Confidential manuscript submitted to Water Resources Research
Confidential: For Review Only - BMJ...2015/02/17 · Manuscript ID BMJ.2017.037996 Article Type:...
Transcript of Confidential: For Review Only - BMJ...2015/02/17 · Manuscript ID BMJ.2017.037996 Article Type:...
Confidential: For Review O
nly
Non-selective high-sensitivity cardiac troponin testing in
the Emergency Department
Journal: BMJ
Manuscript ID BMJ.2017.037996
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 15-Feb-2017
Complete List of Authors: Shah, Anoop; Univerity Of Edinburgh, Centre of Cardiovascular Sciences Noaman, Ala; University of Edinburgh College of Medicine and Veterinary Medicine Vaswani, Amar; University of Edinburgh, Gibbins, Matthew; University of Edinburgh College of Medicine and
Veterinary Medicine Griffiths, Megan; University of Edinburgh College of Medicine and Veterinary Medicine Chapman, Andrew; University of Edinburgh College of Medicine and Veterinary Medicine Strachan, Fiona; University Of Edinburgh, Anand, Atul; University of Edinburgh College of Medicine and Veterinary Medicine Adamson, Philip; University of Edinburgh College of Medicine and Veterinary Medicine D'Souza, Michelle; University of Edinburgh College of Medicine and Veterinary Medicine
Gray, Alasdair; Royal Infirmary of Edinburgh, Emergency Medicine Research Group, Department of Emergency Medicine McAllister, David; University of Glasgow School of Medicine Newby, David; University of Edinburgh, BHF/University Centre for Cardiovascular Sciences Mills, Nicholas; University of Edinburgh, BHF/University Centre for Cardiovascular Sciences
Keywords: troponin, high-sensitivity troponin, positive predictive value, prevalence, emergency department, acute coronary syndrome, myocardial infarction
https://mc.manuscriptcentral.com/bmj
BMJ
Confidential: For Review O
nly
1
ORIGINAL ARTICLE
Non-selective high-sensitivity cardiac troponin testing
in the Emergency Department
Anoop SV Shah MD MPH PhD,1 Ala Noaman MD,
1 Amar Vaswani MD,
1 Mathew Gibbins
MSc,1 Megan Griffiths MD,
1 Andrew R Chapman MD,
1 Fiona S Strachan PhD,
1 Atul Anand
MD,1
Philip D Adamson MD1, Michelle D Souza,
1 Alasdair J Gray MD,
3,4 David A
McAllister MD,2 David E Newby MD PhD
1 and Nicholas L Mills MD PhD
1
1BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom 2Centre for Population Health Sciences, University of Edinburgh, United Kingdom 3Department of Emergency Medicine, Royal Infirmary of Edinburgh, United Kingdom 4Emergency Medicine Research Group Edinburgh (EMeRGE), United Kingdom
Correspondence and requests for reprints:
Dr Anoop S V Shah
BHF/University Centre for Cardiovascular Science
Chancellor’s Building
University of Edinburgh
Edinburgh EH16 4SB
United Kingdom
Tel: +44 7766 544 156
Fax: +44 131 242 6379
E-mail: [email protected]
Abstract: 295
Word Count: 2,952
Table and Figures: 5
References: 46
Support: British Heart Foundation Special Project Grant (SP/12/10/29922),
Project Grant (PG/15/51/31596) and Senior Clinical Research
Fellowship (FS/16/14/32023)
Page 1 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
2
Abstract
Objective: High-sensitivity cardiac troponin assays may improve the diagnosis of myocardial
infarction, but increase the detection of myocardial injury in patients without acute coronary
syndrome. We evaluate how cardiac troponin testing in unselected patients would impact on
the diagnosis of myocardial infarction.
Design: Prospective study of two independent consecutive patient cohorts presenting to the
Emergency Department.
Setting: Secondary and tertiary care hospitals in Scotland
Participants: High-sensitivity cardiac troponin I concentrations were measured in two
independent consecutive patient cohorts presenting to the Emergency Department: 1,054
unselected patients, and 5,815 patients in whom the clinician suspected acute coronary
syndrome following initial assessment. The final diagnosis of type 1 or type 2 myocardial
infarction, or myocardial injury was independently adjudicated.
Main outcome measures: The positive predictive value (PPV) of an elevated cardiac
troponin concentration for a diagnosis of type 1 myocardial infarction.
Results: Cardiac troponin concentrations were elevated in 13.7% (144/1,054) of unselected
patients with 17, 13 and 114 patients classified as type 1 myocardial infarction, type 2
myocardial infarction and myocardial injury respectively. The prevalence of type 1
myocardial infarction was just 1.6% (17/1,054) with a PPV of 13.6% (95% confidence
interval [CI] 8.0-19.7%). When testing was performed only in patients with suspected acute
coronary syndrome, the prevalence of type 1 myocardial infarction was higher at 14.5%
(843/5,815) and the PPV increased to 59.7% (95%CI 57.1-62.2%). The PPV was highest in
patients with chest pain (67.5% [95%CI 64.7-70.3]) compared to those without (34.1%
[95%CI 29.0-39.2]).
Page 2 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
3
Conclusions: When high-sensitivity cardiac troponin testing is performed without prior
clinical assessment, elevated troponin concentrations are common, and predominantly reflect
myocardial injury rather than type 1 myocardial infarction. Our observations highlight the
importance of prior clinical assessment to guide patient selection for testing to optimize the
diagnostic utility of high-sensitivity cardiac troponin.
Page 3 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
4
Introduction
Cardiac troponin is integral to the diagnosis of myocardial infarction, but troponin
concentrations are often elevated in patients who do not have acute coronary syndrome. The
universal definition now classifies myocardial infarction as spontaneous or type 1, due to
plaque rupture and coronary thrombosis, and secondary or type 2 due to myocardial oxygen
supply-demand imbalance.1-5
Patients with elevated cardiac troponin concentrations in the
absence of myocardial ischemia are classified as having myocardial injury. Whilst patients
with type 2 myocardial infarction or myocardial injury are increasingly recognized in clinical
practice,1 they represent a heterogeneous group with overt or covert major illness for whom
there is currently no consensus on the optimal cardiac investigation, management or treatment
strategy.
We have shown that lowering the diagnostic threshold with a more sensitive cardiac troponin
assay reduced recurrent myocardial infarction or death in patients redefined as having type 1
myocardial infarction.6 However, use of these lower diagnostic thresholds more than doubled
the number of patients with type 2 myocardial infarction or myocardial injury with no
improvement in their outcome despite undergoing additional cardiac investigation.1 The
introduction of high-sensitivity cardiac troponin assays will further increase the frequency of
type 2 myocardial infarction or myocardial injury6,7
and may lead to diagnostic uncertainty
and unnecessary investigation of patients without acute coronary syndrome.7,8
Patients attending the Emergency Department often undergo simultaneous testing for both
cardiac and non-cardiac conditions,9 to facilitate early diagnosis or discharge. In this context,
a non-selective approach to high-sensitivity cardiac troponin testing may lead to inappropriate
Page 4 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
5
diagnosis of type 1 myocardial infarction.10
Our aim was to evaluate the impact of non-
selective high-sensitivity cardiac troponin testing on the diagnosis of myocardial infarction.
Page 5 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
6
Methods
Study populations
This prospective observational cohort study was performed in two pre-specified patient
populations with the approval of the national research ethics committee, and in accordance
with the Declaration of Helsinki. In an unselected cohort, we identified all consecutive
patients (n=1,054) presenting to the Emergency Department at the Royal Infirmary of
Edinburgh, Scotland in whom the attending clinician performed blood sampling irrespective
of their clinical presentation (Figure 1). In a separate independent cohort, we identified all
consecutive patients with suspected acute coronary syndrome (n=5,815) presenting to
secondary and tertiary care hospitals in the southeast of Scotland.11,12
Across both cohorts the
attending clinician reviewed all patients and identified those with suspected acute coronary
syndrome through a dedicated proforma embedded into the electronic patient record prior to
troponin testing. Patients across both cohorts were excluded if they had ST-segment elevation
myocardial infarction, or a previous presentation during the study period, or were not resident
in Scotland.
Cardiac troponin I assay
Cardiac troponin testing was performed at the discretion of the attending physician using a
contemporary cardiac troponin I assay (Abbott Laboratories, Abbott Park, IL). Serum surplus
to clinical requirements was used to measure cardiac troponin I concentration using the
ARCHITECTSTAT high-sensitive troponin I assay (Abbott Laboratories, Abbott Park, IL). This
assay has a limit of detection of 1.2 ng/L and the inter-assay CV <10% at 4.7 ng/L. The 99th
centile upper reference limit is 34 ng/L in men and 16 ng/L in women.12
The results from the
high-sensitivity assay were not made available to clinicians and across both cohorts only
Page 6 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
7
results from the contemporary assay, where requested by the attending clinician, were used to
guide patient care.
Clinical characteristics
Baseline clinical characteristics and investigations were obtained from a standardized
electronic patient record as previously described.1,6,12
The National Early Warning Score was
calculated for patients incorporating six simple physiological parameters: pulse rate, blood
pressure, temperature, oxygen saturation, level of consciousness and respiratory rate
measured at admission (Appendix Table 1).13
Classification of myocardial injury and infarction
In all patients with elevated high-sensitivity cardiac troponin I concentrations, the diagnosis
was adjudicated by two cardiologists independently as previously described.1,11,12
Type 1
myocardial infarction was defined as myocardial necrosis in the context of a presentation with
suspected acute coronary syndrome with chest pain or evidence of myocardial ischemia on
the electrocardiogram. Patients with symptoms or signs of myocardial ischemia due to
increased oxygen demand or decreased supply (e.g. tachyarrhythmia, hypotension or anemia)
secondary to an alternative pathology and myocardial necrosis were classified as type 2
myocardial infarction. Myocardial injury was defined as evidence of myocardial necrosis in
the absence of any clinical features of myocardial ischemia. A third adjudicator resolved any
discrepancies in adjudication through in-depth review of source documents. All patients were
followed up for death from any cause using regional and national registries.14
This method
allowed capture of all in-hospital and community deaths ensuring complete follow-up.
Page 7 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
8
Patient and Public Involvement
Patient and public involvement has been incorporated throughout the trial development and
conduct. At study design stage, we assessed feasibility and received feedback on the potential
acceptability of patient participation in the trial. Lay representatives contribute to the
membership of the Trial Steering Committee for the High-STEACS clinical trial and all
related studies (NCT01852123).
