High-Sensitivity Cardiac Troponin Risk Cutoffs for Acute Cardiac Outcomes at Emergency Department Presentation

Accepted Manuscript High-sensitivity cardiac troponin risk-cutoffs for acute cardiac outcomes at emergency department presentation Peter A. Kavsak, PhD, Andrew Worster, MD, MSc, Jinhui Ma, PhD, Colleen Shortt, BSc, Natasha Clayton, CRA, RA, Jonathan Sherbino, MD, Stephen A. Hill, PhD, Matthew McQueen, MBChB, PhD, Shamir R. Mehta, MD, MSc, P.J. Devereaux, MD, PhD PII:

S0828-282X(17)30203-9

DOI:

10.1016/j.cjca.2017.04.011

Reference:

CJCA 2424

To appear in:

Canadian Journal of Cardiology

Received Date: 28 March 2017 Revised Date:

27 April 2017

Accepted Date: 27 April 2017

Please cite this article as: Kavsak PA, Worster A, Ma J, Shortt C, Clayton N, Sherbino J, Hill SA, McQueen M, Mehta SR, Devereaux P, High-sensitivity cardiac troponin risk-cutoffs for acute cardiac outcomes at emergency department presentation, Canadian Journal of Cardiology (2017), doi: 10.1016/ j.cjca.2017.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Running Title: Risk cutoffs for high-sensitivity troponin

High-sensitivity cardiac troponin risk-cutoffs for acute cardiac outcomes at emergency

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department presentation

Peter A Kavsak PhDa,1, Andrew Worster MD, MScb,1, Jinhui Ma PhDc, Colleen Shortt BSca,

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Natasha Clayton CRA, RAd, Jonathan Sherbino MDb, Stephen A. Hill PhDa, Matthew McQueen

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MBChB, PhD, a, Shamir R. Mehta MD, MSce, PJ Devereaux MD, PhDe

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON,

Canada; b Division of Emergency Medicine, McMaster University, Hamilton, ON, Canada; c

School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa,

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and the Children’s Hospital of Eastern Ontario Research Institute ON, Canada; d Department of Medicine, McMaster University, Hamilton, ON, Canada; e Division of Cardiology, and

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Population Health Research Institute, McMaster University, Hamilton, ON, Canada

* Corresponding author: Dr. Peter Kavsak, Juravinski Hospital and Cancer Centre, 711

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Concession Street Hamilton, ON, Canada L8V 1C3 Tel: 905-521-2100; e-mail: [email protected] 1

These authors contributed equally to this manuscript

Keywords: cardiovascular death; myocardial infarction; high-sensitivity cardiac troponin; heart failure; acute coronary syndrome; emergency department; relative risk

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Brief summary The optimal high-sensitivity cardiac troponin (hs-cTn) cutoffs for determining risk in patients presenting with ACS symptoms are unknown. In a North American emergency department

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population, hs-cTn concentrations ≥14ng/L at presentation was associated with nearly a 5-fold higher risk for an acute cardiovascular outcome. A common low-risk cutoff of 14ng/L may be

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used for hs-cTn with higher cutoffs identifying high-risk patients.

Abstract

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The optimal high-sensitivity cardiac troponin (hs-cTn) cutoffs for determining risk in patients presenting with ACS symptoms are unknown. In 1137 emergency department patients we calculated adjusted relative risks (aRR) for a composite outcome (myocardial infarction, unstable angina, heart failure, ventricular arrhythmia, or cardiovascular death) within 7-days for the

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presentation hs-cTnT (Roche) and hs-cTnI (Abbott) concentrations based on literature cutoffs. Patients with hs-cTn concentrations ≥14ng/L had an aRR=4.9 for the composite outcome, with different hs-cTnT/hs-cTnT concentration ranges yielding higher risks. A common low-risk cutoff

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of 14ng/L may be used for hs-cTn with higher cutoffs identifying high-risk patients.

