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High-Sensitivity Cardiac Troponin I vs a Clinical Chemistry Score for Predicting All-Cause Mortality in an Emergency Department Population

Open AccessPublished:March 19, 2020DOI:https://doi.org/10.1016/j.cjco.2020.03.004

      Abstract

      Background

      For patients investigated for suspected acute coronary syndrome, there is uncertainty if a single measurement of high-sensitivity cardiac troponin I (hs-cTnI) at emergency department (ED) presentation can identify patients at both low and high risk for mortality.

      Methods

      We included consecutive adult patients in the ED who had a Clinical Chemistry Score (CCS) taken at presentation (ie, combination of glucose, creatinine for estimated glomerular filtration rate determination, and hs-cTnI assay) in a Canadian city between 2012 and 2013. Outcomes were 3-month, 1-year, and 5-year all-cause mortality using the provincial death registry. Mortality rates and test performance (eg, sensitivity and specificity) with 95% confidence intervals (CIs) were obtained for the CCS or hs-cTnI assay alone using established cutoffs for these tests.

      Results

      Our cohort included 5974 patients with a 1-year mortality rate of 17.2% (95% CI, 16.2-18.3). A CCS ≥ 1 yielded a sensitivity of 99.2% (95% CI, 98.4-99.6) compared with the hs-cTnI ≥ 5 ng/L cutoff sensitivity of 88.4% (95% CI, 86.3-90.3), with the mortality rate being significantly lower for patients with CCS < 1 (2.0%; 95% CI, 0.9-4.0) vs patients with hs-cTnI < 5 ng/L (5.0%; 95% CI, 4.2-6.0) at 1 year (P = 0.01). A CCS of 5 also yielded a higher specificity (88.5%; 95% CI, 87.5-89.3) compared with hs-cTnI > 26 ng/L (83.9%; 95% CI, 82.9-84.9), with no difference in mortality rates (37.4% vs 36.3%; P = 0.66). This trend was consistent at 3-month and 5-year mortality.

      Conclusion

      For patients in the ED with a potential cardiac issue, using the CCS cutoffs can better identify patients at low and high risk for mortality than using published cutoffs for hs-cTnI alone.

      Résumé

      Contexte

      Dans le cas des patients chez qui l’on soupçonne un syndrome coronarien aigu, des doutes subsistent à savoir si la mesure de la troponine I cardiaque à haute sensibilité (TnIc-hs) à l’arrivée au service des urgences peut, à elle seule, permettre de repérer les patients présentant un risque de mortalité faible ou élevé.

      Méthodologie

      L’étude portait sur les patients adultes qui se sont présentés consécutivement au service des urgences dans une ville canadienne entre 2012 et 2013 et pour lesquels un score CCS (Clinical Chemistry Score, ou score des paramètres biochimiques cliniques, c’est-à-dire glycémie, créatininémie [aux fins du calcul du débit de filtration glomérulaire estimé] et dosage de la TnIc-hs) a été établi à leur arrivée. Les critères d’évaluation étaient la mortalité toutes causes confondues à 3 mois, à 1 an et à 5 ans, déterminée à partir des actes de décès inscrits au registre provincial. Les taux de mortalité et la fiabilité des tests (sensibilité et spécificité) avec des intervalles de confiance (IC) à 95 % ont été déterminés pour le score CCS et pour le dosage de la TnIc-hs seulement au moyen des valeurs seuils établies pour ces tests.

      Résultats

      La cohorte réunissait 5 974 patients, et le taux de mortalité à 1 an s’établissait à 17,2 % (IC à 95 % : 16,2-18,3). Un score CCS ≥ 1 a été associé à une sensibilité de 99,2 % (IC à 95 % : 98,4-99,6) comparativement à 88,4 % (IC à 95 % : 86,3-90,3) pour une valeur seuil de TnIc-hs ≥ 5 ng/l, le taux de mortalité à 1 an étant significativement plus bas chez les patients ayant un score CCS < 1 (2,0 %; IC à 95 % : 0,9-4,0) que chez ceux ayant un taux de TnIc-hs < 5 ng/l (5,0 %; IC à 95 % : 4,2-6,0) (p = 0,01). Un score CCS de 5 a en outre été associé à une plus grande spécificité (88,5 %; IC à 95 % : 87,5-89,3) qu’un taux de TnIc-hs > 26 ng/l (83,9 %; IC à 95 % : 82,9-84,9); il n’y avait pas de différence entre les taux de mortalité (37,4 % vs 36,3 %; p = 0,66). Les résultats relatifs à la mortalité à 3 mois et à 5 ans concordaient avec cette tendance.