Statistical analysis
Unselected patients were categorized into five groups a priori. Those patients with elevated
cardiac troponin concentrations >99th
centile upper reference limit (men >34 ng/L and women
>16 ng/L)11
using the high-sensitivity assay were grouped together (group 5). The remaining
patients separated into four quartiles (group 1-4) (see Appendix for full statistical analysis
plan). The distribution of cardiac troponin differed in men and women and were therefore
grouped separately. Prevalence, sensitivity, specificity and positive likelihood ratios were
estimated by sampling from Beta distributions with Jeffrey’s priors (see Appendix for full
statistical analysis plan). All analyses were performed in R Version 3.2.3. Statistical
significance was taken as a two-sided P<0.05.
Page 8 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
9
Results
There were 3,619 visits to the Emergency Department during which 1,130 patients underwent
blood sampling for their presenting complaint (Figure 1). There were 76 patients who met
our exclusion criteria giving a final study population of 1,054 patients with a mean age of
55±23 years (52.1% women) (Table 1). Cardiac troponin was requested by the attending
physician in 3.8% (n=136/3,619) of all visits and in 12.9% (n=136/1,054) of the study
population. Patients who had cardiac troponin requested by the attending physician were
older, and were more likely to be male, to have cardiovascular risk factors or to present with
chest pain and have intermediate or high GRACE scores (Appendix Table 2).15
There were a total of 5,815 consecutive patients with suspected acute coronary syndrome
mean age of 64±16 years (43.9% females) (Figure 1 and Table 1). Patients with suspected
acute coronary syndrome were more likely to present with chest pain and had a higher
prevalence of cardiovascular risk factors compared to unselected patients in the Emergency
Department.
Prevalence and positive predictive value of cardiac troponin
In unselected patients attending the Emergency Department, 13.7% (n=144/1,054) had
cardiac troponin concentrations above the 99th
centile with 17, 13 and 114 patients classified
as type 1 myocardial infarction, type 2 myocardial infarction and myocardial injury
respectively. Of all patients with cardiac troponin concentrations above the 99th
centile, chest
pain (n=36/144, 25%), falls or collapse (n=40/144, 28%), and dyspnea (n=13/144, 9%) were
the most common presenting complaints (Appendix Table 3). The most common diagnoses
were cardiac (n=35/144, 24%), respiratory (n=23/144, 16%) and infectious disease
(n=21/144, 15%) (Appendix Table 4). Overall, the prevalence of type 1 myocardial infarction
Page 9 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
10
was 1.6% (n=17/1,054) with a positive predictive value for type 1 myocardial infarction of
13.6% (95% CI 8.0 to 19.7%) (Figure 2a, 2b and Appendix Figure 1).
In patients with suspected acute coronary syndrome, cardiac troponin was elevated in 24.3%
(95% CI 23.2 to 25.4%) (n=1,403/5,815) of all patients. Type 1 myocardial infarction was
adjudicated in 843 (14.5%) patients, with 229 (3.9%) and 341 (5.9%) of patients classified as
type 2 myocardial infarction and myocardial injury respectively. The prevalence of type 1
myocardial infarction and positive predictive value was 14.5% (n=843/5,825) and 59.7%
(95% CI 57.1 to 62.2%) respectively (Figure 2a, 2b and Appendix Figure 1). The positive
predictive value was highest in patients with chest pain (67.5 [64.7-70.3]%), myocardial
ischemia (69.8 [65.9-73.7]%), or known ischemic heart disease (68.1 [64.2-71.9]%) compared
to those without (34.1 [29.0-39.2]%, 57.8 [54.0-61.0]% and 55.1 [51.6-58.6]% respectively)
(Figure 3). The positive predictive value was 83.0% (95% CI 77.4 to 88.5%) in patients with
all three of these clinical features.
Agreement in the adjudication of type 1 myocardial infarction across both cohorts was
excellent at 0.86 (95% CI 0.83-0.89) and remained robust whether patients underwent serial
sampling or not (0.83 [95%CI 0.79 - 0.87] and 0.86 [95%CI 0.81 – 0.89] respectively).
In a sensitivity analysis, we evaluated the combined prevalence of type 1 or type 2 myocardial
infarction in unselected patients and those with suspected acute coronary syndrome. In
unselected patients, the prevalence of type 1 or type 2 myocardial infarction was 2.9% (95%
CI 1.9 to 3.9%, n=30/1,054) with a positive predictive value of 21.0% (95% CI 14.6 to
27.7%). In patients with suspected acute coronary syndrome, the prevalence was 18.4% (95%
Page 10 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
11
CI 17.4 to 19.4%, n=1,072/5,815) with a positive predictive value of 75.8% (95% CI 73.6 to
78.1%). The presence of chest pain, myocardial ischemia on the electrocardiogram or history
of ischemic heart disease was associated with a higher positive predictive value (Appendix
Table 5).
Determinants and outcomes of patients with elevated cardiac troponin
Unselected patients with elevated cardiac troponin concentrations (group 5), were older
(77±16 versus 35±13 years, P<0.001) and more likely to have comorbid conditions than those
with the lowest cardiac troponin concentrations (group 1) (Table 2). Patients with elevated
cardiac troponin concentrations were also more likely to have abnormal physiology (medium
or high risk National Early Warning Score, 16.8% versus 2.3%, P<0.001), lower hemoglobin
(122±23 versus 139±15 mg/dL, P<0.001) and higher creatinine concentrations (1.3±1.0
versus 0.8±0.2 mg/dL). The prevalence of elevated cardiac troponin concentrations increased
with age, the presence of ischemic heart disease and the number of co-morbid conditions
(Appendix Figure 2). The majority of patients found to have an elevated cardiac troponin
concentration (group 5) were admitted to hospital (124/144, 86.1%).
On logistic regression both age (model 1: odds ratio 2.06, 95% CI 1.75 to 2.47 per 10 year
increment) and comorbidity (model 2: odds ratio 6.88, 95% CI 1.83 to 23.21 for four or more
comorbidities compared to none) were strongly associated with elevated cardiac troponin
concentrations after adjusting for sex, renal function and the National Early Warning Score
(Appendix Table 6). When adjusting for both age and comorbidity, age remained a powerful
determinant of an elevated cardiac troponin concentration (odds ratio 1.99, 95% CI 1.66 to
2.42 per 10 years’ increment, P<0.001).
Page 11 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
12
Discussion
We have evaluated the impact of a non-selective approach to high-sensitivity cardiac troponin
testing on the diagnosis of myocardial infarction in consecutive patients attending the
Emergency Department. We make a number of important observations. First, if testing is
performed in all patients without prior clinical assessment, elevated cardiac troponin
concentrations are frequent, occurring in one in every eight patients. The majority of these
patients were admitted to hospital with an alternative primary diagnosis and were adjudicated
as having type 2 myocardial infarction or myocardial injury. Second, cardiac troponin testing
without prior clinical assessment results in a very low prevalence of type 1 myocardial
infarction (2%). As such, the positive predictive value of an elevated cardiac troponin
concentration for type 1 myocardial infarction is low at 14% in unselected patients. Third, if
prior clinical assessment is used to guide cardiac troponin testing, the prevalence and positive
predictive value increases more than four-fold. These findings highlight the importance of
clinical assessment and patient selection to optimize the diagnostic utility of high-sensitivity
cardiac troponin.
This is the first prospective evaluation of high-sensitivity cardiac troponin in all patients
undergoing blood sampling in the Emergency Department. This is an important distinction
from previous consecutive1,11,12
or selected16,17
patient cohorts of suspected acute coronary
syndrome. Our study has a number of strengths. First, we minimized selection bias by
identifying all consecutive patients presenting to the Emergency Department. Second, we did
not rely on the contemporary cardiac troponin assays, but instead two cardiologists
independently adjudicated the diagnosis using the high-sensitivity cardiac troponin I assay
with sex-specific thresholds as the reference standard.18,19
Together these approaches reduced
Page 12 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
13
case ascertainment bias and the potential to underestimate the prevalence of elevated cardiac
troponin concentrations.
Our study has implications for the adoption of high-sensitivity cardiac troponin assays,
particularly in those regions where the frequency of testing is high. The positive predictive
value is dependent on the prevalence of type 1 myocardial infarction, which in turn is
dependent on the selection of patients for testing which differs widely across health care
systems. In a representative sample of over 44,000 patients attending over 500 Emergency
Departments in the United States, 17% of all patients and 47% of those hospitalized, had
cardiac biomarkers tested,5 compared to just 3% and 16% respectively in our cohort.
Furthermore, over a third of patients tested in this US population did not present with cardiac
symptoms.5 The only previous study of high-sensitivity cardiac troponin I testing in a US
Emergency Department reported a prevalence of type 1 myocardial infarction of 3.2%,20
which we estimate would give a positive predictive value of 13.4% (Figure 2). High-
sensitivity cardiac troponin assays are now being introduced worldwide, with the exception of
the United States where they have only recently been approved by the Food and Drug
Administration.19
Whilst cardiac troponin testing in the undifferentiated patient may be
justified where myocardial infarction is a possibility,21,22
it is important that clinicians are
aware that elevated cardiac troponin concentrations are not exclusive to type 1 myocardial
infarction. If implemented without adopting a considered approach to testing and
interpretation, high-sensitivity cardiac troponin assays may increase diagnostic uncertainty
and increase the need for further invasive and non-invasive cardiac investigations with cost
implications for the health care system.
Page 13 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
14
Where clinical gestalt was used to select patients for cardiac troponin testing, we observed a
much improved positive predictive value. Perhaps unsurprisingly the positive predictive value
was highest in patients with chest pain, myocardial ischemia on the electrocardiogram or
known ischemic heart disease. A more selective approach to cardiac troponin testing is clearly
preferable, but could it potentially lead to clinicians missing a diagnosis of type 1 myocardial
infarction? Our analysis suggests that this is unlikely. In 1,054 unselected patients there were
only two patients with type 1 and three patients with type 2 myocardial infarction in whom
cardiac troponin was not requested by their attending clinician. These patients were already
admitted to hospital for further assessment with the exception of one patient who was
discharged with what was considered to be atypical chest pain (Appendix Table 7).