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Introduction Much of the focus on the utility of high-sensitivity cardiac troponin (hs-cTn) testing in the emergency department (ED) is centered primarily on early rule-out and rule-in of myocardial

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infarction (MI).1-3 However, for ED patients presenting with symptoms suggestive of acute

coronary syndrome (ACS), MI is only one of several serious cardiac events for which these patients are at risk. Emerging evidence indicates a greater role for hs-cTn concentrations with

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respect to risk stratification in both diagnosis and prognosis.4-7 Hence, rather than simply ruling out MI, hs-cTn concentrations at presentation might better determine patient risk for an adverse

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cardiac event.

The upper 99th-percentile limit from a healthy population has been recommended as the single cutoff for cardiac troponin to identify myocardial injury since 2000; however, with the advent of hs-cTn testing, population selection and statistical approaches have yielded widely

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different upper reference limits.8-12 Furthermore, recent evidence suggests that a high concentration of hs-cTnT (i.e., >60 ng/L) at ED presentation may be sufficient for the diagnosis of MI.13 Outside of the ED ACS setting, cutoffs of 20 ng/L and 65 ng/L have also shown utility

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for hs-cTnT to predict mortality at 30 days following noncardiac surgery.14 For this study, we sought to (1) compare the diagnostic accuracy of hs-cTnT and hs-cTnI for MI, other individual

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cardiac outcomes, and a composite cardiac outcome; and (2) assess the relative risks of hs-cTnT and hs-cTnI based on different published cutoffs at ED presentation for the above outcomes with the goal to establish risk cutoffs in this setting.

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Methods Study Design and Population This study was a multicenter prospective cohort study conducted across a North

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American city (Hamilton, ON; study: Optimum Troponin Cutoffs for ACS in the ED [ROMI-3]; ClinicalTrials.gov Identifier: NCT01994577) whose primary outcome measure was a composite cardiac outcome following ED presentation. We followed the STARD guideline for our initial

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reporting of diagnostic accuracy in this population (n=1137), with a focus on the first 7-days following ED presentation.15,16 Briefly, following ethics approval, consecutive ED patients (24

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hours/day during the study period: May-August 2013) who met the inclusion criteria (≥18 years, ED physician ordered cardiac troponin) and exclusion criteria (ST-elevation myocardial infarction, ventricular fibrillation, or ventricular tachycardia at presentation; symptoms not due to ACS; chest trauma; cardiac intervention or MI or pulmonary embolus within 30 days of

hospitals with adult EDs.16

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presentation; sepsis; active malignancy or non-cardiac fatal illness) were enrolled from the 3

Assessment

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High-sensitivity cardiac troponin T, high-sensitivity cardiac troponin I and Outcomes

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The presentation EDTA plasma samples (non-frozen) from the study participants were

measured using Roche’s 5th-generation hs-cTnT assay (E-modular analyzer) and Abbott’s hscTnI assay (ARCHITECT i2000 analyzers) with acceptable laboratory imprecision.16,17 The following cutoffs were assessed in the present study for hs-cTnT: 65 ng/L and 20 ng/L (based on an outcome analysis study from a noncardiac surgical population of >20,000 participants)14, 6 ng/L (the lowest reportable limit in the United States)18, and 14 ng/L (the established overall 99th

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percentile cutoff outside of the United States; in the United States, >19 ng/L is the overall 99th percentile cutoff as listed in the package insert).2,18 For hs-cTnI the following cutoffs: 99 ng/L (the cutoff that yielded 99% specificity for MI in this setting)16, 30 ng/L (a 99th percentile

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derived from a healthy Canadian population)9, 2 ng/L (the proposed lower reportable limit for this assay)1,3, and 14 ng/L (the lowest overall 99th percentile cutoff outside of North America).10,11

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The primary outcome was a composite outcome consisting of MI, unstable angina,

serious ventricular cardiac arrhythmia, decompensated congestive heart failure, or cardiovascular

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death within 7-days of ED presentation as this would most likely prompt immediate hospital admission and treatment in order to avert the event (see Table 1 for complete details). The adjudication process was led by an emergency physician (AW). The outcomes were independently adjudicated by at least two of the authors and disagreements not resolved by

results.