      Conclusion

      Dans le cas des patients admis au service des urgences en raison d’un problème cardiaque potentiel, les valeurs seuils du score CCS peuvent permettre de mieux repérer les patients qui présentent un risque de mortalité faible ou élevé, comparativement aux seules valeurs seuils publiées des taux de TnIc-hs.
      In patients with suspected acute coronary syndrome (ACS), multicenter studies worldwide have indicated that a single measurement of high-sensitivity cardiac troponin I (hs-cTnI) ≥ 5 ng/L at emergency department (ED) presentation may be suitable to rule out myocardial infarction (MI) and identify a low-risk group of patients who may avoid unnecessary hospital admissions.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • Lee K.K.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      • Chapman A.R.
      • Lee K.K.
      • McAllister D.A.
      • et al.
      Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome.
      • Bularga A.
      • Lee K.K.
      • Stewart S.
      • et al.
      High-sensitivity troponin and the application of risk stratification thresholds in patients with suspected acute coronary syndrome.
      These findings were generated with an Abbott Laboratories (Abbott Park, IL) hs-cTnI assay, and recent publications demonstrating a 5 ng/L cutoff might be suitable for one of Siemens Healthcare Diagnostics (Munich, Germany) hs-cTnI assays, suggesting an overall low concentration cutoff of 5 ng/L may be applicable to more than 1 hs-cTnI assay.
      • Chapman A.R.
      • Fujisawa T.
      • Lee K.K.
      • et al.
      Novel high-sensitivity cardiac troponin I assay in patients with suspected acute coronary syndrome.
      ,
      • Sandoval Y.
      • Nowak R.
      • deFilippi C.R.
      • et al.
      Myocardial infarction risk stratification with a single measurement of high-sensitivity troponin I.
      Accordingly, this leads to the concept of a single rule-out cutoff when using hs-cTnI assays, which has been published by the European Society of Cardiology guidelines
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • et al.
      2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      and most recently discussed in the Fourth Universal Definition of MI, which provided the following balanced statement: “Some studies indicate that the single sample approach provides optimal sensitivity and negative predictive accuracy in patients otherwise at low risk and those with a normal electrocardiogram. However, one concern about short rule-out periods is that the precision of the assays may not permit small differences to be distinguished.”
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      ESC Scientific Document Group. Fourth universal definition of myocardial infarction (2018).
      In this regard, we have provided evidence of analytical issues that affect interpretation around and below 5 ng/L.
      • Kavsak P.A.
      • Clark L.
      • Jaffe A.S.
      Effect of repeat measurements of high-sensitivity cardiac troponin on the same sample using the European Society of Cardiology 0-hour/1-hour or 2-hour algorithms for early rule-out and rule-in for myocardial infarction.
      • Kavsak P.A.
      • Worster A.
      • Oliver R.
      • et al.
      Variability between reagent lots for high-sensitivity cardiac troponin I may affect performance of early rule out strategies.
      • Kavsak P.A.
      External quality assessment testing near the limit of detection for high-sensitivity cardiac troponin assays.
      • Kavsak P.A.
      • Ainsworth C.
      • Clark L.
      • Devereaux P.J.
      • Worster A.
      Four different high-sensitivity cardiac troponin assays with important analytical performance differences.
      • Kavsak P.A.
      • Petryayeva E.
      • Clark L.
      Analytical variation and Abbott diagnostics high-sensitivity cardiac troponin I risk categories in asymptomatic individuals.
      Laboratory recommendations on appropriate monitoring of the hs-cTnI assays will help mitigate some of these issues;
      • Wu A.H.B.
      • Christenson R.H.
      • Greene D.N.
      • et al.
      Clinical laboratory practice recommendations for the use of cardiac troponin in acute coronary syndrome: Expert Opinion from the Academy of the American Association for Clinical Chemistry and the Task Force on Clinical Applications of Cardiac Bio-Markers of the International Federation of Clinical Chemistry and Laboratory Medicine.
      however, what has not been evaluated thoroughly is the impact of a low hs-cTnI result for risk stratification in a general ED population in North America. To address this gap, our goal was to compare Abbott hs-cTnI published cutoffs (eg, 5 ng/L and the overall 99th percentile of 26 ng/L) alone vs a simple laboratory algorithm (ie, Clinical Chemistry Score [CCS])
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      at presentation in a general ED population to determine low- and high-risk patients for subsequent all-cause death.