Whilst elevated cardiac troponin concentrations outwith acute coronary syndrome may be
challenging to interpret, they do convey potentially important clinical information. In these
patients cardiac troponin concentrations reflect physiological and hemodynamic stress. Nearly
all of these patients were already recognized by their attending physician as being acutely
unwell and were admitted to hospital. Although cardiac troponin is a powerful prognostic
marker in patients with type 2 myocardial infarction or myocardial injury, there is currently
no guidance on how to investigate these patients, and as yet no evidence to suggest that
cardiovascular treatments will improve outcomes.1 Until we have a better understanding of
the mechanisms and underlying pathophysiology, or effective treatment strategies for these
patients routine screening for these conditions is not recommended.
We acknowledge that whilst the majority of troponin determinations in the Emergency
Department are intended to evaluate patients with suspected acute coronary syndrome,
guidelines do recommend cardiac biomarker testing in other acute presentations including
Page 14 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
15
pulmonary embolus and acute heart failure.23,24
As such, whilst we have demonstrated how
cardiac troponin testing without consideration of pre-test probability impacts on the positive
predictive value of type 1 myocardial infarction, we accept that cardiac troponin testing is not
used exclusively to evaluate patients with suspected acute coronary syndrome.
There are some limitations to our study that merit discussion. First, we did not perform serial
cardiac troponin testing or systematically undertake coronary investigations in our cohort of
unselected patients. As such, in this cohort our adjudication was based on a single
measurement at presentation and those investigations undertaken as part of routine clinical
care. Patients with an elevated cardiac troponin concentration were not classified as having a
type 1 myocardial infarction where the clinical presentation and subsequent investigations
strongly supported an alternative primary diagnosis. Despite our careful attempt to classify
patients we accept a number of patients may have been misclassified. Whilst serial testing
may help to differentiate between acute and chronic myocardial injury, it does not distinguish
between type 1 and type 2 myocardial infarction.25,26
However, critically our study design
eliminated selection bias by systematically measuring cardiac troponin in wastage samples
from all patients without influencing clinical care. This precluded serial sampling, but ensured
our findings are generalisable and relevant to clinical practice. This approach was essential to
evaluate how the routine clinical assessment of pre-test probability influences the positive
predictive value of cardiac troponin testing. We accept this approach may have
underestimated acute myocardial injury in our unselected patients, as a small proportion of
patients with cardiac troponin concentrations in the normal reference range at presentation
may have had elevated concentrations on serial testing. Second, the cohort of unselected
patients was derived from the Emergency Department at a single site. Differing health
systems, including reimbursement systems, and the availability of primary care physicians
Page 15 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
16
may result in regional differences in the patient populations presenting to the Emergency
Department. This may have an impact on the overall prevalence and subsequent positive
predictive value of an elevated cardiac troponin concentration for the diagnosis of type 1
myocardial infarction. However, we modelled the impact of differences in prevalence on the
positive predictive value of cardiac troponin and the findings from our cohort are consistent
with multiple previous studies from centres across the world (Appendix Figure 1).16,27-46
Conclusions
When high-sensitivity cardiac troponin testing is performed in unselected patients, elevated
troponin concentrations are common and predominantly reflect myocardial injury rather than
type 1 myocardial infarction. Our observations highlight the importance of prior clinical
assessment to guide patient selection for testing to optimize the diagnostic utility of high-
sensitivity cardiac troponin.
Page 16 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
17
Acknowledgements
This research was funded by the British Heart Foundation (SP/12/10/29922 and
PG/15/51/31596). NLM and DEN are supported by the Butler Senior Clinical Research
Fellowship (FS/16/14/32023) and John Wheatley Chair (CH/09/002) awards respectively
from the British Heart Foundation. Abbott Laboratories provided high-sensitivity cardiac
troponin I assay reagents, calibrators, and controls.
Data sharing
Patient level data and statistical code will be made available following publication of the
primary study (HighSTEACS: NCT01852123) from the corresponding author at
[email protected]. Participant consent to share data was not obtained but the presented
data are anonymized and risk of identification is low.
Transparency Declaration
Dr Anoop Shah affirms that the manuscript is an honest, accurate, and transparent account of
the study being reported; that no important aspects of the study have been omitted; and that
any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Copyright Statement
The Corresponding Author has the right to grant on behalf of all authors and does grant on
behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group
Ltd to permit this article (if accepted) to be published in BMJ editions and any other
BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our
licence.
Page 17 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
18
Conflicts of interest
NLM and ASVS has acted as a consultant for Abbott Laboratories and Beckman-Coulter. All
other authors have no conflicts of interest.
Contribution statement
ASVS and NLM initially conceived the design and carried out the initial acquisition, analysis,
or interpretation of data. All authors were involved in drafting the manuscript and revising it,
and have given final approval of the version to be published.
Page 18 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
19
References
1. Shah AS, McAllister DA, Mills R, et al. Sensitive troponin assay and the classification
of myocardial infarction. Am J Med. 2015;128:493-501 e493.
2. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus document on
practical clinical considerations in the interpretation of troponin elevations: a report of
the American College of Cardiology Foundation task force on Clinical Expert
Consensus Documents. J Am Coll Cardiol. 2012; 60: 2427–63.
3. Saaby L, Poulsen TS, Hosbond S, et al. Classification of myocardial infarction:
frequency and features of type 2 myocardial infarction. Am J Med. 2013;126:789-797.
4. Saaby L, Poulsen TS, Diederichsen AC, et al. Mortality rate in type 2 myocardial
infarction: observations from an unselected hospital cohort. Am J Med. 2014;127:295-
302.
5. Sandoval Y, Smith SW, Thordsen SE, Apple FS. Supply/demand type 2 myocardial
infarction: should we be paying more attention? J Am Coll Cardiol. 2014;63:2079-
2087.
6. Mills NL, Churchhouse AM, Lee KK, et al. Implementation of a sensitive troponin I
assay and risk of recurrent myocardial infarction and death in patients with suspected
acute coronary syndrome. JAMA. 2011;305:1210-1216.
7. Melanson SE, Conrad MJ, Mosammaparast N, Jarolim P. Implementation of a highly
sensitive cardiac troponin I assay: test volumes, positivity rates and interpretation of
results. Clin Chim Acta. 2008;395:57-61.
8. Makam AN, Nguyen OK. Use of cardiac biomarker testing in the emergency
department. JAMA Intern Med. 2015;175:67-75.
Page 19 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
20
9. Yiadom MY, Jarolim P, Jenkins C, Melanson SE, Conrad M, Kosowsky JM.
Diagnostic implications of an elevated troponin in the emergency department. Disease
markers. 2015;2015:157812.
10. Baxi S, Lakin J, Stapleton S, Redberg R. High-sensitivity troponin: elevated without
infarction, is the horse out of the barn? Emerg Med J. 2014;31:354-355.
11. Shah AS, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at
presentation in patients with suspected acute coronary syndrome: a cohort study.
Lancet. 2015;386:2481-2488.
12. Shah AS, Griffiths M, Lee KK, et al. High sensitivity cardiac troponin and the under-
diagnosis of myocardial infarction in women: prospective cohort study. BMJ.
2015;350:g7873.
13. National early warning score (NEWS): standardising the assessment of acute-illness
severity in the NHS. Royal College of Physicians 2012. Available at
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news
14. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term
follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;
357: 1477–86.
15. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial
infarction in the six months after presentation with acute coronary syndrome:
prospective multinational observational study (GRACE). BMJ. 2006;333:1091.
16. Keller T, Zeller T, Ojeda F, et al. Serial changes in highly sensitive troponin I assay
and early diagnosis of myocardial infarction. JAMA. 2011;306:2684-2693.
17. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction
with sensitive cardiac troponin assays. N Engl J Med. 2009; 361: 858–67
Page 20 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
21
18. Apple FS. A new season for cardiac troponin assays: it's time to keep a scorecard. Clin
Chem. 2009;55:1303-1306.
19. Korley FK, Jaffe AS. Preparing the United States for high-sensitivity cardiac troponin
assays. J Am Coll Cardiol. 2013;61:1753-1758.
20. Korley FK, Schulman SP, Sokoll LJ, et al. Troponin elevations only detected with a
high-sensitivity assay: clinical correlations and prognostic significance. Acad Emerg
Med. 2014;21:727-735.
21. Jairam S, Jones P, Samaraie L, Chataline A, Davidson J, Stewart R. Clinical diagnosis
and outcomes for Troponin T 'positive' patients assessed by a high sensitivity
compared with a 4th generation assay. Emerg Med Australas. 2011;23:490-501.
22. Sherwood MW, Kristin Newby L. High-sensitivity troponin assays: evidence,
indications, and reasonable use. J Am Heart Assoc. 2014;3(1):e000403.
23. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the
diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033-
3069, 3069a-3069k.
24. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure: The Task Force for the diagnosis and
treatment of acute and chronic heart failure of the European Society of Cardiology
(ESC). Developed with the special contribution of the Heart Failure Association
(HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.
25. Sandoval Y, Thordsen SE, Smith SW, et al. Cardiac troponin changes to distinguish
type 1 and type 2 myocardial infarction and 180-day mortality risk. Eur Heart J Acute
Cardiovasc Care. 2014;3:317-325.
26. Collinson P, Lindahl B. Type 2 myocardial infarction: the chimaera of cardiology?
Heart. 2015;101:1697-1703.
Page 21 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
22
27. Invernizzi L, Doka M, Cappellini F, et al. Effectiveness of highly sensitive troponin T
assay for early diagnosis of acute myocardial infarction (AMI). Biochimica Clinica.
2013; 37: 36–9.
28. Lotze U, Lemm H, Heyer A, Muller K. Combined determination of highly sensitive
troponin T and copeptin for early exclusion of acute myocardial infarction: first
experience in an emergency department of a general hospital. Vasc Health Risk
Manag. 2011;7:509-515.
29. Bahrmann P, Bahrmann A, Breithardt OA, et al. Additional diagnostic and prognostic
value of copeptin ultra-sensitive for diagnosis of non-ST-elevation myocardial
infarction in older patients presenting to the emergency department. Clin Chem Lab
Med. 2013;51:1307-1319.
30. Bahrmann P, Christ M, Bahrmann A, et al. A 3-hour diagnostic algorithm for non-ST-
elevation myocardial infarction using high-sensitivity cardiac troponin T in unselected
older patients presenting to the emergency department. J Am Med Dir Assoc.
