Performance of cardiac troponins within the HEART score in predicting major adverse cardiac events at the emergency department

American Journal of Emergency Medicine xxx (xxxx) xxx

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American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Performance of cardiac troponins within the HEART score in predicting major adverse cardiac events at the emergency department☆ Jack Wei Chieh Tan, MBBS, M Med (Int Med), MRCP, FAMS, ACSM Exercise Specialist, RPVI a,⁎, Hong Jie Gabriel Tan, MBBS b, Anders Olof Sahlen, MD, MRCP a, Khung Keong Yeo, MBBS, ABIM, ABIM, ABIM, ABVM, ABVM a, Woon Loong Calvin Chin, MD, MCI, MRCP, PhD, FAMS, FESC a, Fei Gao, PhD c, Eng Hock Marcus Ong, MBBS, FRCSEd, (A&E), FAMS, MPH d, Chin Pin Yeo, MBBS, FRCPA, FAMS e, Wai Yoong Ng, BSc, (Hons), PhD, CSci e, Swee Han Lim, MBBS, FRCSEd, (A&E), FRCP Edin, FAMS d a

Department of Cardiology, National Heart Centre Singapore, Singapore Department of Internal Medicine, SingHealth, Singapore National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore d Department of Emergency Medicine, Singapore General Hospital, Singapore e Department of Clinical Pathology, Singapore General Hospital, Singapore b c

a r t i c l e

i n f o

Article history: Received 23 March 2019 Received in revised form 22 August 2019 Accepted 28 August 2019 Available online xxxx Keywords: High-sensitivity cardiac troponin Acute myocardial infarction Major adverse cardiac event Acute coronary syndrome Emergency department HEART score

a b s t r a c t Background: This study compared the performance of a single blood draw of high-sensitivity troponin T (hsTnT), high-sensitivity troponin I (hsTnI) and conventional troponin I (cTnI) within a modified HEART score for predicting 30-day MACE at Emergency Department (ED) presentation, and established local reference norms for all three assays by determining the cut-off point which yielded the highest sensitivity and negative predictive value for acute myocardial infarction and 30-day MACE. Methods: This single-center prospective cohort study recruited chest pain patients at the ED, whose hsTnT, hsTnI and cTnI were taken on admission. Subjects were classified into low and non-low risk group according to their modified HEART score, with MACE as the primary endpoint. Receiver-operating characteristic (ROC) curves were generated, area under the curves (AUCs) were calculated; the performance characteristics were determined. Results: The performance of modified HEART scores was comparable among the three assays for 30-day MACE (84.9–87.0% sensitivity, 95.6–96.0% NPV, 95%CI) and none of these had very high AUC and specificity (AUC 0.70–0.71, 53.7–56.7% specificity, 95% CI). The modified HEART score using a single blood draw of either hsTnT (3.9 ng/L), hsTnI (0.9 ng/L) or cTnI (0.0 ng/L) at presentation yielded a sensitivity of 100% for 30-day MACE. Conclusion: The modified HEART score using a single blood draw of either hsTnT, hsTnI or cTnI was equally effective in risk-stratifying chest pain patients for safe discharge. The theoretical cut-off points yielding 100% sensitivity are potentially useful (when achieved) for safely discharging low risk patients with undifferentiated chest pain in the ED. © 2019 Elsevier Inc. All rights reserved.

1. Introduction

☆ Source(s) of support: This study was supported by unrestricted funding from Abbott Laboratories, Singapore and Beckman Coulter Foundation, Singapore. ⁎ Corresponding author. E-mail addresses: [email protected] (J.W.C. Tan), [email protected] (A.O. Sahlen), [email protected] (K.K. Yeo), [email protected] (W.L.C. Chin), [email protected] (F. Gao), [email protected] (E.H.M. Ong), [email protected] (C.P. Yeo), [email protected] (W.Y. Ng), [email protected] (S.H. Lim).

https://doi.org/10.1016/j.ajem.2019.158420 0735-6757/© 2019 Elsevier Inc. All rights reserved.

