Journal Pre-proof

Clinical Outcomes for Chest Pain Patients Discharged Home from

Emergency Departments Utilizing High-Sensitivity vs.
Conventional Cardiac Troponin Assays

Geoffrey Lau, Maria Koh, Peter A. Kavsak, Michael J. Schull,

David W.J. Armstrong, Jacob A. Udell, Peter C. Austin, Xuesong
Wang, Dennis T. Ko

PII: S0002-8703(19)30347-3
DOI: https://doi.org/10.1016/j.ahj.2019.12.007
Reference: YMHJ 6036

To appear in: American Heart Journal

Received date: 15 April 2019

Accepted date: 6 December 2019

Please cite this article as: G. Lau, M. Koh, P.A. Kavsak, et al., Clinical Outcomes for
Chest Pain Patients Discharged Home from Emergency Departments Utilizing High-
Sensitivity vs. Conventional Cardiac Troponin Assays, American Heart Journal(2019),
https://doi.org/10.1016/j.ahj.2019.12.007

This is a PDF file of an article that has undergone enhancements after acceptance, such
as the addition of a cover page and metadata, and formatting for readability, but it is
not yet the definitive version of record. This version will undergo additional copyediting,
typesetting and review before it is published in its final form, but we are providing this
version to give early visibility of the article. Please note that, during the production
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© 2019 Published by Elsevier.

 Journal Pre-proof

Clinical Outcomes for Chest Pain Patients Discharged Home from Emergency

Departments Utilizing High-Sensitivity vs. Conventional Cardiac Troponin Assays

Short title: High-Sensitivity vs. Conventional Troponin in EDs

Geoffrey Lau, BHSc1,2; Maria Koh, MSc1; Peter A. Kavsak, PhD3; Michael J. Schull, MD, MSc1;

David W.J. Armstrong, MD, PhD4; Jacob A. Udell, MD1,5; Peter C. Austin, PhD1;

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Xuesong Wang, MSc1; Dennis T. Ko, MD, MSc1,2,6

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1

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ICES, Toronto, Ontario, Canada; 2 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;
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3
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;
4
Department of Medicine, University of Toronto, Toronto, Canada;5 Women's College Hospital,
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University of Toronto, Toronto, Ontario, Canada; 6 Schulich Heart Center, Sunnybrook Health Sciences,
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University of Toronto, Toronto, Ontario, Canada

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Manuscript Word Count: 3,286

Address for Correspondence:

Dennis. T. Ko, MD, MSc
ICES
G106-2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
E-mail: dennis.ko@ices.on.ca
Tel. 416-480-6100, ext. 7686
Fax 416-480-4657

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ABSTRACT

Background: High-sensitivity cardiac troponin (hs-cTn) assays enhance detection of lower

circulating troponin concentrations, but the impact on outcomes in clinical practice is unclear.

Our objective was to compare outcomes of chest pain patients discharged from emergency

departments (EDs) using hs-cTn and conventional troponin (cTn) assays.

Methods: We conducted an observational study of chest pain patients aged 40-105 years who

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presented to an ED from April 1st 2013 to March 31st 2017, and were discharged home. We

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compared 30-day and 1-year outcomes of EDs that utilized hs-cTn vs. cTn assays. The primary

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outcome was a composite of all-cause death, MI or unstable angina. Comparisons were

conducted with i) no adjustment; ii) adjustment for demographic, socioeconomic, and hospital
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characteristics; and iii) full clinical adjustment.
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Results: Among the 394,910 patients, 62,138 (15.7%) were evaluated at hs-cTn EDs and
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332,772 (84.3%) were evaluated at cTn EDs. Patients discharged from hs-cTn EDs were less
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likely to have diabetes, hypertension, or prior heart disease. At 30-days, the unadjusted primary

outcome rate was lower in hs-cTn EDs (0.9% vs. 1.0%, P <0.001). The 30-day hazard ratios (HRs)
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for the primary outcome were 0.84 (95% CI 0.77-0.92) for no adjustment and 0.98 (95% CI 0.88-

1.08) for full adjustment. Over 1-year, patients discharged from hs-cTn EDs had significantly

fewer primary outcomes (3.7% vs. 4.1%, P <0.001), and lower HR 0.93 (95% CI 0.89-0.98) even

after full adjustment.

Conclusions: Hs-cTn testing was associated with a significantly lower adjusted hazard of MI,

angina, and all-cause hospitalization at 1-year, but not 30-days.