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Statistical Analysis

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consensus were referred to a third reviewer. All outcome adjudicators were blinded to the hs-cTn

We used the area under the receiver operating characteristic curve (AUC) to compare the

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diagnostic accuracy of hs-cTnT versus hs-cTnI for the individual outcomes as well as the primary composite outcome. Based on the 7-day hs-cTnI AUC of 0.90 for MI16; for detection of a difference of 0.03 between two AUCs at a significance level of 0.05, at least 846 subjects are needed to achieve a statistical power of 80%19; with our population exceeding this estimate. We used multivariable log-binomial regression model to assess the association between hs-cTnT or hs-cTnI and the outcomes with results expressed as the relative risk (crude) and after adjusting

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for important clinical variables (aRR; models adjusted for age, sex, family history, hypertension, hypercholesterolemia, diabetes mellitus, smoking status, eGFR, history of MI/ACS, history of congestive heart failure, history of cardiac arrest, history of angina, history of atrial fibrillation,

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history of peripheral vascular disease, anti-platelet therapy within 7-days, anti-thrombin therapy within last 7-days, and ASA treatment) with the corresponding 95%CI.20,21 We performed

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analyses using SAS and Analyse-it software.

Results

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The prevalence for the composite outcome (24.0%; 95%CI 21.3, 27.0) was significantly higher than MI (11.7%; 95%CI 9.8, 13.9) in the study population (average(SD) age=66.7(16.5); n=1137). The diagnostic accuracy of hs-cTnI at presentation for MI (AUC=0.90; 95%CI 0.87, 0.93) was significantly higher than hs-cTnT (AUC=0.86; 95%CI 0.83, 0.89) (p<0.001) (Fig. 1a).

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However, there was no difference in diagnostic performance between hs-cTnI and hs-cTnT for the remaining individual cardiac outcomes (Fig. 1b,c,d,e) and for the primary composite cardiac outcome (hs-cTnI AUC=0.86; 95%CI 0.83,0.88 vs. hs-cTnT AUC=0.84; 95%CI 0.82, 0.87)

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(p=0.14, Fig. 1f).

For the primary outcome assessing low hs-cTnT concentrations, the aRR for the 6-14

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ng/L (n=384 patients; aRR=2.07; 95%CI 0.90, 4.49) versus <6 ng/L group (n=248 patients) was not significant; however, the 15-19 ng/L (n=106 patients; aRR=6.32), 20-65 ng/L (n=296 patients; aRR=11.42) and >65 ng/L (n=103 patients; aRR=21.23) groups were at significantly higher risks when compared to the <6 ng/L group. When compared to ≤14 ng/L group (n=632 patients with 46 primary outcomes/7.3% outcome-rate); the 15-19 ng/L group was still at a higher risk (aRR=3.57/20.8% outcome-rate) with a doubling of risk for the 20-65 ng/L

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(aRR=6.22/42.9% outcome-rate) and the >65 ng/L groups (aRR=11.76/75.7% outcome-rate) (Table 2). Low detectable concentrations measured by the hs-cTnI assay (2-13 ng/L, n=633

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patients) did not portend a higher risk group (aRR=2.18; 95%CI 0.86, 5.20) when compared to the <2 ng/L group (n=159 patients). However, the 14-30 ng/L (n=175 patients; aRR=7.09), 3199 ng/L (n=104 patients; aRR=13.93), and >99 ng/L (n=66 patients; aRR=26.98) groups were at

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significantly higher risks when compared to the <2 ng/L group. When compared to <14 ng/L group (n=792 patients with 76 primary outcomes/9.6% outcome-rate); the 14-30 ng/L group was

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still at a higher risk (aRR=3.15/41.1% outcome-rate), as was the 31-99 ng/L (aRR=5.65/61.5% outcome-rate) and >99 ng/L (aRR=9.33/92.4% outcome-rate) groups (Table 2). These RR were also evident for MI, UA and CV death and for MI alone for both hs-cTnT and hs-cTnT (see Supplemental Table 1 for the number of events/rates for the individual outcomes).