Chest pain is one of the leading presenting complaints in the emergency department (ED) and constitutes approximately 5–10% of visits to the emergency department [1]. Annually in the United States, 8–10 million of such patients consume USD $10 - $13 billion for evaluation of possible acute myocardial infarction (AMI) yielding about a 15% diagnosis rate of confirmed AMI [2-5]. Due to medico-legal considerations around safe discharge, the majority of chest pain patients are kept for prolonged observation involving phlebotomy for serial cardiac markers followed by stress testing or cardiac imaging. This strategy is supported

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by the American College of Cardiology and the American Heart Association [6]. However, this practice leads to increased costs and ED overcrowding which is associated with worse outcomes [7,8]. Furthermore, false positives occur when low-risk patients are evaluated with unnecessary cardiac investigation [9]. The History, Electrocardiograph (ECG), Age, Risk, cardiac Troponin (HEART) score, is a well-established widely validated riskstratification tool for major adverse cardiac events (MACE) among patients presenting with undifferentiated chest pain at the ED, yielding a score of 0 (very low risk) up to 10 (very high risk) [10,11]. Although other studies have recently investigated the utility of a HEART Score incorporating a high-sensitivity troponin (hsTn) assay in the algorithm for rapid rule out of AMI in the ED setting [12], this is the first Asian cohort that compares 3 troponin assays, i.e. hsTnT, hsTnI and a conventional TnI (cTnI) applied in a modified HEART score to look at safely discharging low risk patients with a single blood draw. The objective of this study was to determine the performance of a modified HEART score using a single blood draw of three different cardiac troponin assays at presentation in predicting 30-day MACE. The secondary objective was to establish local reference norms by determining the cut-off point which yielded the highest sensitivity and negative predictive value (NPV) for AMI and 30-day MACE for each of the assays used. In this study, we evaluated hsTnT at 14 ng/L (being the 99th percentile URL as per manufacturer's recommendation), as well as the current 30 ng/L as the cut-off for myocardial necrosis. This study is also an opportunity to evaluate other cut offs using troponin I in the analysis. 2. Methods 2.1. Study design and population This single-center cohort study prospectively consented chest pain patients recruited from October 2015–November 2017 at the ED. Patients were included if they were age 21 years and above, able to provide written consent, presented with a chief complaint of chest pain to the ED and were deemed to be having symptoms suggestive of ACS or angina equivalent, had a troponin test ordered in the ED, and were eligible for chest pain protocol. Patients were excluded if they were diagnosed with a clear-cut ST elevation myocardial infarction (STEMI), had poor pre-morbid conditions e.g. bed-ridden, or had terminal illness or malignancy. Written informed consent was obtained from every patient recruited in the ED following initial triage and exclusion of STEMI and within 1 h of initial blood draw at presentation. This study was approved by the SingHealth Centralised Institutional Review Board (cIRB).

A standardized screening case report form (CRF) was used as a data collection tool, which comprises clinical data such as chest pain status, exacerbating factors, relieving factors, symptom onset, duration, radiation, characteristic, severity, current Canadian Cardiovascular Score, associated symptoms, 12 lead ECG at 0- and 2hour, final diagnosis, disposition, medical history, oral concomitant medication, laboratory results as well as risk stratification scoring systems (GRACE, HEART, TIMI and EDAC). These data were stored digitally. Data collection was done by the study coordinators who were research officers trained during the site initiation visit before the study officially commenced. They had further worked on the study prior to commencement. New coordinators who subsequently came on board were trained by existing ones before working on the study. Nevertheless, all of them required ethics approval prior to handling the study.

2.2. Investigational hsTn analysis All patients presenting with chest pain had their blood sample taken at presentation for hsTnT as per current standard of care. A serial blood draw for hsTnT at 2 h after presentation was taken for patient with suspected ACS but for the purpose of this study, only the 0-hour sample was considered. Patients were consented for additional blood to be drawn for hsTnI and cTnI. After centrifugation, sera were analysed for hsTnT routinely on the Roche e602 analyser (Troponin T hs STAT). Specimens for hsTnI (Abbott i2000SR; STAT high sensitive troponin-I) and cTnI (Beckman Coulter DxI800; Access AccuTnI+3 reagent) analyses were stored at -80 °C up to 1 month before analysis. The performance of the assays claimed by the manufacturers for their Limits of Detection (LoD; hsTnT-5 ng/L, hsTnI-2 ng/L and cTnI-10 ng/L) and LoQ (hsTnT13 ng/L, hsTnI-10 ng/L and cTnI-20 ng/L) have been verified mostly. Test runs and analysis are based on valid calibration specifications and acceptable quality control on day of run. Based on clinical experience with our local cohort, we have continued to use 30 ng/L for hsTnT assay as the cut-off granting the Limit of Quantitation (LoQ) is 13 ng/L and a 99th percentile upper limit of 14 ng/L in the healthy population. This was supported by Januzzi JL Jnr et al. (2010) on the diagnostic accuracy of hsTnT assay and the cTnT assay in patients with angina pectoris without MI [13]; cTnT at 0.03 μg/L cut-off demonstrated a PPV-55% and NPV-94% and hsTnT at 13 ng/L yielded PPV-30% and NPV-96%. The study showed better outcome with the use of cTnT at 0.01 μg/L (equivalent to hsTnT 30 ng/L [14]) as it gave PPV-55% and NPV-95%.