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INTRODUCTION Journal Pre-proof

Chest pain is one of the most common reasons to be evaluated in the emergency department (ED) in

North America, with an estimated volume of 8 million patient visits per year.1, 2 Data have shown that

approximately 2% of MI patients were incorrectly discharged to home in the older era where creatinine kinase

was predominately used.3 Since that time, cardiac troponin has been recommended as the preferred cardiac

biomarker to identify myocardial infarction and to help determine if a patient with chest pain is fit for

discharge.4-6 In January 2017, the US Food and Drug Administration approved the first high-sensitivity troponin

assay (5th-generation hs-cTnT) for clinical-use, which was followed by the approval of hs-cTnI assays in the

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summer of 2018.7-10 While hs-cTn has been demonstrated to have superior sensitivity of detecting myocardial

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injury at lower thresholds compared to the conventional assays (cTn), the extent to which it impacts patient

outcomes in the general ED population is unclear. 11-14 -p

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In the province of Ontario, Canada, hs-cTn assays have been increasingly adopted for clinical use over
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the past 6 years.15, 16 Patients presenting with chest pain in Canadian EDs are mainly evaluated with clinical
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assessment and laboratory evaluation, unlike many sites in the US where acute stress testing or CT

angiograms are commonly used as part of the emergency department evaluation.17-21 Therefore, a unique
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opportunity is afforded to investigate the isolated impact of hs-cTn introduction in a large unselected
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population.17, 18, 22 The primary objective of our study was to compare the adverse clinical outcomes in EDs

utilizing hs-cTn vs. EDs utilizing cTn assays.

METHODS

Data sources

We conducted a retrospective observational study using multiple linked longitudinal healthcare

databases in Ontario, Canada. These datasets were linked using unique encoded identifiers and analyzed at

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ICES (formerly known as the Institute for Clinical Pre-proof
Evaluative Sciences). The Canadian Institute for Health

Information (CIHI) National Ambulatory Care Reporting System Database contains information on all patient

visits to Ontario EDs and was used to capture chest pain visits. The Ontario Registered Persons Database

(RPDB) included demographic information of the Ontario population, including date of death for those who

have died. The CIHI Discharge Abstract Database was used to obtain information on hospitalizations and

comorbid conditions. We used the CIHI Same Day Surgery (SDS) Database for information about same-day

surgeries and procedures in Ontario. Ontario Laboratories Information System (OLIS) was used to assess

laboratory test orders and results from hospitals, community labs, and public health labs in the province.

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Finally, the Ontario Drug Benefit database (ODB) captured outpatient prescription drug use for all Ontario

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residents aged ≥ 65.

Study sample -p
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Our cohort included patients aged 40-105 years who presented to ED with chest pain and were
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discharged to home from April 1st 2013 to March 31st 2017. We only included patients who had an
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electrocardiogram during the ED assessment, and individuals younger than 40 years were not included to

capture a population more likely to have chest pain of cardiac origin. A final diagnosis of chest pain was
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identified in the National Ambulatory Care Reporting System Database using International classification 10th
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version ('R071', 'R072', 'R073', 'R074', 'I200', 'I201', 'I208', 'I209'). In cases where a patient presented to the ED

multiple times during the study period, the first visit was used as the index event. The construction of the

study cohort is shown in Figure 1. From April 1, 2013 to March 31, 2017, there were 939,828 patient visits to

an Ontario ED for chest pain evaluation. We excluded 235,918 patients because they were younger than 40

years or older than 105 years, 19,433 patients because of un-linkable health card numbers, 735 patients

because they were non-Ontario residents, 113,273 patients because they were admitted to hospital from the

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ED, and 120,862 visits because of multiple ED Pre-proof
presentations during the study period. Our final cohort included

394,910 patients presenting to the ED with chest pain for evaluation and were discharged to home.

Hs-cTn and cTn ED classification

Information on the types of the troponin assays was obtained from OLIS and confirmed through

surveys of the laboratory director at each ED. In Ontario, only 2 hs-cTn assays were used during this

timeframe: Roche Elecsys Troponin T hs (5thgeneration assay), and Abbott ARCHITECT STAT hs-cTnI assay.23, 24

Conventional assays were defined as any non-hs-cTn assay. Patients were assigned to hs-cTn or cTn groups

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based on the type of troponin assays the EDs were using at the time of their presentation.