      Methods

      Study design and population

      After research ethics board approval was obtained, from November 28, 2012, to February 28, 2013, all ethylenediaminetetraacetic acid blood samples from the ED at 3 adult hospitals in Hamilton, Ontario, Canada, that had an order for cardiac troponin had both the standard cardiac troponin I (cTnI) and hs-cTnI tests performed on the Abbott ARCHITECT instruments, with only the cTnI results being clinically reported. Patients included in this study were adult patients who were investigated for possible ACS as demonstrated by emergency staff ordering the “ED cardiac presentation panel,” which included troponin I, glucose, creatinine, and other laboratory tests at the Hamilton General Hospital, St. Joseph’s Healthcare Hamilton, and Juravinski Hospital (note, troponin I used for clinical decision making during this timeframe was the Abbott Laboratories contemporary sensitive cTnI assay).
      • Collinson P.O.
      • Saenger A.K.
      • Apple F.S.
      • IFCC C.-C.B.
      High sensitivity, contemporary and point-of-care cardiac troponin assays: educational aids developed by the IFCC Committee on Clinical Application of Cardiac Bio-Markers.
      The Abbott hs-cTnI concentrations (limit of detection for the assay being 1 ng/L)
      • Collinson P.O.
      • Saenger A.K.
      • Apple F.S.
      • IFCC C.-C.B.
      High sensitivity, contemporary and point-of-care cardiac troponin assays: educational aids developed by the IFCC Committee on Clinical Application of Cardiac Bio-Markers.
      were obtained in real-time and on the same instruments in the hospitals with the hs-cTnI results not reported to the treating physician.
      • Kavsak P.A.
      • Shortt C.
      • Pond G.
      • Worster A.
      High-sensitivity cardiac troponin I for predicting death in a female emergency department population.
      The flow diagram in Supplemental Figure 1 shows the cohort selection. Briefly, only the presentation hs-cTnI result on the first ED encounter on 6641 patients who presented to the ED was used with further selection dependent on also having a glucose and creatinine result (ie, the “ED cardiac presentation panel,” with creatinine for an estimated glomerular filtration rate [eGFR] as calculated by the CKD-Epidemiology Collaboration equation being performed in 2019).
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      Patients were also excluded if they were not Ontario residents, if age and sex were missing in the registered persons database (n = 625 individuals excluded), or if they were not Ontario Health Insurance Plan eligible at baseline (n = 42). The final cohort consisted of 5974 individuals with the treating emergency physicians blinded to the hs-cTnI in addition to eGFR results calculated by the CKD-Epidemiology Collaboration equation.

      High-sensitivity cardiac troponin I cutoffs and CCS

      The cutoffs used for the Abbott Laboratories hs-cTnI assay were < 5 ng/L, 5 to 26 ng/L, and > 26 ng/L, as previously used in patients with suspected ACS.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • Lee K.K.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      • Chapman A.R.
      • Lee K.K.
      • McAllister D.A.
      • et al.
      Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome.
      • Bularga A.
      • Lee K.K.
      • Stewart S.
      • et al.
      High-sensitivity troponin and the application of risk stratification thresholds in patients with suspected acute coronary syndrome.
      ,
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      The simple laboratory algorithm or CCS has been published in both a multicenter Canadian study and an international study.
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      ,
      • Kavsak P.A.
      • McRae A.
      • Vatanpour S.
      • Ismail O.Z.
      • Worster A.
      A multicenter assessment of the sensitivity and specificity for a single high-sensitivity cardiac troponin test at emergency department presentation for hospital admission.
      Results from glucose, eGFR, and hs-cTnI are converted into an ordinal scale, with the sum ranging from 0 (low risk) to 5 (high risk).
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      ,
      • Kavsak P.A.
      • McRae A.
      • Vatanpour S.
      • Ismail O.Z.
      • Worster A.
      A multicenter assessment of the sensitivity and specificity for a single high-sensitivity cardiac troponin test at emergency department presentation for hospital admission.
      The scores are generated as follows: glucose < 5.6 mmol/L = 0 points or ≥ 5.6 mmol/L = 1 point; eGFR ≥ 90 mL/min/1.73 m2 = 0 points or < 90 mL/min/1.73 m2 = 1 point; hs-cTnI < 4 ng/L = 0 points or 4-14 ng/L = 1 point or 15-30 ng/L = 2 points or > 30 ng/L = 3 points.
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      ,
      • Kavsak P.A.
      • McRae A.
      • Vatanpour S.
      • Ismail O.Z.
      • Worster A.
      A multicenter assessment of the sensitivity and specificity for a single high-sensitivity cardiac troponin test at emergency department presentation for hospital admission.
      The CCS was calculated by the sum of the points from glucose, eGFR, and hs-cTnI. For example, a CCS < 1 (or CCS = 0) would be obtained if glucose < 5.6 mmol/L, eGFR ≥ 90 mL/min/1.73 m2, and hs-cTnI < 4 ng/L, whereas a CCS = 5 would be obtained if glucose ≥ 5.6 mmol/L, eGFR < 90 mL/min/1.73 m2, and hs-cTnI > 30 ng/L from the ED presentation blood work.