Table 1 Components of modified HEART score History

Highly suspicious (3/3 CP status) Moderately suspicious (2/3 CP status) Slightly suspicious (1/3 CP status) Significant ST depression Non-specific repolarization disturbance Normal ≥65 45–65 ≤45 ≥3 or history of atherosclerotic disease 1 or 2 risk factors 0 risk factors

ECG

Age

Risk factors

Roche hsTnT

Troponin level (ng/L)

CP: chest pain.

N3 x normal limit 1-3× normal limit bnormal limit

2 1 0 2 1 0 2 1 0 2 1 0

Abbott hsTnI

Beckman cTnI

Cut-off at 14

Cut-off at 30

Female

Male

N52 14–52 b14

N90 30–90 b30

N45 15–45 b15

N102 34–102 b34

N90 30–90 b30

2 1 0

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troponin component by using a single blood draw of hsTn instead of conventional troponins at presentation for Roche and Abbott troponin assays. Each of these components was assigned a score of 0 to 2 (Table 1). For the history component, three chest pain criteria were used, namely pain site, exacerbating factors and relieving factors. Along with other components in the scoring system, these scores were subsequently added to yield a composite score of 0–10, which were calculated retrospectively by study investigators for each patient. Patients were subsequently classified into low risk if the modified HEART score is 3 or less and non-low risk if the score is 4–10. 2.4. Outcomes

Fig. 1. Patient flow chart. Table 2 Baseline patient characteristics Characteristics

All patients, (n = 1002)

Mean age (SD)

55.1 (±11.8)

%

Male gender

696

69.5

Race Chinese Malay Indian Others

545 195 218 44

54.4 19.5 21.8 4.4

Risk factors Diabetes mellitus Smoking Hypercholesterolemia Hypertension Family history Previous MI Previous stroke

314 211 596 551 458 180 184

31.3 21.1 59.5 55.0 45.7 18.0 18.4

History Slightly suspicious Moderately suspicious Highly suspicious

457 326 219

45.6 32.5 21.9

ECG Normal Non-specific repolarization disturbance Significant ST depression

674 299 29

67.3 29.8 2.9

The primary endpoint was the occurrence of MACE – defined as a composite of AMI, unstable angina (UAP), stroke, all-cause mortality, percutaneous intervention (PCI) and coronary artery bypass graft (CABG), during or within 30 days from index visit. The diagnosis of AMI was defined as recommended by current guidelines, i.e. the detection of a rise and/or fall of cardiac troponins with at least one value above the 99th percentile upper reference limit (URL) in addition to at least one of the following: 1) symptoms of ischemia; 2) new electrocardiogram (ECG) changes of ST-T segments, new left bundle branch block or development of pathological Q waves; 3) imaging evidence of new regional wall motion abnormality or loss of viable myocardium; and/or 4) identification of an intracoronary thrombus by angiography or autopsy [15]. UAP was defined as an acute coronary syndrome (ACS) with the absence of biochemical evidence of myocardial damage, i.e. normal troponin level and often normal ECG finding for this study. The final diagnosis for each patient was adjudicated by an independent cardiologist and an ED physician, both of whom had access to all clinically-reported data of recruited patients as documented in the electronic medical record including history, physical examination findings, discharge summary, ECG reports, lab results including hsTnT results (which is part of current clinical practice to distinguish between NSTEMI from UAP), stress test data, radiology tests, coronary angiography, provider and consultant notes. However, they were blinded to hsTnI and cTnI results for the purpose of this study. Patients were adjudicated into one of the four diagnostic categories: 1) NSTEMI; 2) UAP; 3) Stable angina; 4) Non-cardiac chest pain. A second cardiologist was engaged to review the adjudication in case of disagreement. Patients were followed up via telephone and medical records for MACE information at 30 days after discharge. We also took the opportunity to evaluate the utility of a standalone hsTnT assay in the absence of other clinical parameters and history. Hence the secondary outcome in this study was to compare this against incorporating hsTnT assay value into the modified HEART score. 2.5. Statistical analysis