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Outcomes

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The primary outcome was a composite of all-cause death, and hospitalization from myocardial
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infarction (MI) or unstable angina. Secondary outcomes assessed included individual endpoints of death, MI or
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unstable angina, and all-cause hospital admissions. Outcomes were evaluated at 30-days, 90 days, and 1-year

after ED discharge.
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Statistical analysis
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Demographic and clinical characteristics of patients presenting to hs-cTn EDs were compared with
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those of patients presenting to cTn EDs using χ2 tests for categorical variables and the Wilcoxon rank sum test

for continuous variables.

Troponin results influence which chest pain patients are admitted or discharged home, therefore,

differences in baseline characteristics of discharged patients are of interest when comparing these assays. For

example, if patients discharged from conventional EDs were sicker at baseline than patients in the hs-cTn

group, it could imply that cTn was not as effective at identifying high-risk cases for admission. Consequently,

examining these baseline differences could be useful in comparing the utility of each assay.
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We conducted sequential adjustment Pre-proof
using multivariable proportional hazard models to compare

clinical outcomes between the cTn and hs-cTn group for the following reasons. We hypothesized that troponin

results would influence whether patients would be admitted or discharged home after being seen in the ED.

For hospitals that utilized hs-cTn, one would expect patients who are more elderly and had more

comorbidities to be admitted (i.e. patients less sick are discharged). Through 3 adjustment models, we aimed

to illustrate the effect of initial patient selection and ED factors on future outcomes. First, the unadjusted

model represents the unadjusted differences between the troponin groups. Second was adjustment for

demographic, socioeconomic, and hospital factors that included age, sex, rurality, neighbourhood income

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quintile, and teaching hospital status. For this model, we hypothesize an attenuated effect size if differences

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between hs-cTn and cTn EDs were mediated by ED factors. The third model included additional adjustment for

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clinical factors that included diabetes, hypertension, dyslipidemia, prior history of myocardial infarction,
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arrhythmia, heart failure, peripheral vascular disease, percutaneous coronary intervention, coronary artery
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bypass grafting, chronic obstructive pulmonary disease, renal disease, dialysis, liver disorders, stroke, cancer,

and Charlson comorbidity. For this full adjustment model, we would expect further attenuation if differences
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between groups were driven by patient selection for ED discharge. For example, if hs-cTn EDs had better
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outcomes due to selecting healthier patients for discharge, we would anticipate the outcome differences to be
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diminished in this full adjustment model. Statistical significance was established with a 2-sided P value of <

0.05.

All analyses were performed using SAS 9.1.3 software (SAS Institute Inc., Cary, NC). The use of data in

this project was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which

does not require review by a Research Ethics Board.

SOURCES OF FUNDING

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 Funding of this analysis was providedJournal
in part byPre-proof
a Foundation Grant (154333) provided by the Canadian

Institutes of Health research. The authors are solely responsible for the design and conduct of this study, all

study analyses, the drafting and editing of the paper and its final contents

RESULTS

Baseline characteristics of chest pain patients discharged from hs-cTn vs. cTn EDs

The mean age of the discharged study cohort was 59.8 years and 53.7% were female. Out of 203 EDs,

34 used hs-cTn (11 hs-cTnT, 24 hs-cTnI) that evaluated 62,138 (15.7%) patients, and 169 EDs used cTn that

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evaluated 332,772 (84.3%) patients. Patients discharged from hs-cTn EDs had lower rates of diabetes (22.3%

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vs. 24.6%, P<0.001), hypertension (48.6% vs. 51.9%, P<0.001), and prior cardiac history (5.0% vs. 5.8% for MI;

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2.8% vs. 3.3% for unstable angina; 2.5% vs. 2.7% for heart failure, and cardiac procedures, all P < 0.05)
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compared with cTn EDs (Table 1). Patients older than 65 years discharged from hs-cTn EDs were also less likely
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to have a history of prescribed antihypertensives, statins, beta blockers, calcium channel blockers,

antiplatelets, and long-acting nitrates (all P<0.001). Emergency departments employing hs-cTn were more
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likely to be teaching hospitals (59.7% vs. 11.8%, P<0.001) with capability to perform cardiac catheterizations
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(43.3% vs. 29.7%, P<0.001) (Table 1). For the primary outcome both at 30 day and 1-year time points, we did

not observe any significant interaction by sex (eTable 3).

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Subgroup of admitted patients

10.8% of the total chest pain patients presenting to hs-cTn EDs and 9.8% of patients presenting to cTn

EDs were admitted to hospital.