2013;14:409-416.
31. Hammerer-Lercher A, Ploner T, Neururer S, et al. High-sensitivity cardiac troponin T
compared with standard troponin T testing on emergency department admission: how
much does it add in everyday clinical practice? J Am Heart Assoc. 2013;2(3):e000204.
32. Thelin J, Borna C, Erlinge D, Ohlin B. The combination of high sensitivity troponin T
and copeptin facilitates early rule-out of ACS: a prospective observational study. BMC
Cardiovasc Disord. 2013;13:42.
33. Freund Y, Chenevier-Gobeaux C, Bonnet P, et al. High-sensitivity versus
conventional troponin in the emergency department for the diagnosis of acute
myocardial infarction. Crit Care. 2011;15:R147.
Page 22 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
23
34. Santalo M, Martin A, Velilla J, et al. Using high-sensitivity troponin T: the importance
of the proper gold standard. Am J Med. 2013;126:709-717.
35. Hoeller R, Rubini Gimenez M, Reichlin T, et al. Normal presenting levels of high-
sensitivity troponin and myocardial infarction. Heart. 2013;99:1567-1572.
36. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction
in patients with undetectable troponin using a high-sensitivity assay. J Am Coll
Cardiol. 2011;58:1332-1339.
37. Aldous SJ, Florkowski CM, Crozier IG, Than MP. The performance of high
sensitivity troponin for the diagnosis of acute myocardial infarction is underestimated.
Clin Chem Lab Med. 2012;50:727-729.
38. Aldous SJ, Richards AM, Cullen L, Than MP. Early dynamic change in high-
sensitivity cardiac troponin T in the investigation of acute myocardial infarction. Clin
Chem. 2011;57:1154-1160.
39. Christ M, Popp S, Pohlmann H, et al. Implementation of high sensitivity cardiac
troponin T measurement in the emergency department. Am J Med. 2010;123:1134-
1142.
40. Giannitsis E, Kehayova T, Vafaie M, Katus HA. Combined testing of high-sensitivity
troponin T and copeptin on presentation at prespecified cutoffs improves rapid rule-
out of non-ST-segment elevation myocardial infarction. Clin Chem. 2011;57:1452-
1455.
41. Collinson P, Goodacre S, Gaze D, Gray A. Very early diagnosis of chest pain by
point-of-care testing: comparison of the diagnostic efficiency of a panel of cardiac
biomarkers compared with troponin measurement alone in the RATPAC trial. Heart.
2012;98:312-318.
Page 23 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
24
42. Sebbane M, Lefebvre S, Kuster N, et al. Early rule out of acute myocardial infarction
in ED patients: value of combined high-sensitivity cardiac troponin T and
ultrasensitive copeptin assays at admission. Am J Emerg Med. 2013;31:1302-1308.
43. Inoue K, Suwa S, Ohta H, et al. Heart fatty acid-binding protein offers similar
diagnostic performance to high-sensitivity troponin T in emergency room patients
presenting with chest pain. Circ J. 2011;75:2813-2820.
44. Eggers KM, Venge P, Lindahl B. High-sensitive cardiac troponin T outperforms novel
diagnostic biomarkers in patients with acute chest pain. Clin Chim Acta.
2012;413:1135-1140.
45. Normann J, Mueller M, Biener M, Vafaie M, Katus HA, Giannitsis E. Effect of older
age on diagnostic and prognostic performance of high-sensitivity troponin T in
patients presenting to an emergency department. Am Heart J. 2012;164:698-705 e694.
46. Khan DA, Sharif MS, Khan FA. Diagnostic performance of high-sensitivity troponin
T, myeloperoxidase, and pregnancy-associated plasma protein A assays for triage of
patients with acute myocardial infarction. Korean J Lab Med. 2011;31:172-178.
Page 24 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
25
Figure legends
Figure 1. Flow diagram summarizing the patients recruited in the unselected Emergency
Department cohort (Red) and the in the suspected acute coronary syndrome cohort (Green).
Figure 2.
A) Infographic summarizing the prevalence of elevated cardiac troponin and type 1
myocardial infarction in the unselected Emergency Department patient cohort (Red)
and in patients with suspected acute coronary syndrome (Green)
B) Influence of prevalence on the positive predictive value of an elevated cardiac
troponin concentration for the diagnosis of type 1 myocardial infarction.
Red dot represents cohort of unselected patients in the Emergency Department
(n=1,054) and the green dot represents cohort of selected patients with suspected
acute coronary syndrome (n=5,815). Red line represents the central estimate of the
positive predictive value with the 95% confidence interval (dashed blue) derived from
the unselected Emergency Department cohort.
Figure 3. Influence of clinical characteristics on the positive predictive value of an elevated
cardiac troponin for a diagnosis of type 1 myocardial infarction in patients with suspected
acute coronary syndrome.
Dashed red line represents the positive predictive value across the whole cohort with dashed
grey lines representing the 95% confidence intervals.
Page 25 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
26
Table 1. Baseline characteristics of unselected patients in the Emergency Department
and selected patients with suspected acute coronary syndrome
Unselected patients
n=1,054
Suspected acute
coronary syndrome
n=5,815
Sex, male (%) 549 (52.0) 2,552 (43.9)
Age (years) 54 (23) 64 (16)
Chest pain, n (%) 183 (17.6) 4,825 (83.0)
Risk factors
Smoker, n (%) 183 (17.6) 1,105 (30.6)
Hypertension, n (%) 337 (32.4) 1,969 (37.6)
Hyperlipidaemia, n (%) 299 (28.7) 1,611 (30.8)
Past medical history
Ischemic heart disease, n (%) 193 (18.5) 1,846 (35.2)
Myocardial infarction, n (%) 109 (10.5) 1,082 (20.7)
Cerebrovascular disease, n (%) 99 (9.5) 475 (9.1)
Diabetes mellitus, n (%) 106 (10.1) 842 (16.1)
PCI, n (%) 52 (5.0) 611 (11.7)
CABG, n (%) 32 (3.1) 330 (6.3)
Medications at presentation
Aspirin, n (%) 180 (17.5) 1,344 (33.7)
Clopidogrel, n (%) 81 (7.9) 468 (11.8)
Beta blockers, n (%) 149 (14.5) 1,082 (27.2)
ACE-I/ARB, n (%) 189 (18.3) 1,311 (32.9)
Statin, n (%) 249 (24.2) 1,578 (39.6)
Warfarin, n (%) 44 (4.3) 278 (7.0)
Haemodynamics
Systolic blood pressure (mmHg) 130.5 (22.2) 137.5 (26.0)
Pulse rate (bpm) 86.9 (22.3) 81.2 (22.9)
Killip class, n (%)
I 930 (89.7) 4,847 (90.8)
II 85 (8.2) 408 (7.6)
III 15 (1.4) 75 (1.4)
IV 1 (0.1) 6 (0.1)
Baseline electrocardiography
ST elevation, n (%) 13 (2.0) 218 (4.2)
ST depression, n (%) 21 (3.2) 397 (7.7)
T-wave inversion, n (%) 58 (8.9) 726 (14.1)
Diagnosis
Type 1 myocardial infarction 17 (1.6) 843 (14.5)
Type 2 myocardial infarction 13 (1.2) 229 (3.9)
Myocardial injury 114 (10.8) 341 (5.9)
Abbreviations: bpm – breaths/beats per minute; PCI – percutaneous coronary intervention, CABG – coronary artery bypass grafting,
ACE-I/ARB: angiotensin converting enzyme inhibitor/ Angiotensin receptor blocker
Page 26 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only 27
Table 2. Baseline characteristics in unselected patients attending the Emergency Department stratified by cardiac troponin concentration
Group 1
Group 2
Group 3
Group 4
Group 5
(TnI > 99th centile)
n 341 150 210 209 144
Troponin concentration, ng/L
Male ≤2 3 4 - 8 9 - 34 >34
Female ≤1 2 3 - 4 5 - 16 >16
Sex, male (%) 174 (51.0) 66 (44.0) 108 (51.4) 102 (48.8) 55 (38.2)
Age (years) 35.3 (14.0) 47.3 (16.0) 59.9 (17.8) 70.2 (17.8) 77.0 (15.7)
Chest pain, n (%) 42 (12.5) 26 (17.6) 41 (19.6) 38 (18.4) 36 (25.4)
Risk factors
Smoker, n (%) 109 (36.9) 50 (38.8) 60 (33.5) 46 (25.0) 34 (29.6)
Hypertension, n (%) 23 (6.9) 33 (22.1) 87 (41.8) 101 (48.8) 93 (65.5)
Hyperlipidaemia, n (%) 25 (7.5) 31 (20.8) 71 (34.1) 96 (46.6) 76 (53.1)
Past medical history
Ischemic heart disease, n (%) 16 (4.8) 14 (9.4) 44 (21.2) 60 (29.0) 59 (41.3)
Myocardial infarction, n (%) 11 (3.3) 7 (4.7) 26 (12.5) 33 (15.9) 32 (22.4)
Cerebrovascular disease, n (%) 4 (1.2) 10 (6.7) 27 (13.0) 27 (13.0) 31 (21.7)
Diabetes mellitus, n (%) 14 (4.2) 11 (7.4) 25 (11.9) 35 (16.8) 21 (14.7)
Previous revascularisation
PCI, n (%) 9 (2.7) 6 (4.1) 12 (5.7) 14 (6.7) 11 (7.7)
CABG, n (%) 1 (0.3) 1 (0.7) 6 (2.9) 11 (5.3) 13 (9.1)
Physiological parameters
Respiratory rate (bpm) 17.6 (3.6) 17.3 (2.9) 17.6 (3.4) 18.6 (4.0) 20.7 (6.2)
Temperature (oC) 36.8 (0.8) 36.9 (0.8) 36.8 (0.8) 37.0 (0.9) 37.0 (1.1)
Pulse rate (bpm) 85.7 (19.3) 84.6 (20.2) 86.0 (22.6) 86.1 (22.1) 94.1 (28.3)
Systolic blood pressure (mmHg) 126.9 (16.7) 129.0 (21.2) 132.0 (23.7) 135.4 (24.8) 131.0 (26.2)
Oxygen saturations (%) 97.8 (1.9) 97.3 (2.3) 96.7 (2.4) 95.9 (3.3) 95.3 (4.3)
Page 27 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only 28
On oxygen, n (%) 5 (1.7) 1 (0.7) 12 (6.4) 17 (8.9) 27 (20.5)
Consciousness, n (%)
Alert 331 (98.2) 144 (96.6) 205 (98.1) 202 (97.1) 132 (91.7)
Verbal 3 (0.9) 3 (2.0) 2 (1.0) 1 (0.5) 5 (3.5)
Pain 2 (0.6) 0 (0.0) 1 (0.5) 3 (1.4) 2 (1.4)