      Outcomes and statistical analysis

      We evaluated all-cause death at 3 months, 1 year, and 5 years after the presentation blood work.
      • Kavsak P.A.
      • Wang X.
      • Ko D.T.
      • MacRae A.R.
      • Jaffe A.S.
      Short- and long-term risk stratification using a next-generation, high-sensitivity research cardiac troponin I (hs-cTnI) assay in an emergency department chest pain population.
      • Than M.P.
      • Aldous S.J.
      • Troughton R.W.
      • et al.
      Detectable high-sensitivity cardiac troponin within the population reference interval conveys high 5-year cardiovascular risk: an observational study.
      • Lau G.
      • Koh M.
      • Kavsak P.A.
      • et al.
      Clinical outcomes for chest pain patients discharged home from emergency departments using high-sensitivity versus conventional cardiac troponin assays.
      Administrative and clinical databases linked at ICES (Toronto, Ontario, Canada) via unique encrypted patient identifier were used to obtain medical history and outcomes. The Ontario registered persons database contained all information on patient demographics and death date. All inpatient hospital discharges were captured in the Canadian Institute for Health Information (CIHI) Discharge Abstract Database. We used the Ontario Health Insurance Plan database to capture all physician billings and outpatient visits.
      We compared baseline characteristics (demographic and clinical) with a 5-year look-back across the following categorizations: (1) hs-cTnI (<5 ng/L vs 5-26 ng/L vs >26 ng/L) and (2) CCS (all individual values on 0-5 ordinal scale). To assess test performance, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) (with 95% confidence intervals [CIs]). These metrics were calculated to assess the prognostic performance of hs-cTnI alone vs in combination with other laboratory tests to rule out those at low risk of experiencing the outcome and rule in those at high risk. We compared hs-cTnI ≥ 5 ng/L vs CCS ≥ 1 and hs-cTnI ≥ 5 ng/L vs CCS ≥ 2 to assess if sensitivity ≥ 99% or NPV ≥ 99.5%, 2 metrics that have been selected as necessities for a test to rule out.
      • Than M.P.
      • Pickering J.W.
      • Sandoval Y.
      • et al.
      Machine learning to predict the likelihood of acute myocardial infarction.
      In contrast, for high risk, we compared hs-cTnI > 26 ng/L (the overall 99th percentile) vs CCS = 5 and hs-cTnI > 26 ng/L vs CCS ≥ 4 to assess if specificity ≥ 90% or PPV ≥ 75% could be attained.
      • Than M.P.
      • Pickering J.W.
      • Sandoval Y.
      • et al.
      Machine learning to predict the likelihood of acute myocardial infarction.
      We also compared the rate of death between the CCS of < 1 or < 2 with that of hs-cTnI < 5 ng/L as surveys of Canadian, American, and Australasian ED physicians suggest a miss rate not exceed 2%.
      • McRae A.D.
      • Innes G.
      • Graham M.
      • et al.
      Comparative evaluation of 2-hour rapid diagnostic algorithms for acute myocardial infarction using high-sensitivity cardiac troponin T.
      Kaplan–Meier survival curves for all-cause mortality over 5 years were also constructed for both the CCS categories and hs-cTnI ranges with censoring at the end of the 5-year observation window (P value by log-rank). Analyses were performed using SAS 9.1.3 software (SAS Institute Inc., Cary, NC) and MedCalc Statistical Software version 19.1.6 (MedCalc Software Ltd., Ostend, Belgium).