Healthcare utilization by hs-cTn vs. cTn

Rates of cardiac evaluations were low in Ontario EDs. Overall, 0.5% of patients had echocardiography,

and 1.2% had stress testing, and 0.7% had cardiologist consult during the ED visit. Patients evaluated in EDs
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with hs-cTn assays had lower use of echocardiography and stress testing than patients in cTn EDs. In contrast,

cardiologist consultations prior to discharge were slightly higher in patients evaluated in EDs with hs-cTn

compared to cTn (Table 2).

Healthcare use within 30-days of ED discharge is shown in Table 2. Rates of physician follow-up were

not substantially different among EDs that used hs-cTn compared to cTn. For cardiac evaluation, patients

discharged from hs-cTn EDs were less likely to receive echocardiography (11.5% vs. 17.0%, P < 0.001), stress

testing (24.1% vs. 31.2%, P < 0.001), and cardiac catheterization (1.7% vs. 2.0%, P<0.001).

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Rates of clinical outcomes

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The composite endpoint of death or hospitalization for MI or unstable angina at 30-days after

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discharge occurred in 0.9% of the hs-cTn ED group and 1.0% of the cTn ED group (P<0.001) (Table 3). Except
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for mortality, rates of 30-day non-fatal outcomes were lower in hs-cTn EDs compared with cTn EDs
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(hospitalization for MI or unstable angina (0.7% vs. 0.8%, P<0.001), all-cause hospitalization (3.8% vs. 4.0%,

P=0.006)). Similarly, 1-year outcomes with the exception of death (composite of death, MI or unstable angina,
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death or all-cause hospitalization, MI or unstable angina, all-cause hospitalisation) were all significantly lower
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in hs-cTn EDs. The 1-year absolute difference was 0.4% for the primary outcome of death or MI or unstable

angina (3.7% vs. 4.1%, P<0.001), and 1.0% for all-cause hospitalization (14.1% vs. 15.1%, P<0.001). Outcomes
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at 90-days are shown in eTable 1 in the supplement.

Sequential adjustment of clinical outcomes

Table 4 shows 30-day and 1-year outcomes with no adjustment, adjustment for demographic,

socioeconomic, and hospital factors, and full clinical adjustment. For the 30-day observational window of the

primary outcome, the hs-cTn group experienced a lower hazard compared to the cTn group in the unadjusted

model (hazard ratio (HR): 0.84; 95% CI 0.77-0.92). This lower rate was attenuated after adjusting for

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demographic, socioeconomic, and hospital factors (HR:Pre-proof
0.92; 95% CI 0.84-1.02) and when full patient

characteristics were accounted for (HR: 0.98; 95% CI 0.89-1.08). The 30-day hazard for the composite of death

or hospital admission was significantly lower for hs-cTn in the unadjusted model (HR: 0.94; 95% CI 0.90-0.98)

and the partially adjusted model (HR: 0.91; 95% CI 0.87-0.96), but not after full adjustment (HR: 0.96; 95% CI

0.91-1.01).

Over 1-year, the reduced hazard for the primary outcome in the hs-cTn group persisted in all the

models (unadjusted HR: 0.90; 95% CI 0.86-0.94; partially adjusted HR:0.87; 95% CI 0.83-0.92; fully adjusted HR:

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0.93; 95% CI 0.89-0.98). Death or all-cause hospitalization at 1-year post discharge was also significantly lower

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in the hs-cTn group (unadjusted HR: 0.93; 95% CI 0.91-0.95; partially adjusted HR:0.87; 95% CI 0.85-0.89; fully

adjusted HR: 0.91; 95% CI 0.89-0.93) (Table 4). Outcomes at 90-days are available in the online data
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supplement (eTable 2). We also generated 1-year fully adjusted and unadjusted Kaplan-Meier curves for the
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primary outcome to visualize these results (Figure 2).
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DISCUSSION
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In this study of nearly 400,000 discharged chest pain patients, we observed a modest but significant
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decrease in adverse clinical outcomes associated with hs-cTn use in the ED. A slightly larger percentage of

patients presenting to hs-Tn EDs were admitted to hospital, and patients discharged from hs-cTn EDs had a
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lower prevalence of diabetes, hypertension, and prior heart diseases – confirming the notion that hs-cTn

affected admission and discharge thresholds. Concordantly, hs-cTn use was associated with lower risk of

death, MI or angina after adjustment for baseline comorbidities at 1-year post-discharge. The associated

decrease was largest for all-cause hospitalization, estimated to be 1 out of 100 patients at 1-year. However,

the absolute rate of events was low (30-day death, MI, or angina: 0.9% for hs-cTn, 1% for cTn; 1-year death

2.2% in both groups).