Unresponsive 1 (0.3) 2 (1.3) 1 (0.5) 2 (1.0) 5 (3.5)
NEWS risk (medium/high), n (%) 5 (2.3) 1 (1.1) 6 (4.4) 7 (5.1) 17 (16.8)
Killip class, n (%)
I 1 (0.3) 0 (0.0) 0 (0.0) 2 (1.0) 3 (2.1)
II 327 (98.5) 145 (98.0) 184 (88.9) 172 (82.7) 102 (71.8)
III 4 (1.2) 3 (2.0) 19 (9.2) 28 (13.5) 31 (21.8)
IV 0 (0.0) 0 (0.0) 4 (1.9) 6 (2.9) 5 (3.5)
Haematology and biochemistry
Haemoglobin (g/dL) 13.9 (1.5) 13.6 (1.7) 13.4 (1.8) 12.7 (2.1) 12.2 (2.3)
Creatinine (mg/dL), median (IQR) 0.8 (0.7-0.9) 0.79 (0.7-0.9) 0.8 (0.7-0.9) 0.9 (0.8-1.2) 1.0 (0.8-1.4)
Urea (mg/dL) 4.4 (1.6) 5.0 (2.2) 5.6 (2.7) 7.5 (4.4) 9.5 (5.4)
Medication at presentation
Aspirin, n (%) 13 (3.9) 16 (10.8) 35 (17.3) 65 (31.7) 51 (36.2)
Clopidogrel, n (%) 8 (2.4) 9 (6.1) 17 (8.4) 29 (14.1) 18 (12.8)
Beta blockers, n (%) 12 (3.6) 13 (8.8) 34 (16.8) 48 (23.4) 42 (29.8)
ACE-I/ARB, n (%) 14 (4.2) 21 (14.2) 53 (26.2) 51 (24.9) 50 (35.5)
Statin, n (%) 19 (5.7) 29 (19.6) 58 (28.7) 83 (40.5) 60 (42.6)
Oral anticoagulant, n (%) 2 (0.6) 4 (2.7) 9 (4.5) 16 (7.8) 13 (9.3)
Admission ECG
ST-segment elevation, n (%) 1 (0.6) 2 (2.4) 1 (0.8) 3 (2.0) 6 (5.1)
ST-segment depression, n (%) 0 (0.0) 4 (4.8) 1 (0.8) 2 (1.4) 14 (12.0)
T-wave inversion, n (%) 4 (2.3) 7 (8.3) 9 (7.1) 22 (14.9) 16 (13.7)
Management
Page 28 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only 29
Chest pain nurse referral, n (%) 3 (0.9) 5 (3.4) 6 (2.9) 7 (3.4) 15 (10.4)
Cardiology referral, n (%) 1 (0.3) 3 (2.0) 7 (3.3) 15 (7.2) 24 (16.7)
Admitted to hospital, n (%) 140 (41.5) 74 (49.7) 121 (57.9) 150 (72.1) 124 (86.1)
Echocardiogram, n (%) 0 (0.0) 1 (0.7) 0 (0.0) 6 (2.9) 10 (6.9)
Coronary angiogram, n (%) 1 (0.3) 1 (0.7) 1 (0.5) 4 (1.9) 10 (6.9)
PCI, n (%) 1 (0.3) 0 (0.0) 1 (0.5) 2 (1.0) 6 (4.2)
CABG, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.7)
Abbreviations: bpm – breaths/beats per minute, PCI – percutaneous coronary intervention, CABG – coronary artery bypass grafting,
ACE-I/ARB: angiotensin converting enzyme inhibitor/ Angiotensin receptor blocker, NEWS – National early warning score
SI conversion factors: To convert creatinine to µmol/L, multiply values by 88.4; To convert urea to mmol/L, multiply values by 0.357
Page 29 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
3,619 ED attendances
Patients undergoing blood sampling
n = 1,130
76 exclusions• inadequate volume• repeat attenders• non-residents
Final study populationn=1,054
Unselected testing
232,000 ED attendances
Suspected acute coronary syndrome
1,155 exclusions• repeat attenders• unable to link records• non-residents
Final study populationn=5,815
Suspected acute coronary syndrome
Patients undergoing blood sampling
n = 54,000
* Troponin only used to guide clinical care in patients with suspected acute
coronary syndrome
Yes*n=136
Non=918
Suspected acute coronary syndrome
Yes*n=6,970
Non=47,030
Figure1 Page 30 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Unselectedpatients
TnI > 99th centile(13.7%)
Type 1 myocardialinfarction (1.6%)
Suspected acute coronary syndrome
TnI > 99th centile(24.2%)
Type 1 myocardialinfarction (14.5%)
Figure2aPage 31 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review OnlyUnselected
Suspected ACS
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Prevalence (%)
Pred
icte
d po
sitiv
e pr
edic
tive
valu
e (%
)
Figure 2b Page 32 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
32
Figure 2.
0 10 20 30 40 50 60 70 80 90 100Positive predictive value (95% Confidence Intervals)
Age
Chest pain
Ischaemic ECG
Hypertension
Hyperlipidaemia
Diabetes
Ischaemic heart disease
<40
40−49
50−59
60−69
70−79
>80
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
3.7 (2.0−5.5)
8.8 (6.8−10.9)
10.4 (8.6−12.2)
14.2 (12.2−16.2)
18.2 (16.1−20.4)
22.5 (20.1−25.0)
15.1 (14.1−16.2)
11.5 (9.5−13.5)
31.0 (28.4−33.6)
11.0 (10.0−12.0)
19.2 (17.4−20.9)
13.1 (11.9−14.3)
20.3 (18.3−22.2)
13.2 (12.1−14.3)
18.0 (15.4−20.6)
14.8 (13.8−15.9)
20.5 (18.7−22.3)
12.6 (11.5−13.7)
1 2 3
Variable StrataPrevalence.of.type.1.
myocardial.infarction,. %.(95%.CI)
≥"80
Positive(predictive( value(for(type(1(myocardial(infarction( (95%(CI)
Figure 3
Page 33 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
1
APPENDIX
Non-selective high-sensitivity cardiac troponin testing
in the Emergency Department Anoop SV Shah MD MPH PhD,1 Ala Noaman MD,1 Amar Vaswani MD,1 Mathew Gibbins
MSc,1 Megan Griffiths MD,1 Andrew R Chapman MD,1 Fiona Strachan PhD,1 Atul Anand
MD,1 Philip Adamson MD1, Michelle D Souza,1 Alasdair J Gray MD,3,4 David A McAllister
MD,2 David E Newby MD PhD1 and Nicholas L Mills MD PhD1
1BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom 2Centre for Population Health Sciences, University of Edinburgh, United Kingdom 3Department of Emergency Medicine, Royal Infirmary of Edinburgh, United Kingdom 4Emergency Medicine Research Group Edinburgh (EMeRGE), United Kingdom Correspondence and requests for reprints: Dr Anoop S V Shah BHF/University Centre for Cardiovascular Science Chancellor’s Building University of Edinburgh Edinburgh EH16 4SB United Kingdom Fax: +44 131 242 6379 E-mail: [email protected]
Supplementary Tables and Figures: 10
Page 34 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
2
Appendix Table 1. Parameters and scoring system of the National Early Warning Score (NEWS)
Points 3 2 1 0 1 2 3
Physiological parameter
Respiratory rate, breaths per minute
≤8 - 9 to 11 12 to 20 - 21 to 24 ≥25
Oxygen saturations, % ≤91 92 to 93 94 to 95 ≥96 - -
Any supplemental oxygen - Yes - No - - -
Temperature, oC ≤35.0 35.1 to 36.0 36.1 to 38.0 38.1 to 39 ≥39.1 -
Systolic blood pressure, mmHg
≤90 91 to 100 101 to 110 111 to 219 - - -
Heart rate, beats per minute ≤40 - 41 to 50 51 to 90 91 to 110 111 to 130 ≥131
Consciousness - - - Alert - Voice, Pain or Unresponsive -
Page 35 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
3
Appendix Table 2. Baseline characteristics of unselected patients in the Emergency Department with and without cardiac troponin testing requested by the attending clinician Cardiac troponin testing following
clinical assessment No (n=918) Yes (n=136)
Sex, male (%) 426 (46.4) 79 (58.1)
Age (years), mean (SD) 53.0 (23.0) 64.9 (16.4)
Chest pain, n (%) 75 (8.3) 108 (79.4)
Risk factors
Smoker, n (%) 258 (33.2) 41 (32.5)
Hypertension, n (%) 257 (28.4) 80 (59.3)
Hyperlipidaemia, n (%) 230 (25.4) 69 (51.5)
Past medical history
Ischemic heart disease, n (%) 127 (14.0) 66 (48.9)
Myocardial infarction, n (%) 61 (6.7) 48 (35.6)
Cerebrovascular disease, n (%) 83 (9.2) 16 (11.9)
Diabetes mellitus, n (%) 81 (8.9) 25 (18.5)
Percutaneous coronary intervention, n (%) 28 (3.1) 24 (17.8)
CABG, n (%) 19 (2.1) 13 (9.6)
Admission physiological parameters
Respiratory rate (bpm), mean (SD) 18.3 (4.3) 17.8 (3.4)
Temperature (oC), mean (SD) 36.9 (0.9) 36.6 (0.6)
Pulse rate (bpm), mean (SD) 87.7 (22.1) 81.8 (23.0)
Systolic blood pressure (mmHg), mean (SD) 130.5 (22.3) 130.8 (21.9)
Oxygen saturations (%), mean (SD) 96.8 (3.0) 96.7 (2.2)
On oxygen, n (%) 52 (6.3) 10 (8.1)
Consciousness, n (%)
Alert 880 (96.6) 134 (98.5)
Verbal 14 (1.5) 0 (0.0)
Pain 7 (0.8) 1 (0.7)
Unresponsive 10 (1.1) 1 (0.7)
Killip class, n (%)
I 819 (90.8) 111 (82.2)
II 65 (7.2) 20 (14.8)
III 11 (1.2) 4 (3.0)
IV 1 (0.1) 0 (0.0)
Haematology and biochemistry
Haemoglobin (mg/dL), mean (SD) 132.8 (19.5) 131.9 (16.8)
Creatinine (mg/dL), mean (SD) 1.0 (0.7) 1.0 (0.6)
Urea (mg/dL), mean (SD) 5.9 (3.71) 6.8 (3.8)
Troponin I (ng/L), median [IQR] 3.0 [2.0, 9.0] 5.0 [3.0, 19.5]
Medications on presentation
Page 36 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
4
Aspirin, n (%) 130 (14.5) 50 (37.6)
Clopidogrel, n (%) 62 (6.9) 19 (14.3)
Beta blockers, n (%) 109 (12.1) 40 (30.1)
ACE-I/ARB, n (%) 143 (15.9) 46 (34.6)
Statin, n (%) 192 (21.4) 57 (42.9)
Warfarin, n (%) 35 (3.9) 9 (6.8)
Baseline electrocardiography
ST-segment elevation, n (%) 5 (1.0) 8 (6.0)
ST-segment depression, n (%) 9 (1.7) 12 (9.0)
T-wave inversion, n (%) 34 (6.5) 24 (18.0)
GRACE Risk category
Low 260 (59.0) 45 (40.2)
Medium/ High 179 (41.0) 67 (59.8)
Management
Chest pain nurse referral, n (%) 5 (0.5) 31 (22.8)
Cardiology referral, n (%) 14 (1.5) 36 (26.5)
Admitted to hospital, n (%) 512 (56.2) 97 (71.3)
Echocardiogram, n (%) 5 (0.5) 12 (8.8)
Coronary angiogram, n (%) 2 (0.2) 15 (11.0)
PCI, n (%) 0 (0.0) 10 (7.4)
CABG, n (%) 0 (0.0) 1 (0.7)
Diagnosis
No myocardial injury 804 (87.6) 106 (77.9)
Type 1 myocardial infarction 2 (0.2) 15 (11.0)
Type 2 myocardial infarction 3 (0.3) 10 (7.4)
Myocardial injury 109 (11.9) 5 (3.7)
Page 37 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
5
Appendix Table 3. Presenting complaint in patients with cardiac troponin concentrations > 99th centile in the unselected cohort (n=144).