2.3. Modified HEART score criteria Several prior studies have described the components of the conventional HEART score, which includes history, ECG, age risk factors and a conventional troponin. In this study, modification was made to the

Clinical characteristics were summarized using mean ± standard deviation (SD) for continuous data and proportion for categorical data. Receiver-operating characteristic (ROC) curves were generated, with calculation of area under the curve (AUC) and estimation of sensitivity, specificity, positive predictive value (PPV) and negative predictive value

Table 3 Number of MACE events

MACE at index admission (n = 143)

MACE within 30 days among patients discharged at index visit (n = 859) Total

Events

No. of patients

Revascularization at index visit

Staged revascularization at 30 days

UAP NSTEMI STEMI Stroke UAP NSTEMI

78 (54.5%) 60 (42.0%) 4 (2.8%) 1 (0.7%) 1 (0.1%) 2 (0.2%) 146

32 25 3 0

12 11 2 0 0 1 26

60

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Table 4 Comparison of incidence of total MACE within 30 days by modified HEART score risk group between three assays Assays

No MACE

MACE

Roche hsTnT (b14 ng/L) Low Risk (mHEART score ≤ 3) Non-low risk (mHEART score N 3) Roche hsTnT (b30 ng/L) Low Risk (mHEART score ≤ 3) Non-low risk (mHEART score N 3) Abbott hsTnI Low Risk (mHEART score ≤ 3) Non-low risk (mHEART score N 3) Beckman cTnI Low Risk (HEART score ≤ 3) Non-low risk (HEART score N 3)

n = 856 460 396

n = 146 19 127

483 373 n = 810 454 356 n = 802 455 347

22 124 n = 138 20 118 n = 141 20 121

index MACE

30-day MACE

18 125

1 2

21 122

1 2

19 116

1 2

19 119

1 2

Total

Rate of MACE p-value (low risk vs non-low risk)

n = 1002 479 523

b0.0001

505 497 n = 948 474 474 n = 943 475 468

b0.0001

b0.0001

b0.0001

Table 5 Performance comparison of modified HEART score for predicting 30-day MACE between three assays Assay Sensitivity (95% CI) Specificity (95% CI) ROC area (95% CI) Positive predictive value (95% CI) Negative predictive value (95% CI)

Roche hsTnT (b14 ng/L)

Roche hsTnT (b30 ng/L)

87.0% (80.4–92.0%) 53.7% (50.3–57.1%) 0.70 (0.67–0.74) 24.3% (20.7–28.2%) 96.0% (93.9–97.6%)

84.9% (78.1–90.3%) 56.4% (53.0–59.8%) 0.71 (0.67–0.74) 24.9% (21.2–29.0%) 95.6% (93.5–97.3%)

Abbott hsTnI

Beckman cTnI

85.5% (78.5–90.9%) 56.0% (52.6–59.5%) 0.71 (0.67–0.74) 24.9% (21.1–29.0%) 95.8% (93.6–97.4%)

85.8% (78.9–91.1%) 56.7% (53.2–60.2%) 0.71 (0.68–0.75) 25.9% (21.9–30.1%) 95.8% (93.6–97.4%)

Fig. 2. ROC of modified HEART score using Roche hsTnT b14 ng/L for 30-Day MACE.

Fig. 4. ROC of modified HEART score using Abbott hsTnI for 30-Day MACE.

Fig. 3. ROC of modified HEART score using Roche hsTnT b30 ng/L for 30-Day MACE.

Fig. 5. ROC of modified HEART score using Beckman cTnI for 30-Day MACE.

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(NPV) of HEART scores for 30-day MACE. These were compared between the three assays. P values of b0.05 have been considered statistically significant throughout the study. Analysis was done using STATA version 15.

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3. Results In this study, a total of 1200 patients were recruited, 5 of whom were lost to withdrawal from the study. Of the remaining 1195 patients, 1002

Fig. 6. Sensitivity and specificity of modified HEART score using hsTnT assay for 30-day MACE.