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Employing a common cutoff of 14 ng/L for both hs-cTnT and hs-cTnI yielded similar relative risks for the primary outcome. Patients with presentation hs-cTnT >14 ng/L had an aRR of 4.92 (95%CI 3.70, 6.29) and patients with presentation hs-cTnI ≥14 ng/L had an aRR of 4.99

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Discussion

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(95%CI 4.04, 5.96).

There are a couple of noteworthy findings from the present analyses. First, the

performance between hs-cTnI and hs-cTnT laboratory tests are equivalent when assessing important cardiac outcomes whose diagnosis is not dependent on a cardiac troponin concentration exceeding the 99th percentile. The incorporation bias that is present when evaluating new, more analytically sensitive versions of cardiac troponin tests for the diagnosis of

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MI extends further to whether cTnI or cTnT were used for the initial diagnosis and event adjudication. Employing a composite cardiac outcome as the primary outcome demonstrates that hs-cTnI and hs-cTnT perform equally well in identifying ED patients at high risk for an acute

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cardiovascular outcome.

Second, at ED presentation, a common cutoff of 14 ng/L may be used for both Roche’s hs-cTnT and Abbott’s hs-cTnI to define a low-risk group for an acute cardiac event. Patients

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with hs-cTnT concentrations within the 15-19 ng/L range or hs-cTnI concentrations within the 14-30 ng/L range are at a 3-fold higher risk for an adverse cardiac outcome, with a doubling of

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risk for those with hs-cTnT concentrations between 20-65 ng/L or hs-cTnI concentrations between 31-99 ng/L (~6-fold). Patients with hs-cTnT >65 ng/L or hs-cTnI >99 are at highest risk (aRR>9) as compared to the low-risk group. These data also lend support to the fact that in the emergency setting, slightly detectable concentrations (hs-cTnT:6-14 ng/L or hs-cTnI:2-13

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ng/L) do not portend a higher risk group in the short-term versus undetectable concentrations; consistent with analytical data suggesting it will be difficult for laboratories and physicians for

making.17,22-24

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Limitations

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monitoring patients at these low cardiac troponin concentrations for acute clinical decision

As only the presentation sample was used in the analysis, it is uncertain how many

patients with hs-cTnT <20 ng/L or hs-cTnI <31 ng/L (overall 99th percentiles established from North American populations) would have a subsequent measurement ≥20 ng/L or ≥31 ng/L, respectively. However, risk stratification often occurs based on the presentation cardiac troponin result; as supported by a large prospective study cohort that has indicated that <50% of patients

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with cardiac troponin concentration below the 99th percentile have repeat testing.25 Also, we did not explore in these analyses how eGFR may be used with hs-cTn to further aid in riskstratification, with preliminary data suggestion inclusion of this variable may further identify

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low-risk patients.26

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Conclusions

Patients presenting to the ED with undetectable and low hs-cTn concentrations below 14

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ng/L are at lower risk for an acute cardiac outcome as compared to those patients with concentrations above the proposed North American 99th percentiles, with hs-cTnT ≥20 ng/L and hs-cTnI ≥31 ng/L representing a high-risk group. Hence, application of risk-cutoffs for hs-cTn at ED presentation can better determine patient risk for an adverse cardiac event as compared to

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using one overall 99th-percentile cutoff. Additional population-based studies are needed to

References

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further refine these hs-cTn risk-estimates.

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1. Sandoval Y, Smith SW, Apple FS. Present and Future of Cardiac Troponin in Clinical Practice: A Paradigm Shift to High-Sensitivity Assays. Am J Med 2016;129:354-65.

2. Pickering JW, Greenslade JH, Cullen L, et al. Validation of presentation and 3 h highsensitivity troponin to rule-in and rule-out acute myocardial infarction. Heart 2016;102:1270-8.

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3. Pickering JW, Greenslade JH, Cullen L, et al. Assessment of the European Society of Cardiology 0-Hour/1-Hour Algorithm to Rule-Out and Rule-In Acute Myocardial Infarction. Circulation 2016;134:1532-1541.