Presenting complaint Number Percentage
Fall/Collapse 40 28%
Chest pain 36 25%
Dyspnea 13 9%
Abdominal pain 8 6%
Dizziness 4 3%
Confusion 3 3%
Other 42 29%
Page 38 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
6
Appendix Table 4. Primary clinical diagnostic in patients with cardiac troponin concentrations > 99th centile in the unselected cohort (n=144).
Diagnostic category Number Percentage
Cardiac* 35 24%
Respiratory* 23 16%
Infective / sepsis 21 15%
Other 16 11%
Mechanical fall 15 10%
Trauma / Orthopaedic 10 7%
Gastrenterology / hepatology 9 6%
Renal 6 4%
Surgical 5 3%
Neurological 4 3% * In patients with a cardiac diagnosis (n=35/144), acute coronary syndrome (n=17) and atrial fibrillation (n=10) accounted for the majority of patients. In those patients with a respiratory diagnosis (n=23/144), pneumonia (n=11) and chronic obstructive pulmonary disease (n=7) accounted for the majority of patients.
Page 39 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
7
Appendix Table 5. Influence of clinical characteristics on the positive predictive value of an elevated cardiac troponin for a diagnosis of type 1 or type 2 myocardial infarction in patients with suspected acute coronary syndrome.
Variable Strata PPV (95%CI) Age, years <40 76.8% (61.3-91.2)
40-49 88.7% (81.9-95.0)
50-59 83.5% (77.7-89.2)
60-69 81.3% (76.3-86.1)
70-79 75.7% (71.4-79.9)
≥80 68.8% (64.8-72.7)
Chest pain Yes 83.5% (81.3-85.7)
No 50.9% (45.5-56.3)
Ischemic ECG Yes 87.9% (85.1-90.6)
No 72.9% (69.7-76.0)
Hypertension Yes 78.0% (74.7-81.2)
No 76.2% (73.0-79.3)
Hyperlipidaemia Yes 83.7% (80.4-87.0)
No 73.4% (70.4-76.3)
Diabetes Yes 75.0% (69.6-80.2)
No 77.6% (75.1-80.0)
Ischemic heart disease Yes 82.1% (78.9-85.2)
No 73.7% (70.6-76.8)
Page 40 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
8
Appendix Table 6. Logistic regression models for determinants of elevated cardiac troponin in unselected patients attending the Emergency Department Variable Model 1, OR (95% CI) Model 2, OR (95% CI) Model 3, OR (95% CI)
Age, per 10 years 2.06 ( 1.75 - 2.47 )*** - 1.99 ( 1.66 - 2.42 )***
Creatinine, per 0.1 mg/dL 1.03 ( 1.00 - 1.07 )* 1.03 ( 1.00 - 1.06 ) 1.03 ( 1.00 - 1.06 )*
Sex (Male) 0.56 ( 0.33 - 0.93 )* 0.40 ( 0.24 - 0.66 )*** 0.51 ( 0.30 - 0.86 )*
NEWS, per 1 unit 1.46 ( 1.27 - 1.70 )*** 1.51 ( 1.32 - 1.73 )*** 1.48 ( 1.28 - 1.72 )***
Comorbidity
None (referent) - 1 1
One - 3.78 ( 2.05 – 7.00 )*** 1.1 ( 0.55 - 2.19 )
Two - 5.69 ( 2.97 - 10.98 )*** 1.33 ( 0.64 - 2.76 )
Three - 8.13 ( 3.5 - 18.57 )*** 1.73 ( 0.69 - 4.25 )
Four - 6.88 ( 1.83 - 23.21 )** 2.58 ( 0.65 - 9.28 )
AIC (model fit) 411 478 413
***P value <0.001 **P value <0.05
Page 41 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
9
Appendix Table 7. Case series of patients classified as type 1 or type 2 myocardial infarction in whom the attending clinician did not request cardiac troponin Age Sex Classification Presenting
complaint Known IHD
TnI, ng/L
Ischemia on ECG
Admitted Clinical details
94 M Type 1 Chest pain No 1,377 Yes Yes Late presentation myocardial infarction, not for escalation of care
44 M Type 1 Chest pain No 132 No No Atypical history of chest pain 65 M Type 2 Breathlessness No 46 Yes Yes Patient with multiple comorbidities and
admitted with shortness of breath secondary to exacerbation of COPD
94 F Type 2 Chest pain No 24 No Yes Admitted with fast ventricular response to atrial fibrillation and associated chest tightness
72 M Type 2 Chest pain No 36 Yes Yes Admitted with fast ventricular response to atrial fibrillation and associated chest pain with rate related left bundle branch block
Page 42 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
10
Appendix Figure 1. Influence of prevalence on the positive predictive value of an elevated cardiac troponin concentration for the diagnosis of type 1 myocardial infarction.
Red dots represent our cohorts of unselected patients in the Emergency Department (n=1,054) and selected patients with suspected acute coronary syndrome (n=5,815). Black dots represent the reported positive predictive values for cardiac troponin by prevalence of type 1 myocardial infarction in previously published cohorts using high-sensitivity cardiac troponin T (blue) and high-sensitivity cardiac troponin I (red) assays.1-21 Dot size reflects the number of patients in each cohort (small dot <500 patients, medium dot 500-1,000 patients, large dot >1,000 patients). Red line represents the central estimate of the positive predictive value with the 95% confidence interval (dashed blue) derived from the unselected Emergency Department cohort.
31
Figure 1.
Unselected
Aldous
Aldous
Bahrmann
Body
Christ
Collinson
Eggers
Freund
Hammerer−Lercher
HoellerInoue
Invernizi
Lotze
SantalolSebbaneGiannitis
Khan
Normann
Thelin
Suspected ACS
KellerHoeller
Korley
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Prevalence of type 1 myocardial infarction (%)
Posi
tive
pred
ictiv
e va
lue
(%)
Page 43 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
11
Appendix Figure 2. Prevalence of myocardial injury in unselected patients attending the Emergency Department
All
Sex
Age (years)
Ischaemic heart disease
No. of comorbidities
GFR (ml/min)
Males
Females
<40
40 to 49
50 to 59
60 to 69
70 to 79
Over 80
No
Yes
Zero
One
Two
Over three
< 30
30 to 59
Over 60
144 /1054
55 /505
89 /549
5 /312
6 /157
8 /128
19 /128
31 /142
75 /187
84 /849
59 /193
32 /602
38 /200
42 /151
29 /85
98 /559
17 /81
29 /407
13.7 (11.6−15.8)
11 (8.3−13.7)
16.3 (13.2−19.4)
1.8 (0.5−3.2)
4.1 (1.3−7.2)
6.6 (2.7−10.9)
15.1 (9.2−21.4)
22 (15.4−28.9)
40.2 (33.2−47.2)
9.9 (8−12)
30.7 (24.3−37.2)
5.4 (3.6−7.2)
19.2 (13.8−24.6)
28 (21−35.1)
34.3 (24.5−44.3)
17.6 (14.5−20.8)
21.3 (12.8−30.3)
7.2 (4.8−9.8)
1 2 3 4 0 5 10 15 20 25 30 35 40 45
Prevalence of elevated cardiac torponin > 99th centile (95% Confidence Intervals)
Variable Strata Number Prevalence1(95%1CI)
≥80
≥3*
None*
1
2*
≥*60*
Page 44 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
12
References
1. Invernizzi L, Doka M, Cappellini F, et al. Effectiveness of highly sensitive troponin T
assay for early diagnosis of acute myocardial infarction (AMI). Biochimica Clinica
2013;37(1):36-39.