      Results

      The median age (interquartile range) for the study population was 70 years (56-82), 50.6% were female, and approximately one-third of the population (32.8%) had diabetes. The prevalence of cardiovascular disease and risk factors increased with the higher hs-cTnI concentrations and the higher CCS (Table 1), with survival curves also displaying separation of low- and high-risk groups per hs-cTnI ranges or the CCS over 5 years (Fig. 1).
      Table 1Characteristics of all-comer ED population classified by the CCS or hs-cTnI concentration categories
      CharacteristicClinical chemistry scoreP valuehs-cTnI concentrationP value
      012345< 5 ng/L5-26 ng/L> 26 ng/L
      N = 399N = 923N = 1405N = 1486N = 853N = 908N = 2374N = 2324N = 1276
      Age (y)Median (IQR)46 (36-53)53 (44-63)66 (56-78)77 (67-84)79 (67-86)80 (69-87)< 0.00158 (47-70)76 (65-84)78 (66-86)< 0.001
      Sex, femaleN (%)210 (52.6%)434 (47.0%)802 (57.1%)792 (53.3%)373 (43.7%)414 (45.6%)< 0.0011324 (55.8%)1154 (49.7%)547 (42.9%)< 0.001
      Risk factors
      ArrhythmiaN (%)12 (3.0%)49 (5.3%)164 (11.7%)295 (19.9%)236 (27.7%)231 (25.4%)< 0.001157 (6.6%)509 (21.9%)321 (25.2%)< 0.001
      Congestive heart failureN (%)11 (2.8%)49 (5.3%)177 (12.6%)381 (25.6%)329 (38.6%)343 (37.8%)< 0.001172 (7.2%)634 (27.3%)484 (37.9%)< 0.001
      DiabetesN (%)26 (6.5%)158 (17.1%)390 (27.8%)612 (41.2%)342 (40.1%)433 (47.7%)< 0.001526 (22.2%)906 (39.0%)529 (41.5%)< 0.001
      HypertensionN (%)110 (27.6%)380 (41.2%)931 (66.3%)1181 (79.5%)691 (81.0%)752 (82.8%)< 0.0011181 (49.7%)1840 (79.2%)1024 (80.3%)< 0.001
      MIN (%)15 (3.8%)44 (4.8%)105 (7.5%)169 (11.4%)157 (18.4%)184 (20.3%)< 0.001121 (5.1%)318 (13.7%)235 (18.4%)< 0.001
      Renal diseaseN (%)0 (0.0%)6 (0.7%)26 (1.9%)61 (4.1%)88 (10.3%)104 (11.5%)< 0.00115 (0.6%)124 (5.3%)146 (11.4%)< 0.001
      StrokeN (%)≤ 5
      Suppressed for privacy reasons.
      15 (1.6%)23 (1.6%)51 (3.4%)36 (4.2%)56 (6.2%)< 0.00135 (1.5%)87 (3.7%)64 (5.0%)< 0.001
      AnginaN (%)12 (3.0%)27 (2.9%)79 (5.6%)118 (7.9%)59 (6.9%)79 (8.7%)< 0.00197 (4.1%)172 (7.4%)105 (8.2%)< 0.001
      Percutaneous coronary interventionN (%)7 (1.8%)31 (3.4%)68 (4.8%)78 (5.2%)56 (6.6%)66 (7.3%)< 0.00172 (3.0%)148 (6.4%)86 (6.7%)< 0.001
      Coronary artery bypass graftingN (%)≤ 5
      Suppressed for privacy reasons.
      7 (0.8%)29 (2.1%)41 (2.8%)40 (4.7%)29 (3.2%)< 0.00125 (1.1%)78 (3.4%)44 (3.4%)< 0.001
      Serum creatinine, μmol/LMedian (IQR)67 (61-73)72 (65-79)78 (69-94)89 (74-116)101 (77-144)114 (89-169)< 0.00174 (67-85)88 (73-119)107 (80-163)< 0.001
      Glucose, mmol/LMean ± SD4.98 ± 0.426.19 ± 2.177.03 ± 3.358.42 ± 5.607.92 ± 4.489.45 ± 4.82< 0.0016.84 ± 3.347.95 ± 5.038.41 ± 4.55< 0.001