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The majority of studies on hs-cTn testing Pre-proof
have focused on its biochemical profile and its ability to

diagnose patients with an acute coronary syndrome. 14, 26-36 Relatively few studies have evaluated the

downstream impact on discharged patients.11, 12, 37-39 The High-STEACS trial evaluated 48 282 patients with

suspected acute coronary syndrome and found the introduction of Abbott’s hs-cTnI assay reclassified 1 in 6

patients as having myocardial injury. However, only 1/3rd of the reclassified patients were diagnosed with

type 1 myocardial infarction. The trial also found no difference in one-year MI or cardiovascular death (Odds

ratio: 1.10, 95% CI 0.75-1.61, P=0.620).11 In the present study, we observed hs-cTn was associated with a

higher rate of overall hospital admission, and a slightly lower diagnosis rate of MI among admitted patients

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compared to cTn (11.1% vs. 13.9%). Dissimilar to the High-STEACS trail, we showed a significant but modest

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decrease in the 1-year risk of MI, unstable angina, or death. The use of hs-cTn in rapid diagnosis algorithms

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and prognostication of future adverse events has gained focus over recent years. 23, 24, 40-53 This population
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study corroborates previous works by further demonstrating that decisions guided by hs-cTn safely discharge
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chest pain patients. However, outcomes after ED discharge in the contemporary era are excellent and

associated with very low event rates.54, 55

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Observational studies are potentially influenced by selection biases. Adjustment for baseline
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characteristics and confounders is commonly performed to minimize these biases. However, our design
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differed from a traditional observational study because the intention of the hs-cTn assay is to refine risk

prediction, i.e., to detect higher risk patients for admission, and conversely, to identify lower risk patients for

discharge. Indeed, we found that a significantly higher proportion of patients evaluated in hs-cTn EDs were

hospitalized. Therefore, the troponin assay results can greatly influence the baseline patient characteristics of

discharged patients, and adjustment for all available clinical factors would likely cause an over-adjustment

bias. Accordingly, we showed unadjusted results, performed adjustment of non-clinical factors to show the

potential influence of intrinsic differences between EDs, and finally also adjusted for clinical factors to show

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the changes in estimates. In general, the fullJournal Pre-proof
adjustment model provided the estimates closer to the null,

suggesting that the benefit of hs-cTn is largely mediated by the ability to select lower risk patients for

discharge. These results are concordant with an evaluation of 65,696 patients, which found that the benefit

associated with hs-cTnT in 30-day cardiovascular events was no longer significant after adjustment for

baseline factors.12 An unexpected finding was that patients discharged from hs-cTn EDs had better outcomes

at one year even after full clinical adjustment.

Our study extends prior findings by assessing patient care after ED discharge. We hypothesized that

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patients discharged from hs-cTn EDs would receive more specialist follow-up and cardiac testing because the

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hospitals were more often located in non-rural areas. In fact, we observed the opposite. Despite similar rates

of follow-up, patients discharged from hs-cTn EDs had significantly fewer cardiac evaluations such as
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echocardiography and stress testing, and were less likely to be prescribed cardiac medications. This
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observation may further support the ability of hs-cTn to select patients for discharge who are at lower risk,
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and thus do not require further evaluations downstream of ED management. However, given that more
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patients were admitted to hospital after hs-cTn evaluations, increased inpatient costs may offset the reduction

of outpatient evaluations and care.

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Several potential limitations merit consideration. First, although a randomized design may be ideal for
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the comparison of two types of troponin assays, we showed that rates of adverse clinical outcomes are very

rare and it would be difficult to recruit adequate number of patients for evaluation. Accordingly, a large

population-based observational study is likely the best possible study design to examine the impact of real-

world adoption of troponin assays. Second, although the characteristics of EDs differed in terms of their

academic status and locations, we have previously demonstrated that admission thresholds of EDs across

Ontario are not substantially different, likely indicating the similarity of evaluating and managing patients

presented to EDs with chest pain. 17, 18, 22, 25 Third, we did not have clinical information such as characteristics

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of chest pain or findings on electrocardiograms, which Pre-proof
would provide further insight into each ED’s chest pain

patient population and management.