2. Lotze U, Lemm H, Heyer A, et al. Combined determination of highly sensitive troponin T
and copeptin for early exclusion of acute myocardial infarction: first experience in an
emergency department of a general hospital. Vasc Health Risk Manag 2011;7:509-15.
doi: 10.2147/VHRM.S21753
3. Bahrmann P, Bahrmann A, Breithardt OA, et al. Additional diagnostic and prognostic
value of copeptin ultra-sensitive for diagnosis of non-ST-elevation myocardial infarction
in older patients presenting to the emergency department. Clin Chem Lab Med
2013;51(6):1307-19. doi: 10.1515/cclm-2012-0401
4. Bahrmann P, Christ M, Bahrmann A, et al. A 3-hour diagnostic algorithm for non-ST-
elevation myocardial infarction using high-sensitivity cardiac troponin T in unselected
older patients presenting to the emergency department. J Am Med Dir Assoc
2013;14(6):409-16. doi: 10.1016/j.jamda.2012.12.005
5. Hammerer-Lercher A, Ploner T, Neururer S, et al. High-sensitivity cardiac troponin T
compared with standard troponin T testing on emergency department admission: how
much does it add in everyday clinical practice? J Am Heart Assoc 2013;2(3):e000204.
doi: 10.1161/JAHA.113.000204
6. Thelin J, Borna C, Erlinge D, et al. The combination of high sensitivity troponin T and
copeptin facilitates early rule-out of ACS: a prospective observational study. BMC
Cardiovasc Disord 2013;13:42. doi: 10.1186/1471-2261-13-42
7. Freund Y, Chenevier-Gobeaux C, Bonnet P, et al. High-sensitivity versus conventional
troponin in the emergency department for the diagnosis of acute myocardial infarction.
Crit Care 2011;15(3):R147. doi: 10.1186/cc10270
8. Santalo M, Martin A, Velilla J, et al. Using high-sensitivity troponin T: the importance of
the proper gold standard. Am J Med 2013;126(8):709-17. doi:
10.1016/j.amjmed.2013.03.003
9. Hoeller R, Rubini Gimenez M, Reichlin T, et al. Normal presenting levels of high-
sensitivity troponin and myocardial infarction. Heart 2013;99(21):1567-72. doi:
10.1136/heartjnl-2013-303643
Page 45 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
13
10. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in
patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol
2011;58(13):1332-9. doi: 10.1016/j.jacc.2011.06.026
11. Aldous SJ, Florkowski CM, Crozier IG, et al. The performance of high sensitivity
troponin for the diagnosis of acute myocardial infarction is underestimated. Clin Chem
Lab Med 2012;50(4):727-9. doi: 10.1515/cclm.2011.830
12. Aldous SJ, Richards AM, Cullen L, et al. Early dynamic change in high-sensitivity
cardiac troponin T in the investigation of acute myocardial infarction. Clin Chem
2011;57(8):1154-60. doi: 10.1373/clinchem.2010.161166
13. Christ M, Popp S, Pohlmann H, et al. Implementation of high sensitivity cardiac
troponin T measurement in the emergency department. Am J Med 2010;123(12):1134-
42. doi: 10.1016/j.amjmed.2010.07.015
14. Giannitsis E, Kehayova T, Vafaie M, et al. Combined testing of high-sensitivity troponin
T and copeptin on presentation at prespecified cutoffs improves rapid rule-out of non-
ST-segment elevation myocardial infarction. Clin Chem 2011;57(10):1452-5. doi:
10.1373/clinchem.2010.161265
15. Collinson P, Goodacre S, Gaze D, et al. Very early diagnosis of chest pain by point-of-
care testing: comparison of the diagnostic efficiency of a panel of cardiac biomarkers
compared with troponin measurement alone in the RATPAC trial. Heart
2012;98(4):312-8. doi: 10.1136/heartjnl-2011-300723 [published Online First:
2011/11/15]
16. Sebbane M, Lefebvre S, Kuster N, et al. Early rule out of acute myocardial infarction in
ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive
copeptin assays at admission. Am J Emerg Med 2013;31(9):1302-8. doi:
10.1016/j.ajem.2013.04.033
17. Inoue K, Suwa S, Ohta H, et al. Heart fatty acid-binding protein offers similar diagnostic
performance to high-sensitivity troponin T in emergency room patients presenting with
chest pain. Circ J 2011;75(12):2813-20.
18. Eggers KM, Venge P, Lindahl B. High-sensitive cardiac troponin T outperforms novel
diagnostic biomarkers in patients with acute chest pain. Clin Chim Acta 2012;413(13-
14):1135-40. doi: 10.1016/j.cca.2012.03.011 [published Online First: 2012/03/30]
19. Normann J, Mueller M, Biener M, et al. Effect of older age on diagnostic and prognostic
performance of high-sensitivity troponin T in patients presenting to an emergency
department. Am Heart J 2012;164(5):698-705 e4. doi: 10.1016/j.ahj.2012.08.003
Page 46 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
14
20. Khan DA, Sharif MS, Khan FA. Diagnostic performance of high-sensitivity troponin T,
myeloperoxidase, and pregnancy-associated plasma protein A assays for triage of
patients with acute myocardial infarction. Korean J Lab Med 2011;31(3):172-8. doi:
10.3343/kjlm.2011.31.3.172
21. Keller T, Zeller T, Ojeda F, et al. Serial changes in highly sensitive troponin I assay and
early diagnosis of myocardial infarction. Jama 2011;306(24):2684-93. doi:
10.1001/jama.2011.1896 [published Online First: 2011/12/29]
Page 47 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
1
APPENDIX: STATISTICAL ANALYSIS PLAN
Non-selective high-sensitivity cardiac troponin testing
in the Emergency Department
Anoop SV Shah MD MPH PhD,1 Ala Noaman MD,
1 Amar Vaswani MD,
1 Mathew Gibbins MSc,
1
Megan Griffiths MD,1 Andrew R Chapman MD,1 Fiona Strachan PhD,1 Atul Anand MD,1 Philip
Adamson MD1, Michelle D Souza,
1 Alasdair J Gray MD,
3,4 David A McAllister MD,
2 David E
Newby MD PhD1 and Nicholas L Mills MD PhD1
1BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom
2Centre for Population Health Sciences, University of Edinburgh, United Kingdom
3Department of Emergency Medicine, Royal Infirmary of Edinburgh, United Kingdom
4Emergency Medicine Research Group Edinburgh (EMeRGE), United Kingdom
Correspondence and requests for reprints:
Dr Anoop S V Shah
BHF/University Centre for Cardiovascular Science
Chancellor’s Building
University of Edinburgh
Edinburgh EH16 4SB
United Kingdom
Fax: +44 131 242 6379
E-mail: [email protected]
Page 48 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
2
Contents
Contents ............................................................................................................................... 2
1 Introduction .................................................................................................................. 3
1.1 Background ............................................................................................................................. 3
1.2 Study objectives ....................................................................................................................... 4
1.2.1 Hypothesis .......................................................................................................................... 4
2 Statistical analysis plan ................................................................................................. 5
2.1.1 Objectives ........................................................................................................................... 5
2.1.2 General Statistical Principles .............................................................................................. 5
2.1.3 Analysis population ............................................................................................................ 5
2.1.4 Software ............................................................................................................................. 6
3 List of analyses .............................................................................................................. 7
3.1 Baseline Characteristics ......................................................................................................... 7
3.2 Primary outcome ..................................................................................................................... 9
3.2.1 Event summary ................................................................................................................... 9
3.2.2 Primary analysis ................................................................................................................. 9
3.2.3 Secondary analysis ........................................................................................................... 10
4 References ................................................................................................................... 12
Page 49 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
3
1 Introduction
1.1 Background
Patients attending the Emergency Department often undergo simultaneous testing for both cardiac and
non-cardiac conditions to facilitate early diagnosis or discharge (Yiadom et al., 2015). Cardiac
troponin is integral to the diagnosis of myocardial infarction (Mills et al., 2011), and testing is used
widely in the Emergency Department although approach to testing varies between region, country and
health care system (Melanson et al., 2008, Jairam et al., 2011, Yiadom et al., 2015). In a
representative sample of patients attending the Emergency Department in the USA, cardiac troponin
was measured in one in five and over half of those patients who were hospitalised. Moreover, a third
of patients did not have any cardiac symptoms (Makam and Nguyen, 2015). Myocardial injury,
defined as an elevation in cardiac troponin concentration in the absence of myocardial ischemia, is
common in many cardiac and non-cardiac conditions and increasingly recognised using high-
sensitivity cardiac troponin assays (Shah et al., 2015c, Newby et al., 2012). Here cardiac troponin
testing may contribute to diagnostic uncertainty, particularly in those regions where testing is
performed without prior clinical assessment (Melanson et al., 2008, Makam and Nguyen, 2015).
Across three prospective cohorts of patients attending the Emergency Department with and without
suspected acute coronary syndrome, we evaluate the impact of clinical assessment and patient
selection for cardiac troponin testing on the diagnosis of myocardial infarction.
This analysis will include patients with suspected acute coronary syndrome recruited to all sites in
NHS Lothian during the validation phase of the High-Sensitivity Troponin in the Evaluation of
patients with Acute Coronary Syndrome (HighSTEACS) randomised clinical trial (n=5,815)
(clinicaltrials.gov: NCT01852123). The High-STEACS study is a stepped-wedge cluster randomised
controlled trial divided into validation and implementation phases across ten centres in Scotland. The
ARCHITECT STAT high-sensitivity troponin I assay will be run in parallel with the existing
contemporary sensitive troponin I assay (standard care) throughout the validation phase. Only the
results from the contemporary assay are used for clinical decision-making during the validation phase
Page 50 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
4
and the diagnostic threshold for myocardial infarction will remain unchanged. This phase will provide
baseline information on patients with suspected acute coronary syndrome for each site. Centres will
then be randomised 1:1 to early or late implementation of the high-sensitivity assay. In the
implementation phase, all centres will implement the high-sensitivity assay for at least 6 months.
An independent unselected cohort, we identified all consecutive patients (n=1,054) presenting to the
Emergency Department at the Royal Infirmary of Edinburgh, Scotland in whom the attending
clinician performed blood sampling irrespective of their clinical presentation.
1.2 Study objectives
To evaluate the impact of clinical assessment and patient selection for high-sensitivity cardiac
troponin testing in the Emergency Department on the diagnosis of myocardial infarction.
1.2.1 Hypothesis
Clinical assessment to guide the selection of patients for high-sensitivity cardiac troponin testing will
improve the positive predictive value for a diagnosis of myocardial infarction compared to an
unselected approach to testing in the Emergency Department.
Page 51 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
5
2 Statistical analysis plan
2.1.1 Objectives
The objective of this SAP is to describe the statistical analyses contributing to the final report and
primary publication(s) of the analyses described below.