      hs-cTnI, ng/LMedian (IQR)2 (1-2)2 (1-3)4 (2-6)8 (6-12)24 (18-42)67 (39-179)< 0.0012 (1-4)10 (7-15)62 (38-170)< 0.001
      eGFR, mL/min/1.73 m2Median (IQR)102 (96-110)94 (85-103)77 (63-87)63 (46-78)54 (34-76)46 (27-66)< 0.00186 (73-98)63 (44-81)49 (29-74)< 0.001
      Outpatient cardiologist follow-up: 30 d after ED visitN (%)25 (6.3%)71 (7.7%)133 (9.5%)192 (12.9%)132 (15.5%)155 (17.1%)< 0.001188 (7.9%)287 (12.3%)233 (18.3%)< 0.001
      Outpatient GP/FP follow-up: 30 d after ED visitN (%)190 (47.6%)405 (43.9%)673 (47.9%)699 (47.0%)380 (44.5%)403 (44.4%)1120 (47.2%)1094 (47.1%)536 (42.0%)
      No outpatient follow-up: 30 d after ED visitN (%)184 (46.1%)447 (48.4%)599 (42.6%)595 (40.0%)341 (40.0%)350 (38.5%)1066 (44.9%)943 (40.6%)507 (39.7%)
      All-cause mortality, 90 dN (%)≤ 5
      Suppressed for privacy reasons.
      31 (3.4%)68 (4.8%)137 (9.2%)145 (17.0%)217 (23.9%)< 0.00165 (2.7%)254 (10.9%)282 (22.1%)< 0.001
      All-cause mortality, 1 yN (%)8 (2.0%)47 (5.1%)134 (9.5%)253 (17.0%)248 (29.1%)340 (37.4%)< 0.001119 (5.0%)448 (19.3%)463 (36.3%)< 0.001
      All-cause mortality, 5 yN (%)32 (8.0%)137 (14.8%)335 (23.8%)657 (44.2%)526 (61.7%)612 (67.4%)< 0.001350 (14.7%)1113 (47.9%)836 (65.5%)< 0.001
      Medical history calculated using 5-y look-back.
      CCS, Clinical Chemistry Score; ED, emergency department; eGFR, estimated glomerular filtration rate; FP, family practice; GP, general practice; hs-cTnI, high-sensitivity cardiac troponin I; IQR, interquartile range; MI, myocardial infarction.
      Suppressed for privacy reasons.
      Figure thumbnail gr1
      Figure 1Kaplan–Meier survival curves for all-cause death based on (A) Clinical Chemistry Score (CCS) (0 to 5) and (B) high-sensitivity cardiac troponin I (hs-cTnI) categories (<5 ng/L, 5-26 ng/L, >26 ng/L).
      Overall, 40.8% of the population was discharged home from the ED with 79.4% (95% CI, 70.9-88.7) of patients with a CCS < 1 discharged compared with 64.4% (95% CI, 61.2-67.7) of patients with an hs-cTnI < 5 ng/L (P < 0.01). The mortality rate was ≤ 2.0% in patients (n = 399 or 6.7% of the total population) with a CCS < 1 (ie, CCS = 0) at both 3 months and 1 year compared with 2.7% and 5.0% in patients (n = 2374 or 39.7% of the total population) with hs-cTnI < 5 ng/L at these timeframes, respectively (Table 1). At 1 year, the difference in mortality rates was significant (CCS < 1 mortality was 2.0%; 95% CI, 0.9-4.0 vs mortality in patients with hs-cTnI < 5 ng/L of 5.0%; 95% CI, 4.2-6.0; P = 0.01). By applying the CCS cutoff of ≥ 1, the sensitivity for mortality was 99.5% (95% CI, 98.5-99.9) at 3 months, 99.2% (95% CI, 98.4-99.6) at 