokhtari et al19 that reported an NPV of 97.8% for the hs-cTnT 0/1-h algorithm for 30-day MACEs when used alone versus 99.5% when combined with clinical variables (ie, clinical history and a nonischemic ECG).
In this cohort, the 0/1-h algorithm had a PPV <60% for all outcomes, including a PPV of 55.3% for index MI. These results differ from prior studies in which the PPV for index MI ranged from 63.4% to 84.0%.39,39,48–50 Our lower-than-expected PPV occurred despite inclusion of adjudicated type 2 MIs as part of the index MI outcome definition, which improved PPV. The PPV for index visit type 1 MI was only 26.8%. Furthermore, using the HEART score with the 0/1-h algorithm lowered PPV to <50% for each outcome. The low PPV of the 0/1-h algorithm with or without the HEART score suggests that its use may be associated with overtriage and overtesting. Higher hs-cTnT cut points and delta values for the rule-in range of the 0/1-h algorithm may need to be explored and validated in the US chest pain population to improve PPV.
Although an ischemic ECG is well recognized as a predictor of adverse cardiac events, in this analysis, the addition of ischemic ECG changes to hs-cTnT strategies (the 0/1-h algorithm and initial hs-cTnT below the LOQ) did not improve diagnostic performance.11 None of the patients with 30-day MACEs who had initial hs-cTnT measures below the LOQ or were in the rule-out range of the 0/1-h algorithm had an ischemic ECG as determined by their treating provider. These findings are consistent with a subanalysis of TRAPID-MI, which found that adding an ischemic ECG to an initial hs-cTnT <5 ng/L correctly reclassified only 2 patients with 30-day MACEs as not low risk.9 In contrast, the HEART score, which includes ECG findings in its scoring along with other historical features, was able to improve the diagnostic performance of hs-cTnT strategies in this analysis. Thus, these data suggest that ECGs should be used as part of the assessment of patients with possible ACS within the broader context of the historical and hs-cTn data.
Although it is well described that time of chest pain onset influences the diagnostic performance of hs-cTn cut points,15–17,51–53 in our cohort, these differences were small and nonsignificant. The combination of a low-risk HEART score and an initial hs-cTnT measure below the LOQ yielded high sensitivity and NPV for MACEs even among early presenters. Last, sensitivity analyses testing a variety of assumptions yielded similar diagnostic performance of the LOQ and the 0/1-h algorithm when used with or without clinical variables.
Our study has limitations. Although our study was conducted across 8 US EDs, our sites were mostly urban academic medical centers. Thus, our results may not be generalizable to all US ED settings. Furthermore, our cohort had a higher MACE rate than has been reported in many prior US studies.42,54 Although our lost to follow-up rate was small,55,56 we were unable to contact <4% (56 of 1442) of the cohort, which may have caused misclassification and underestimation of MACEs. However, a sensitivity analysis imputing events based on patient variables (demographics, risk factors, and hs-cTnT measures) did not substantively change our results (Tables X and XI in the Data Supplement). This study used only the Roche hs-cTnT assay, and results cannot be extrapolated to other hs-cTn assays. Our classification of patients as early or late presenters was susceptible to patient recall bias.57 In addition, subgroup analysis of early presenters was limited to 516, that is, 35% of the total population. Thus, the CIs for this group are somewhat broader than those for the overall population. Last, no patient was managed according to the use of the hs-cTnT assay or the strategies evaluated. Thus, the efficacy and safety of hs-cTnT strategies need to be evaluated prospectively in the setting of implementation into clinical practice in a US population.