2.1.2 General Statistical Principles
Baseline data will be summarised as proportions for categorical data. Parametric and non-parametric
continuous data will be presented as mean and standard deviations or median and interquartile range
respectively.
2.1.3 Analysis population
2.1.3.1 Unselected emergency department cohort
The unselected Emergency Department cohort will consist of consecutive patients presenting to the
Emergency Department at the Royal Infirmary of Edinburgh, Scotland in whom the attending
clinician has performed blood sampling irrespective of their clinical presentation. Excess serum stored
will be used to measure high-sensitivity cardiac troponin I. The results will not be used to guide
clinical care and requests for cardiac troponin for clinical use will remain at the discretion of the
attending clinician. To ensure confidence in our estimates of the prevalence of type 1 myocardial
infarction in the unselected cohort, we determined that at least 1,000 patients would be required to
estimate a prevalence of 2.5% with an upper 95% confidence limit of less than 5% at greater than
90% power with an α of 0.05.
Page 52 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
6
2.1.3.2 Suspected acute coronary syndrome
Approximately 6,000 patients with suspected acute coronary syndrome will be included from two
cohorts across three centres as previously described (Shah et al., 2015b, Shah et al., 2015a). In all of
these patients troponin was measured using both the contemporary sensitive and high-sensitivity
troponin I assay. Only the contemporary assay results were used for clinical decision-making.
2.1.3.3 Adjudication of diagnosis
The diagnosis of each patient was adjudicated using the high-sensitivity troponin assay. Where serial
samples were available, we used peak and change in troponin concentration. Two independent
cardiologists reviewed all clinical information, including non-invasive and invasive investigations,
and outcomes from admission to 30-days. Patients were classified as having type 1 myocardial
infarction, type 2 myocardial infarction or myocardial injury.
2.1.4 Software
Analyses will be performed in R (Vienna, Austria).
Page 53 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
7
3 List of analyses
3.1 Baseline Characteristics
Summary statistics will be provided for the baseline characteristics for both the Emergency
Department cohort and suspected acute coronary syndrome cohorts. The following variables where
available will be reported:
• Age (years) – mean(standard deviation)
• Sex (male/female) n(%)
• Cardiovascular risk factors (smoking status, hypertension, hyperlipidaemia, diabetes mellitus)
n(%)
• Past medical history (ischaemic heart disease, stroke, previous coronary revascularisation)
n(%)
• Medical therapy on admission (dichotomous) n(%)
o Aspirin
o Clopidogrel
o Beta blocker
o Angiotensin converting enzyme (ACE) inhibitor / angiotensin receptor blocker
(ARB)
o Statin
• 12-lead electrocardiogram n(%)
o ST elevation (yes/no)
o ST depression (yes/no)
o T wave inversion (yes/no)
Patients prospectively recruited into the Emergency Department cohort will be divided into five
groups a priori; those patients with cardiac troponin concentrations >99th centile upper reference limit
(men >34 ng/L and women >16 ng/L) (group 5) and the remaining patients separated into four equal
Page 54 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
8
quartiles (group 1-4). Continuous variables will be compared using parametric and non-parametric
tests as appropriate. Categorical variables will be compared using the chi-square or fisher’s exact test
where appropriate.
Page 55 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
9
3.2 Primary outcome
3.2.1 Event summary
The following primary analyses will be presented:
• Predicted positive predictive value for a range of pre-test probabilities from 1% to 50%
• Impact of clinical features and bedside investigations on the positive predictive value in
patients with suspected acute coronary syndrome.
Positive predictive value refers to the post-test probability of a diagnosis of type 1 myocardial
infarction in patients with any cardiac troponin concentration above the 99th centile sex-specific upper
reference limit.
3.2.2 Primary analysis
3.2.2.1 Impact of pre-test probability on the diagnosis of myocardial infarction
Using the unselected Emergency Department cohort, we will calculate the sensitivity, specificities and
positive predictive values for a range of pre-test probabilities, including that observed in this cohort.
Using the unselected Emergency Department cohort we will calculate the observed prevalence of type
1 myocardial. We sampled from a Beta distribution in R (10,000 iterations) in order to estimate
confidence intervals for all proportions, using a Jeffrey’s prior (both shape parameters = 0.5), as this
approach allows us to straightforwardly estimate the positive predictive values for different a priori
values, and this approach also has excellent frequentist properties.
3.2.2.2 Impact of clinical features and baseline investigations in patients with suspected acute
coronary syndrome on the diagnosis of myocardial infarction
Using the same method as in the unselected Emergency Department cohort, in the two cohorts of
consecutive patients with suspected acute coronary syndrome we will calculate the observed positive
Page 56 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
10
predictive value and the 95% confidence interval with both cohorts combined. We will then calculate
the observed positive predictive value across pre-specified groups stratified by age, presenting
symptoms, risk factors, presence of ischemia on ECG and known ischemic heart disease.
3.2.3 Secondary analysis
3.2.3.1 Prevalence and determinants of myocardial injury in the Emergency Department
In patients recruited to the Emergency Department cohort we will calculate the prevalence of
myocardial injury (troponin concentrations >99th centile upper reference limit) across the whole
population and stratified by pre-specified groups including age, sex, known ischemic heart disease,
renal function and number of comorbidities (hypertension, ischemic heart disease, peripheral vascular
disease, diabetes mellitus or cerebrovascular disease).
We will develop logistic regression models to explore clinical factors associated with myocardial
injury (defined as cardiac troponin above the 99th centile upper reference limit). We will sequentially
adjust for age, sex, renal function, comorbidity and the National Early Warning Score (NEWS). The
NEWS score will be calculated for patients incorporating six simple physiological parameters (pulse
rate, blood pressure, temperature, oxygen saturations, level of consciousness and respiratory rate
measured at admission.
3.2.3.2 Association of cardiac troponin levels at presentation and mortality in the unselected
Emergency Department
All patients recruited in the Emergency Department cohort will be followed up for death from any
cause using regional and national registries including the General Register of Scotland (Ford et al.,
2007). This method allowed capture of all in-hospital and community deaths ensuring complete
follow-up. Occurrence of death will be modeled using a Cox proportional hazards regression model
Page 57 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
11
with troponin (natural log) as the explanatory variable both as a single parameter and after adjusting
for age, sex, renal function and NEWS score. We will examine the linearity of the association
between troponin concentration and risk of death using penalized splines .
Page 58 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review O
nly
12
4 References
FORD, I., MURRAY, H., PACKARD, C. J., SHEPHERD, J., MACFARLANE, P. W. & COBBE, S.
M. 2007. Long-term follow-up of the West of Scotland Coronary Prevention Study. The New
England Journal Of Medicine, 357, 1477-86.
JAIRAM, S., JONES, P., SAMARAIE, L., CHATALINE, A., DAVIDSON, J. & STEWART, R.
2011. Clinical diagnosis and outcomes for Troponin T 'positive' patients assessed by a high
sensitivity compared with a 4th generation assay. Emerg Med Australas, 23, 490-501.
MAKAM, A. N. & NGUYEN, O. K. 2015. Use of cardiac biomarker testing in the emergency
department. JAMA Intern Med, 175, 67-75.
MELANSON, S. E., CONRAD, M. J., MOSAMMAPARAST, N. & JAROLIM, P. 2008.
Implementation of a highly sensitive cardiac troponin I assay: test volumes, positivity rates
and interpretation of results. Clin Chim Acta, 395, 57-61.
MILLS, N. L., CHURCHHOUSE, A. M., LEE, K. K., ANAND, A., GAMBLE, D., SHAH, A. S.,
PATERSON, E., MACLEOD, M., GRAHAM, C., WALKER, S., DENVIR, M. A., FOX, K.
A. & NEWBY, D. E. 2011. Implementation of a sensitive troponin I assay and risk of
recurrent myocardial infarction and death in patients with suspected acute coronary
syndrome. JAMA : the journal of the American Medical Association, 305, 1210-6.
NEWBY, L. K., JESSE, R. L., BABB, J. D., CHRISTENSON, R. H., DE FER, T. M., DIAMOND,
G. A., FESMIRE, F. M., GERACI, S. A., GERSH, B. J., LARSEN, G. C., KAUL, S.,
MCKAY, C. R., PHILIPPIDES, G. J. & WEINTRAUB, W. S. 2012. ACCF 2012 expert
consensus document on practical clinical considerations in the interpretation of troponin
elevations: a report of the American College of Cardiology Foundation task force on Clinical
Expert Consensus Documents. Journal Of The American College Of Cardiology, 60, 2427-63.
SHAH, A. S., ANAND, A., SANDOVAL, Y., LEE, K. K., SMITH, S. W., ADAMSON, P. D.,
CHAPMAN, A. R., LANGDON, T., SANDEMAN, D., VASWANI, A., STRACHAN, F. E.,
FERRY, A., STIRZAKER, A. G., REID, A., GRAY, A. J., COLLINSON, P. O.,
MCALLISTER, D. A., APPLE, F. S., NEWBY, D. E., MILLS, N. L. & HIGH, S. I. 2015a.
High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary
syndrome: a cohort study. Lancet, 386, 2481-8.
SHAH, A. S., GRIFFITHS, M., LEE, K. K., MCALLISTER, D. A., HUNTER, A. L., FERRY, A. V.,
CRUIKSHANK, A., REID, A., STODDART, M., STRACHAN, F., WALKER, S.,
COLLINSON, P. O., APPLE, F. S., GRAY, A. J., FOX, K. A., NEWBY, D. E. & MILLS, N.
L. 2015b. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction
in women: prospective cohort study. BMJ, 350, g7873.
SHAH, A. S., MCALLISTER, D. A., MILLS, R., LEE, K. K., CHURCHHOUSE, A. M., FLEMING,
K. M., LAYDEN, E., ANAND, A., FERSIA, O., JOSHI, N. V., WALKER, S., JAFFE, A. S.,
FOX, K. A., NEWBY, D. E. & MILLS, N. L. 2015c. Sensitive troponin assay and the
classification of myocardial infarction. Am J Med, 128, 493-501 e3.
YIADOM, M. Y., JAROLIM, P., JENKINS, C., MELANSON, S. E., CONRAD, M. &
KOSOWSKY, J. M. 2015. Diagnostic implications of an elevated troponin in the emergency
department. Dis Markers, 2015, 157812.
Page 59 of 59
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960