1 year, and 98.6% (95% CI, 98.0-99.0) at 5 years (Table 2). Patients with a CCS < 2 had outcome rates similar to those patients with only hs-cTnI < 5 ng/L; however, the sensitivities for a CCS ≥ 2 were higher (3-month sensitivity = 94.3% to 5-year sensitivity = 92.6%) than hs-cTnI ≥ 5 ng/L (3-month sensitivity = 89.1% to 5-year sensitivity = 84.7%) (Table 2). The highest observed NPV (99.2%; 95% CI, 97.8-99.8) was at 3 months when using the CCS cutoff ≥ 1. At 5 years, only the CCS of 5 yielded a specificity ≥ 90% (91.9%; 95% CI, 91.0-92.8) for all-cause mortality, with no PPVs > 75% for the CCS or hs-cTnI above the 99th percentile cutoffs.
      Table 2Prognostic performance of CCS ≥ 1 or ≥ 2 for rule-out and CCS = 5 or ≥ 4 for rule-in vs hs-cTnI alone (≥ 5 ng/L for rule-out or > 26 ng/L for rule-in) for all-cause mortality
      ParameterTimeRule-outRule-in
      CCS ≥ 1CCS ≥ 2hs-cTnI ≥ 5 ng/LCCS = 5CCS ≥ 4hs-cTnI > 26 ng/L
      Sensitivity3 mo0.995 (0.985-0.999)0.943 (0.921-0.960)0.891 (0.864-0.915)0.361 (0.322-0.400)0.602 (0.561-0.641)0.462 (0.422-0.503)
      1 y0.992 (0.984-0.996)0.946 (0.931-0.959)0.884 (0.863-0.903)0.330 (0.301-0.359)0.570 (0.540-0.601)0.442 (0.412-0.473)
      5 y0.986 (0.980-0.990)0.926 (0.915-0.936)0.847 (0.832-0.862)0.266 (0.248-0.284)0.495 (0.474-0.515)0.358 (0.339-0.378)
      NPV3 mo0.992 (0.978-0.998)0.974 (0.964-0.982)0.972 (0.965-0.978)0.924 (0.916-0.931)0.943 (0.935-0.950)0.931 (0.924-0.938)
      1 y0.979 (0.960-0.991)0.958 (0.946-0.968)0.949 (0.940-0.958)0.863 (0.854-0.873)0.895 (0.885-0.904)0.878 (0.868-0.887)
      5 y0.919 (0.888-0.944)0.872 (0.853-0.889)0.852 (0.837-0.866)0.667 (0.653-0.680)0.724 (0.710-0.737)0.688 (0.674-0.701)
      Specificity3 mo0.073 (0.066-0.081)0.239 (0.228-0.251)0.429 (0.416-0.443)0.871 (0.862-0.880)0.739 (0.727-0.751)0.819 (0.808-0.829)
      1 y0.079 (0.071-0.087)0.256 (0.244-0.268)0.456 (0.442-0.470)0.885 (0.875-0.893)0.762 (0.750-0.774)0.839 (0.829-0.849)
      5 y0.099 (0.090-0.110)0.313 (0.298-0.329)0.550 (0.534-0.566)0.919 (0.910-0.928)0.830 (0.817-0.842)0.884 (0.873-0.894)
      PPV3 mo0.107 (0.099-0.115)0.121 (0.112-0.131)0.148 (0.137-0.160)0.239 (0.211-0.268)0.205 (0.186-0.225)0.222 (0.199-0.246)
      1 y0.183 (0.173-0.193)0.209 (0.198-0.221)0.253 (0.238-0.267)0.374 (0.342-0.406)0.333(0.311-0.356)0.365 (0.338-0.392)
      5 y0.406 (0.393-0.419)0.457 (0.443-0.472)0.541 (0.524-0.557)0.674 (0.642-0.704)0.646 (0.623-0.668)0.660 (0.633-0.686)
      CCS, Clinical Chemistry Score; hs-cTnI, high-sensitivity cardiac troponin I; NPV, negative predictive value; PPV, positive predictive value.
      Bold text represent estimates that are ≥ 99% sensitivity or ≥ 90% specificity.