Our study focused on discharged patients, and did not follow the outcomes and treatment patterns of

admitted patients. There is concern that hs-cTn may cause overdiagnosis of MI, and thus admission of patients

who do not require extra testing or treatment. Indeed, introducing hs-cTn modestly increased MI diagnoses in

some studies.45, 56 Reichlin et al. showed that patients comprising the additional MI cases were at high risk of

mortality, and therefore appropriately diagnosed.56 Twerenbold and colleagues observed an associated 20%

reduction in outpatient costs and decreased time to discharge after hs-cTn implementation.45 In another

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investigation, hs-cTn adoption raised the number of patients with abnormal troponin, though there was no

evidence of overdiagnosis or overtreatment.57 Although this was not the primary aim of our study, the effect
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of hs-cTn on overdiagnosis and resource utilization merits further investigation.
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Our study also combined highly sensitive T and I in one group and compared with hospitals that used
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the conventional counterparts. There was inadequate power to generate differential clinical outcomes
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according to assay subtypes. Yet, other studies have suggested high diagnostic and prognostic accuracy of

both highly sensitive assays.23, 24 Ultimately, we chose to group the two because the primary goal was an inter-
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generational troponin comparison rather than an inter-assay one. We were unable to identify if patients were
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tested with troponin during their ED visit because cardiac troponin values were incompletely captured in our

population study. Instead, we attempted to examine intended users of cardiac troponin by including chest

pain patients who received an electrocardiogram during ED assessment. Consequently, this analysis compared

EDs by type of troponin assay (i.e., high-sensitivity versus conventional). Finally, while the majority of

institutions in Ontario use the manufacturer recommended 99th percentiles, the exact cut-offs used to make

clinical decisions were not captured for this population. EDs in our study may have also used different cut-offs

over time, leading to an inconsistent admittance threshold during our study. As a result, our data represent

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the effects of employing hs-cTn at the system-level Pre-proof
rather than a patient-level comparison of troponin assay

performance. Despite these potential limitations, this hospital-level approach is less subjected to selection

bias as the target population of discharged chest pain patients were identified from organic ED practice rather

than investigator determined clinical criteria.

CONCLUSION

In conclusion, in a large real-world cohort of chest pain patients discharged from EDs in Ontario,

Canada, EDs using hs-cTn testing was associated with sending home lower-risk patients compared with EDs

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who used cTn testing. Events were rare in both groups, but hs-cTn was associated with slightly lower rates of

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short-term MI, angina, and all-cause hospitalization. After full clinical adjustment, the results remained

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significant at 1-year, but not 30-days. Future work should investigate whether these differences are clinically

meaningful.
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ACKNOWLEDGEMENTS Journal Pre-proof

This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of

Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those

of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario

MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled

and provided by CIHI. The analyses, conclusions, opinions and statements expressed herein are those of the

author, and not necessarily those of CIHI.

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DISCLOSURES

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Dr. Kavsak has received grants /reagents/ consultant /advisor /honoraria from Abbott Laboratories,

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Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman Coulter, Ortho Clinical Diagnostics, Randox
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Laboratories, Roche Diagnostics and Siemens Healthcare Diagnostics. McMaster University has filed patents
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with Dr. Kavsak listed as an inventor in the acute cardiovascular biomarker field. Dr. Udell is supported in part

by a Heart and Stroke Foundation of Canada National New Investigator/Ontario Clinician Scientist Award,
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Women’s College Research Institute and the Department of Medicine, Women’s College Hospital; Peter Munk
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Cardiac Center, University Health Network; Department of Medicine and Heart and Stroke Richard Lewar

Center of Excellence in Cardiovascular Research, University of Toronto. Dr. Ko and Dr. Austin are by Mid-
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Career Investigator Awards from the Heart and Stroke Foundation, Ontario Provincial Office.

AFFILIATIONS

ICES, Toronto, Ontario, Canada (G.L., M.K., M.J.S., J.A.U., P.C.A., X.W., D.T.K.); Faculty of Medicine,

University of Toronto, Toronto, Ontario, Canada (G.L., D.T.K.); Department of Pathology and Molecular

Medicine, McMaster University, Hamilton, Ontario, Canada (P.A.K.); Department of Medicine, University of

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Toronto, Toronto, Ontario, Canada (D.W.J.A.); Pre-proof
Women's College Hospital, University of Toronto, Toronto,

Ontario, Canada (J.A.U.); Schulich Heart Center, Sunnybrook Health Sciences Center, University of Toronto,

Toronto, Ontario, Canada (D.T.K.)

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Figure 1. Cohort selection

Using the entire Ontario population aged 40 to 105 years who were discharged from the emergency

department with chest pain between April 1, 2013 to March 31, 2017, a total of 394,910 discharged chest

pain patients were included in final cohort.