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4. Kavsak PA, Xu L, Yusuf S, McQueen MJ. High-sensitivity cardiac troponin I

measurement for risk stratification in a stable high-risk population. Clin Chem 2011;57:1146-53.

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5. McQueen MJ, Kavsak PA, Xu L, et al. Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable

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population. Clin Biochem 2013;46:5-9.

6. Gore MO, Seliger SL, Defilippi CR, et al. Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. J Am Coll Cardiol 2014;63:1441-8. 7. Eggers KM, Jernberg T, Lindahl B. Prognostic Importance of Sex-Specific Cardiac

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Troponin T 99(th) Percentiles in Suspected Acute Coronary Syndrome. Am J Med 2016;129:880.e1-880.e12.

8. Koerbin G, Tate J, Potter JM, et al. Characterisation of a highly sensitive troponin I assay

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and its application to a cardio-healthy population. Clin Chem Lab Med 2012;50:871-8. 9. Kavsak PA, Rezanpour A, Chen Y, Adeli K. Assessment of the 99th or 97.5th percentile

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for cardiac troponin I in a healthy pediatric cohort. Clin Chem 2014;60:1574-6.

10. Koerbin G, Abhayaratna WP, Potter JM, et al. Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays. Clin Biochem 2013;46:1636-43.

11. Kimenai DM, Henry RM, van der Kallen CJ, et al. Direct comparison of clinical decision limits for cardiac troponin T and I. Heart 2016;102:610-6.

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12. Eggers KM, Apple FS, Lind L, Lindahl B. The applied statistical approach highly influences the 99th percentile of cardiac troponin I. Clin Biochem 2016;49:1109-1112. 13. Mueller-Hennessen M, Mueller C, Giannitsis E, et al. Serial Sampling of High-

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Sensitivity Cardiac Troponin T May Not Be Required for Prediction of Acute Myocardial Infarction Diagnosis in Chest Pain Patients with Highly Abnormal Concentrations at Presentation. Clin Chem 2017;63:542-551

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14. Devereaux PJ, Biccard BM, Sigamani A, et al, on behalf of the Vascular Events in Noncardiac Surgery Patients cohort evaluation (VISION) Study Investigators. Association of postoperative

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high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017; 317: 1642-1651.

15. Bossuyt PM, Reitsma JB, Bruns DE, et al. STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies. Clin Chem 2015;61:1446-52.

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16. Shortt C, Ma J, Clayton N, et al. Rule-in and rule-out of myocardial infarction using cardiac troponin and glycemic biomarkers in patients with symptoms suggestive of acute coronary syndrome. Clin Chem 2017;63:403-414.

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17. Kavsak PA, Jaffe AS, Greene DN, et al. Total Analytic Error for Low Cardiac Troponin Concentrations (≤10 ng/L) by Use of a High-Sensitivity Cardiac Troponin Assay. Clin

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Chem 2017, Mar 2017, clinchem.2017.271361; DOI: 10.1373/clinchem.2017.271361.

18. Roche Diagnostics Elecsys Troponin T Gen 5 STAT 2017-02, V 1.0 English US package insert, 2017.

19. Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J Biomed Inform 2014;48:193-204. 20. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77 11/16

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21. Zhang J, Yu KF. What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA1998;280:1690-1.

cardiac troponin T assay. Clin Chem 2013;59:574-6.

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22. Kavsak PA, Hill SA, McQueen MJ, et al. Implications of adjustment of high-sensitivity

23. Kavsak PA, Don-Wauchope AC, Hill SA, et al. Acceptable analytical variation may exceed high-sensitivity cardiac troponin I cutoffs in early rule-out and rule-In acute

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myocardial infarction algorithms. Clin Chem 2016;62:887-9.

24. Lyon AW, Kavsak PA, Lyon OA, et al. Simulation models of misclassification error for

Clin Chem 2017;63:585-592.

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single thresholds of high-sensitivity cardiac troponin I due to assay bias and imprecision.