Conclusions
In this first multisite prospective US cohort study to evaluate hs-cTnT strategies, our results suggest that use of a single hs-cTnT measure below the LOQ alone had insufficient sensitivity and NPV to rule out 30-day MACEs. For 30-day cardiac death and MI, using a single hs-cTnT <LOQ was associated with a NPV of 99%, which is widely considered acceptable.28 Adding a low-risk HEART score to a hs-cTnT measure <LOQ improves NPV for 30-day cardiac death and MI to 99.7%. In addition, this first large prospective multisite validation of the hs-cTnT 0/1-h algorithm in the United States yielded an NPV of <99% for MACEs and cardiac death or MI at 30 days and 99% for index MI. However, when the HEART score is combined with a 0/1-h hs-cTnT algorithm, the NPV and sensitivity for cardiac events improved to the acceptable range. These data indicate that in a US population of patients with symptoms concerning for ACS, combining hs-cTnT strategies with a HEART score achieves acceptable performance for the diagnosis of adverse cardiac events.
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Received: 9 June 2020
Accepted: 7 January 2021
Published online: 21 January 2021
Published in print: 27 April 2021
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Disclosures Dr Allen receives research funding/support from Roche Diagnostics and Beckman Coulter. Dr Allen is a consultant for Roche Diagnostics. Dr Nowak receives research funding/support from Roche Diagnostics, Beckmann Coulter, Siemens, Abbott Diagnostics, and Ortho Clinical Diagnostics. Dr Nowak is a consultant for Roche Diagnostics, Beckman Coulter, Siemens, Abbott Diagnostics, and Ortho Clinical Diagnostics. Dr Mahler receives research funding/support from Roche Diagnostics, Abbott Laboratories, Ortho Clinical Diagnostics, Creavo Medical Technologies, Siemens, Pathfast, Grifols, Rigel Pharmaceuticals, the Agency for Healthcare Research and Quality, the Patient-Centered Outcomes Research Institute, the National Heart, Lung, and Blood Institute (1 R01 HL118263-01), and the Health Resources and Services Administration (1 H2ARH399760100). Dr Mahler is a consultant for Roche Diagnostics and Amgen and is the chief medical officer for Impathiq Inc. Dr McCord receives research funding/support from Roche Diagnostics, Beckmann Coulter, Siemens, and Abbott. Dr McCord is a consultant for Siemens, Beckman Coulter, and Roche Diagnostics. Dr Mumma has research support from the National Heart, Lung, and Blood Institute (No. 5K08HL130546) and Roche Diagnostics. Dr Christenson is a consultant for and receives funding/support from Roche Diagnostics, Siemens Healthineers, Beckman Coulter Diagnostics, Becton Dickinson and Co, Quidel Corp, and Sphingotec GMBH. The other authors report no conflicts.
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This investigator-initiated study was funded by Roche Diagnostics.
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- High-Sensitivity Cardiac Troponin Assays: From Implementation to Resource Utilization and Cost Effectiveness, The Journal of Applied Laboratory Medicine, (2025).https://doi.org/10.1093/jalm/jfae161
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- Evaluation of the analytical and clinical performance of a high-sensitivity troponin I point-of-care assay in the Mersey Acute Coronary Syndrome Rule Out Study (MACROS-2), Clinical Chemistry and Laboratory Medicine (CCLM), 63, 2, (422-432), (2024).https://doi.org/10.1515/cclm-2024-0138
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- Risk scores and coronary artery disease in patients with suspected acute coronary syndrome and intermediate cardiac troponin concentrations, Open Heart, 11, 2, (e002755), (2024).https://doi.org/10.1136/openhrt-2024-002755
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- Performance of the 0/2‐hour high‐sensitivity cardiac troponin T diagnostic protocol in a multisite United States cohort, Academic Emergency Medicine, 31, 3, (239-248), (2024).https://doi.org/10.1111/acem.14827
- Chest Pain in the Emergency Department, Journal of the American College of Cardiology, 83, 13, (1191-1193), (2024).https://doi.org/10.1016/j.jacc.2024.02.018
- Validation of the ACC Expert Consensus Decision Pathway for Patients With Chest Pain, Journal of the American College of Cardiology, 83, 13, (1181-1190), (2024).https://doi.org/10.1016/j.jacc.2024.02.004
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