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A
hs-cTn EDs cTn EDs
1.00

0.99
Probability of event free

0.98

0.97

0.96

0.95

of
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)

ro
B 1.00
-p hs-cTn EDs cTn EDs
re
0.99
Probability of event free

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0.98
na

0.97
ur

0.96
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0.95
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Figure 2. Kaplan-

Meier curves for 1-year death MI, or angina

1-year survival curves using an unadjusted model (A), and a fully-adjusted model (B).

Abbreviations: hs-cTn, high-sensitivity cardiac troponin; cTn, conventional cardiac troponin; ED, emergency department

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Table 1. Baseline characteristics of chest pain patientsPre-proof
discharged from high-sensitivity vs conventional
troponin EDs
Troponin assay type
Overall High sensitivity Conventional P-value
Number of N=394,910 N=62,138 N=332,772
patients
Demographics, %
Age, mean ± SD 59.77 ± 13.07 59.76 ± 13.23 59.78 ± 13.03 0.707
Sex
Male 46.3 45.5 46.4 <.001
Female 53.7 54.5 53.6
Rural resident 13.2 5.3 14.7
Neighbourhood
income quintile
1 20.1 21.2 19.9 <.001
2 20.1 18.9 20.3

of
3 20.2 17.5 20.7
4 21.0 19.8 21.3

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5 18.6 22.6 17.8
Cardiac risk
factors, %
Diabetes
Hypertension
24.2
51.4
-p
22.3
48.6
24.6
51.9
<.001
<.001
re
Dyslipidemia 14.6 15.1 14.5 <.001
Prior cardiac
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conditions and
medical
comorbidities, %
na

Myocardial 5.7 5.0 5.8 <.001

infarction
Unstable angina 3.2 2.8 3.3 <.001
Arrhythmia 5.0 5.0 4.9 0.374
ur

Heart failure 2.7 2.5 2.7 0.047

Peripheral 4.5 4.1 4.5 <.001
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vascular disease
Percutaneous 4.9 4.6 5.0 <.001
coronary
intervention
Coronary artery 1.4 1.2 1.5 <.001
bypass grafting
surgery
Chronic 18.2 16.8 18.4 <.001
obstructive
pulmonary disease
Renal disease 1.3 1.1 1.3 0.006
Dialysis 0.2 0.3 0.2 0.118
Liver disorder* 0.1 0.1 0.1 0.636
Stroke 0.9 0.9 0.9 0.319
History of cancer 3.1 3.3 3.0 <.001
Charlson index, 0.51 ± 1.23 0.49 ± 1.22 0.52 ± 1.23 <.001
23
 mean ± SD Journal Pre-proof
Medication N=125,838 N=19,779 N=106,059
history (over 65),
%
ACE inhibitor or 55.6 52.4 56.2 <.001
ARB
Statins 56.7 55.1 57.0 <.001
Beta-blocker 35.9 33.7 36.3 <.001
Calcium channel 29.9 28.5 30.2 <.001
blocker
Antiplatelets† 11.5 10.2 11.7 <.001
Long-acting 11.6 10.5 11.8 <.001
nitrates
Hospital
characteristics, %
Teaching hospital 19.3 59.7 11.8 <.001

of
Cardiac 31.8 43.3 29.7 <.001
catheterization

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laboratory
available
Abbreviations: ED, emergency department; SD, standard deviation; IQR, interquartile range
*
Moderate to severe liver disorder -p
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† Antiplatelet agents included clopidogrel, ticagrelor, prasugrel
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Table 2. Healthcare utilization by troponin assay type Pre-proof

Troponin assay type

Overall High sensitivity Conventional P-Value
Number of N=394,910 N=62,138 N=332,772
patients
Cardiac
evaluations during
initial ED visit, %
Echocardiogram 0.5 0.4 0.5 <.001
Stress test 1.2 0.8 1.2 <.001
Cardiologist 0.7 1.2 0.7 <.001
consult
Physician follow-
up within 30 days

of
of ED discharge, %
Primary care 59.6 60.3 59.5 <.001
physician or

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cardiologist
Primary care 52.9 53.6 52.8 <.001
physician
Cardiologist
Cardiac
15.7 15.4 -p 15.8 0.01
re
evaluations within
30 days of ED
lP

discharge, %
Echocardiogram 16.1 11.5 17.0 <.001
Stress test 30.1 24.1 31.2 <.001
na

Cardiac 2.0 1.7 2.0 <.001

catheterization
Medication within N=125,838 N=19,779 N=106,059
ur

30 days of
discharge (over
65), %
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ACE inhibitor or 27.0 25.3 27.3 <.001