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(83.9%) agreed for additional blood draw for hsTnI and cTnI specimens. However, no patient was lost to follow up. The patient flow chart is illustrated in Fig. 1, and the baseline patient characteristics are illustrated in Table 2. Of the 1002 patients analysed, a total of 143 (14.3%) had MACE on index admission (Table 3). Of the 859 discharged patients, 3 (0.4%) developed ACS within 30 days follow-up. Of the 143 patients who had MACE on index visit, 78 (54.5%) patients were diagnosed to have UAP, 28 (35.9%) of whom had revascularization at index visit itself while 12 (15.4%) had either staged or re-revascularization done at 30 days. Sixty (42.0%) patients were diagnosed with NSTEMI among those who had MACE on index visit, 11 (18.3%) of whom had revascularization done at index visit while 1 (1.7%) had staged revascularisation done at 30 days. Patients with modified HEART score of 3 or less (low risk) had significantly lower rate of MACE than those with score of 4 and above (nonlow risk) in all three assays (p b 0.0001) (Table 4). For hsTnT (b14 ng/L), the rate of MACE among low risk patient was significantly much lower than that of non-low risk patients, i.e. 4.0% and 24.3% respectively. Similarly, these rates were 4.4% and 24.95% for hsTnT (b30 ng/L), 4.2% and 24.9% for hsTnI as well as 4.2% and 25.9% for cTnI. Non-low risk group constituted approximately 85% of all 30-day MACE across all assays, i.e. 87% by hsTnT (b14 ng/L), 84.9% by hsTnT (b30 ng/L), 85.5% by hsTnI and 85.8% by cTnI. The performance of modified HEART scores in predicting 30-day MACE was comparable among the three assays (Table 5). The hsTnT assay (b14 ng/L) yielded the highest sensitivity of 87.0% (80.4–92%; 95% Cl), followed by cTnI, hsTnI and hsTnT (b30 ng/L) assays at 85.8% (78.9–91.1%; 95% Cl), 85.5% (78.5–90.9%; 95% Cl) and 84.9% (78.1–90.3%; 95% Cl) respectively. Specificity was low across all assays,

ranging from 53.7 to 56.7% at 95% CI. The PPVs were comparably low among all assays ranging from 24.3 to 25.9% at 95% CI, while the NPVs were comparably high, with the highest yielded by hsTnT assay (b14 ng/L) at 96.0% (93.9–97.6%), followed by hsTnI and cTnI both at 95.8% (93.6–97.4%), and hsTnT (b30 ng/L) at 95.6% (93.5–97.3%). ROC curves for all assays showed no difference across the three assays (Figs. 2-5), with AUC values in the range of 0.70–0.71 at 95% CI. Further analysis also showed that a modified HEART score using a single blood draw of either hsTnT (3.9 ng/L), hsTnI (0.9 ng/L) or cTnI (0.0 ng/L) at presentation could yield a sensitivity of 100% for 30-day MACE (Figs. 6-8). Proportion of patients having such low values of these assays are illustrated in Table 6. A comparison of the performance of modified HEART score using hsTnT assay to that of standalone hsTnT value in predicting 30-Day MACE, but only a slight difference was found between the two, i.e. AUC value of 0.79 and 0.81 respectively (Figs. 8-9).

4. Discussion In a study on patients managed in an observation unit, Hartsell et al., reported false-positive rates of 42.9%, 66.7% and 75.0% for coronary computed tomography angiography (CCTA), myocardial perfusion imaging and stress echocardiography respectively [9]. Hoffman et al., reported that low-risk chest pain patients randomized to CCTA received N2.5 times more radiation exposure, although mean length of hospital stay was reduced by 7.6 h and more were discharged directly from the ED [16]. The increased radiation exposure from the increased use of CCTA has been estimated to be associated with 2% of all cancers in the US [17]. In light of the above, we advocate the use of a suitable and

Fig. 7. Sensitivity and specificity of modified HEART score using hsTnI assay for 30-day MACE.