      Discussion

      In an ED population who were investigated for ACS, were clinically managed with a contemporary cTnI assay, and had hs-cTnI results that were blinded to the treating physicians, our findings indicate that an hs-cTnI cutoff of ≥ 5 ng/L at ED presentation would not be sufficiently safe to rule out mortality because the sensitivity estimates were below 90%. Only a CCS ≥ 1 would yield diagnostic test estimates that could be considered safe for identifying low-risk patients because the sensitivity was > 99% and the event rate was ≤ 2% (for those with a CCS < 1) for up to 1 year after patient presentation. For identifying high-risk patients, only the CCS of 5 yielded a specificity > 90% for mortality, but this was evident at only 5 years. These data extend previous findings on the CCS
      • Kavsak P.A.
      • Neumann J.T.
      • Cullen L.
      • et al.
      Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.
      to a general ED population, who are more representative of patients who have cardiac troponin ordered in the emergency setting. Moreover, these findings further support data that patients with hs-cTnI concentrations below the 99th percentile (or “normal levels”) early after ED presentation may still be at a higher risk for an adverse outcome over both the short and long term.
      • Kavsak P.A.
      • Wang X.
      • Ko D.T.
      • MacRae A.R.
      • Jaffe A.S.
      Short- and long-term risk stratification using a next-generation, high-sensitivity research cardiac troponin I (hs-cTnI) assay in an emergency department chest pain population.
      ,
      • Than M.P.
      • Aldous S.J.
      • Troughton R.W.
      • et al.
      Detectable high-sensitivity cardiac troponin within the population reference interval conveys high 5-year cardiovascular risk: an observational study.
      ,
      • Neumann J.T.
      • Twerenbold R.
      • Ojeda F.
      • et al.
      Application of high-sensitivity troponin in suspected myocardial infarction.
      Additional laboratory and clinical variables may further aid in risk stratification as demonstrated by the simple CCS in this setting.

      Limitations

      Our study includes some important limitations. First, we were unable to capture the time of pain onset and thus cannot differentiate early pain onset from late pain onset because hs-cTn testing for rule-out is not recommended in the population with early chest pain onset.
      • Bularga A.
      • Lee K.K.
      • Stewart S.
      • et al.
      High-sensitivity troponin and the application of risk stratification thresholds in patients with suspected acute coronary syndrome.
      ,
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • et al.
      2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
      Second, we only included all-cause death, a hard end point, whereas others have also included MI and other cardiovascular outcomes. Third, the study population was derived from 3 hospitals from the same city. Further research could validate the results from other geographic locations. Fourth, the laboratory ordering practice of including glucose and creatinine with cardiac troponin (ie, the “ED cardiac presentation panel”) may differ at different hospitals. To our understanding, there are no recommendations on what laboratory tests besides cardiac troponin should be ordered when considering myocardial injury.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      ESC Scientific Document Group. Fourth universal definition of myocardial infarction (2018).
      ,
      • Wu A.H.B.
      • Christenson R.H.
      • Greene D.N.
      • et al.
      Clinical laboratory practice recommendations for the use of cardiac troponin in acute coronary syndrome: Expert Opinion from the Academy of the American Association for Clinical Chemistry and the Task Force on Clinical Applications of Cardiac Bio-Markers of the International Federation of Clinical Chemistry and Laboratory Medicine.
      Fifth, no adjustments were made for subsequent MI post-ED assessment, other cardiovascular disease risk factors, or medication use during the 5-year period for long-term mortality because there may be other important variables that have contributed to long-term mortality. Sixth, the prevalence of patients with a CCS < 1 (~7%) was approximately 6-fold lower compared with patients with an hs-cTnI < 5 ng/L (~40%). Clinicians may want to use additional screening tools, besides laboratory tests, to identify patients at low risk for an adverse outcome.

      Conclusions

      In patients in the ED being investigated for suspected ACS, using a simple CCS at presentation improves the ability to identify both low-risk and high-risk patients for short- and long-term mortality.

      Funding Sources

      This study was supported by ICES , which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Contents are based on data provided by CIHI. Analyses, opinions, and statements expressed are those of the authors and not necessarily those of CIHI; no endorsement is intended or should be inferred. The authors thank IMS Brogan Inc., for use of their Drug Information Database. This study was supported by a Canadian Institutes of Health Research grant (PK, Funding Reference #155964) with past financial and reagent support by Abbott Laboratories . The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or final approval of the manuscript.

      Disclosures

      Dr Kavsak has received grants/reagents/consultant/advisor/honoraria from Abbott Laboratories , Abbott Point of Care, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics, and Siemens Healthcare Diagnostics. McMaster University has filed patents with Drs Kavsak and Worster listed as an inventor in the acute cardiovascular biomarker field; in particular, a patent has been filed on aspects related to the data presented in this study.

      Supplementary Material

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