25. Shah AS, Anand A, Sandoval Y, Lee KK, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet

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2015;386(10012):2481-8.

26. Kavsak PA, Shortt C, Ma J, et al. A laboratory score at presentation to rule-out serious cardiac outcomes or death in patients presenting with symptoms suggestive of acute

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coronary syndrome. Clin Chim Acta 2017 Mar 23;469:69-74.

Figure 1. Comparison of the Receiver Operating Characteristic (ROC) curves between hs-cTnI and hs-cTnT for the individual outcomes and the primary composite outcome.

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Table 1. Outcome definition for the components that were used for the composite outcome (note:some patients may have had more than one outcome) Definition & Description

Myocardial Infarction (n=133/11.7%)

Myocardial infarction was defined as per the Third Universal Definition and used the contemporary Abbott cTnI as the reference assay making no distinction between type I and type II MI. Briefly, a cTnI concentration of >0.03ug/L (>99th) with a significant rise/fall (defined as: absolute change of 0.03ug/L or more in concentrations <0.1ug/L or 20% change in concentrations ≥0.1ug/L), or new ST segment elevation or depression indicative of ischemia; new left bundle branch block; coronary artery intervention (e.g., coronary angioplasty) or pathologic findings of an acute myocardial infarction.

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Outcome (number/%)

Unstable Angina (n=76/6.7%)

Unstable Angina was defined as admission to the hospital with any of the following objective criteria: i) discharge diagnosis of UA as per discharge summary; ii) admission to hospital and ACS treatment [heparin or low molecular weight heparin, cardiac catheterization resulting in increased treatment (i.e., Plavix/ASA) or revascularization]

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Heart Failure (n=159/14%)

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Serious Ventricular Arrhythmia (n=13/1.1%)

Cardiovascular Death (n=9/0.8%)

Decompensated congestive heart failure was defined as admission to the hospital with any 2 of the following: i) chest radiograph reported by radiologist as congestive HF or equivalent; ii) clinical signs and symptoms of HF; iii) administration of diuretics or non-invasive positive pressure ventilation. Serious ventricular cardiac arrhythmia was defined as any of the following: ventricular fibrillation; ventricular tachycardia; asystole; pulseless electrical activity; second- or third-degree heart block requiring cardioversion; atropine; an anti-arrhythmic; rate-slowing or sympathomimetic drug; or cardiac pacing. Cardiovascular death was defined as death from a cardiovascular cause, including a revascularization procedure, cardiac arrest, MI, stroke or unknown cause

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Table 2. Relative risks for different hs-cTnT and hs-cTnI concentrations for the primary composite outcome, MI, UA or CV death or MI alone within the first week after presentation to

hs-cTn (ng/L) Categories

MI alone (n=133) RR (95%CI)

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the emergency department

Outcome MI, UA, or CV death (n=170) RR (95%CI)

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Model 1 (Crude) hs-cTnT≤14 (n=632) Reference Reference 15≤ hs-cTnT≤19 (n=106) 5.50 (2.46, 12.30) 4.62 (2.67, 7.99) 20≤ hs-cTnT≤ 65(n=296) 11.09 (5.74, 21.45) 6.05 (3.81, 9.60) hs-cTnT>65 (n=103) 31.88 (16.80, 60.49) 15.28 (9.80, 23.82) Model 2 (adjusted for important clinical variables) hs-cTnT≤14 (n=632) Reference Reference 15≤ hs-cTnT≤19 (n=106) 6.34 (2.61, 14.09) 4.72 (2.62, 7.96) 20≤ hs-cTnT≤65(n=296) 14.21 (7.29, 24.59) 6.23 (3.82, 9.54) hs-cTnT>65 (n=103) 37.05 (23.91, 47.74) 15.38 (10.78, 19.58)

Primary Outcome (n=273) RR (95%CI)