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reliable troponin assay as a first line test to safely rule out AMI in the ED setting. Patients who attended ED with chest pain in our local setting with a non-low risk (N3) modified HEART score had a 85% 30-day MACE rate and should either be admitted or have a protocol for early rule out of underlying symptomatic coronary artery disease within 48 h if they are discharged from the ED. The PPVs and NPVs for all three assays which were approximately 25% and 96% respectively, were statistically nonsignificant between the assays. Our institutional practice of using hsTnT b30 ng/L instead of b14 ng/L shifted three patients from non-low risk into the low risk modified HEART score classification (Table 4), dropping the assay sensitivity from 87.0% to 84.9% although the NPV and PPV were not significantly altered (Table 5). Among 859 patients discharged at index visit, three were not picked up by all three assays and suffered a 30-day MACE (i.e. a 0.4% 30-day MACE with a single blood draw) – one with low risk and two with non-low risk. It is worthy to note that the low-risk patient missed had a normal ECG with unremarkable troponins on his index visit, but in view of his symptomatology which included a leftsided chest pain associated with diaphoresis, a myocardial perfusion scan was done two days later which revealed moderate ischemia. The patient had an adjudicated diagnosis of unstable angina. Thus, while this patient was strictly not picked up on index visit, his ACS was picked up relatively soon after his visit and not towards the end of the 30-day window period. The identified required assay values for hsTnT, hsTnI and cTnI, for which a 100% sensitivity was obtained with regards to safe discharge of chest pain presenters were very low (Figs. 5-7), which might not

7

Table 6 Proportion of patients with assay values yielding 100% sensitivity for 30-day MACE Assay values hsTnT ≤3.9 ng/L (n = 1002) hsTnI ≤0.9 ng/L (n = 948) cTnI b0.0 ng/L (n = 943)

Number of patients

Proportion (%)

244 93 247

24.4 9.8 26.2

seem to be clinically meaningful initially. These levels are near or lower than the assays present LoDs, a performance not yet near the routine reportable quantitation levels needed. Akin to the development of new generation assays for thyroid-stimulating hormone, the achievable utility of troponins will have to wait for the next generation of highsensitivity troponin assays. However, as noted in Table 6, a considerable 10–25% of chest pain presenters could be safely discharged with a single assay value when combined with the modified HEART score at initial presentation, thus reducing the patient load at the ED by potentially up to a quarter. The slight difference between the performance of modified HEART score using hsTnT assay and that of standalone hsTnT value in predicting 30-Day MACE (Figs. 9-10) may seemingly imply that standalone hsTnT value performs marginally better as compared to incorporating it within a risk-scoring system. Nevertheless, by no means are we advocating the use of biochemical markers alone in the absence of clinical judgment involving synthesizing the patient's history and physical findings to diagnose ACS. A remarkable example would be the two non-low risk patients missed from the single blood draw at presentation, which serves to further emphasize the importance of risk-

Fig. 8. Sensitivity and specificity of HEART score using cTnI assay for 30-day MACE.

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Research Office for coordinating ground work from obtaining patient consent, data collection to providing database support.

1.00

Heart Score

0.00

0.25

Sensitivity 0.50

0.75

References

0.00

0.25

0.50 1 - Specificity

0.75

1.00

Area under ROC curve = 0.7943

Fig. 9. ROC of modified HEART score using Roche hsTnT for 30-Day MACE.

scoring system over sole reliance on biochemical markers alone for diagnosis of ACS. Further studies need to be done to explore the likely cause of the seemingly better performance of standalone hsTnT value as compared to its incorporation into a risk-scoring system. This study was limited by its small sample size. Also, although all patients had hsTnT values at presentation, about 5% of patients had missing data on hsTnI assay levels due to insufficient blood draw. There were three cases requiring input of the second cardiologist to resolve disagreements between the two primary adjudicators. However, interobserver disagreement was not formally measured. In summary, the modified HEART score using a single blood draw of either hsTnT (either 14 or 30 ng/L), hsTnI or cTnI was equally effective in risk stratifying chest pain patients for safe discharge. In view that hsTnT/ I performed similarly to cTnI, it is seemingly implied that hsTnT may not be as great compared to conventional test as it is touted to be. Although none of the tests had very high AUC and specificity, the theoretical cutoff point which yielded 100% sensitivity and the highest NPV for AMI and 30-day MACE for each of these assays establishes the desired local reference norms which are potentially useful for safely discharging low risk patients with undifferentiated chest pain in the ED. Acknowledgment We would like to thank Ms. Siti Aishah Mohd Hassan and Ms. Syamimi Atiqa Rahmat from the NHCS Clinical and Translational

0.00

0.25

Sensitivity 0.50

0.75

1.00

TropT

0.00

0.25

0.50 1 - Specificity

0.75

Area under ROC curve = 0.8185

Fig. 10. ROC of standalone Roche hsTnT for 30-Day MACE.

1.00

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