ARB
Statins 26.8 25.4 27.0 <.001
Beta-blocker 20.1 18.6 20.4 <.001
Calcium channel 15.8 14.9 15.9 <.001
blocker
Antiplatelets* 7.2 6.4 7.3 <.001
Long-acting 9.6 8.1 9.9 <.001
nitrates
* Antiplatelet agents included clopidogrel, ticagrelor, prasugrel

P-value is a comparison between high sensitivity hospitals (hsTnT and hsTnI) and contemporary Tn

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Table 3. Unadjusted outcomes by troponin assay

Troponin assay type

High sensitivity Conventional P-value
Number of patients N=62,138 N=332,772
30-days after ED
discharge, events (%)
Death, MI or angina 0.9 1.0 <.001
Death or all-cause 3.9 4.1 0.008
hospital admission
Death 0.2 0.2 0.986
Angina 0.4 0.5 0.002

of
MI 0.3 0.4 0.003
MI or angina 0.7 0.8 <.001
All-cause hospital 3.8 4.0 0.006

ro
admission
1-year after ED
discharge, events (%)
Death, MI or angina 3.7 -p 4.1 <.001
re
Death or all-cause 14.5 15.5 <.001
hospital admission
lP

Death 2.2 2.2 0.715

Angina 0.9 1.1 <.001
MI 0.9 1.1 <.001
na

MI or angina 1.7 2.1 <.001

All-cause hospital 14.1 15.1 <.001
admission
ur

Abbreviations: ED, emergency

department; MI, myocardial
infarction
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26
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Table 4. Adjusted outcomes comparing high-sensitivity to conventional troponin EDs at 30-days and 1-year
30-days HR Forest Plot P Value
(95% CI)
Death or MI or
Angina
Unadjusted 0.84 (0.77-0.92) 0.0002
Partially-adjusted 0.92 (0.84-1.02) 0.1250
Fully-adjusted 0.98 (0.88-1.08) 0.6724
Death or Hospital
Admission

of
Unadjusted 0.94 (0.90-0.98) 0.0080
Partially-adjusted 0.91 (0.87-0.96) 0.0003

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Fully-adjusted 0.96 (0.91-1.01) 0.0866
Death
Unadjusted
Partially-adjusted
1.00 (0.84-1.19)
0.93 (0.76-1.13) -p 0.9858
0.4618
re
Fully-adjusted 0.97 (0.79-1.18) 0.7374
MI or Angina
lP

Unadjusted 0.80 (0.72-0.88) <.0001

Partially-adjusted 0.92 (0.82-1.03) 0.1524
Fully-adjusted 0.98 (0.87-1.09) 0.6784
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 Journal Pre-proof
Table 4 (Cont.). Adjusted outcomes comparing high-sensitivity to conventional troponin EDs at 30-days and
1-year
1-year HR Forest Plot P Value
(95% CI)
Death or MI or
Angina
Unadjusted 0.90 (0.86-0.94) <.0001
Partially-adjusted 0.87 (0.83-0.92) <.0001
Fully-adjusted 0.93 (0.89-0.98) 0.0063
Death or Hospital
Admission
Unadjusted 0.93 (0.91-0.95) <.0001
Partially-adjusted 0.87 (0.85-0.89) <.0001
Fully-adjusted 0.91 (0.89-0.93) <.0001

of
Death
Unadjusted 1.01 (0.95-1.07) 0.7230

ro
Partially-adjusted 0.94 (0.88-1.00) 0.0556
Fully-adjusted 0.98 (0.92-1.05) 0.5577
MI or Angina
Unadjusted 0.78 (0.73-0.83) -p <.0001
re
Partially-adjusted 0.80 (0.74-0.86) <.0001
Fully-adjusted 0.87 (0.81-0.93) 0.0001
lP

Abbreviations: CI, confidence interval; HR, hazard ratio; MI, myocardial infarction.
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The partially-adjusted model adjusts for: sex, income quintile, rurality, and teaching hospital status
The fully adjusted model adjusts for: age, sex, income quintile, rurality, and teaching hospital status, diabetes, hypertension, dyslipidemia, prior
history of myocardial infarction, arrhythmia, heart failure, peripheral vascular disease, percutaneous coronary intervention, coronary artery bypass
grafting, chronic obstructive pulmonary disease, renal disease, dialysis, liver disorders, stroke, cancer, Charlson index score, and medications
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