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Model 1 (Crude) hs-cTnI <14 (n=792) Reference Reference 14≤ hs-cTnI≤30 (n=175) 4.33 (2.47, 7.59) 3.29 (2.15, 5.03) 31≤ hs-cTnI≤ 99 (n=104) 9.93 (6.00, 16.43) 6.23 (4.22, 9.20) hs-cTnI >99 (n=66) 30.26 (20.03, 45.72) 15.82 (11.71, 21.37) Model 2 (adjusted for important clinical variables) hs-cTnI<14 (n=792) Reference Reference 14≤ hs-cTnI≤30 (n=175) 4.03 (2.12, 7.27) 2.75 (1.67, 4.32) 31≤ hs-TnI≤99 (n=104) 10.33 (5.99, 16.05) 6.35 (4.14, 8.97) hs-TnI>99 (n=66) 30.41 (25.66, 32.78) 15.49 (13.03, 16.83)

Reference 3.99 (2.57, 6.19) 7.32 (5.17, 10.36) 12.92 (9.20, 18.14)

Reference 3.57 (2.21, 5.46) 6.22 (4.43, 8.27) 11.76 (9.20, 13.78)

Reference 4.29 (3.25, 5.66) 6.41 (4.93, 8.34) 9.63 (7.69, 12.06) Reference 3.15 (2.27, 4.19) 5.65 (4.28, 6.97) 9.33 (7.95, 9.98)

Note: When log-binomial regression model did not converge, relative risk was calculated based on the odds ratio obtained from multivariable logistic regression using a method proposed by Zhang et al.21

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Acknowledgments

Funding and support: This study was supported by a Canadian Institutes of Health Research

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grant with reagent support from Roche Diagnostics and Abbott Diagnostics.

Conflict of Interest: Dr. Kavsak has received grants/reagents/consultant/advisor/honoria from

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Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman

Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics and Siemens

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Healthcare Diagnostics. McMaster University has filed patents with Dr. Kavsak listed as an inventor in the acute cardiovascular biomarker field

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Clinical trial registration number: ClinicalTrials.gov:NCT01994577

Author Contributions: PK and AW conceived the study, and are responsible for the study design, obtained funding, supervised data collection, and writing of the first draft of the article. All

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authors contributed substantially to interpretation of data and critical revision of the article for

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important intellectual content.

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Myocardial Infarction ( n=133 events / AUC difference=0.04;p<0.001)

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0.7

Heart Failure ( n=159 events / no AUC difference; p=0.47)

0.5 0.4

0.6 0.5 0.4

TE D

hs-cTnI presentation AUC=0.83 (95%CI:0.80,0.86)

Sensitivity

0.6

SC

1

M AN U

1

RI PT

d

0.3

0.3

Serious Ventricular Arrhythmia ( n=13 events / no AUC difference; p=0.32)

hs-cTnI presentation AUC=076 (95%CI:0.65,0.87)

hs-cTnT presentation AUC=0.69 (95%CI:0.54,0.85)

hs-cTnT presentation AUC=0.84 (95%CI:0.81,0.87)

0.2

EP

0.2 0.1 0 0

0.2

0.4

AC C

Sensitivity

c

0.6

1-Specificity

0.8

0.1 0 1

0

0.2

0.4

0.6

1-Specificity

0.8

1

ACCEPTED MANUSCRIPT

1

0.9

0.9

0.8

0.8 0.7

Cardiovascular Death (n=9 outcomes / no AUC difference; p=0.40)

0.5

hs-cTnI presentation AUC=0.82 (95%CI:0.70,0.95)

0.4

hs-cTnT presentation AUC=0.81 (95%CI:0.67,0.95)

TE D

0.6

EP

0.3

0.1 0 0

0.2

0.4

AC C

0.2

0.6

1-Specificity

0.8

Sensitivity

0.7

Sensitivity

M AN U

1

RI PT

f

SC

e

0.6 0.5

Primary Composite Outcome (n=273 outcomes / no AUC difference; p=0.14)

0.4

hs-cTnI presentation AUC=0.86 (95%CI:0.83,0.88)

0.3 hs-cTnT presentation AUC=0.84 (95%CI:0.82,0.87)

0.2 0.1 0 1

0

0.2

0.4

0.6 1-Specificity

0.8

1