High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome: A Randomized Controlled Trial
Phase: NA
Conditions: Acute Coronary Syndrome, Myocardial Infarction
Sponsor: University of Edinburgh

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High-sensitivity Troponin in the Evaluation of patients 
with Acute Coronary Syndrome (HighSTEACS):  
A randomised controlled trial 
 
 
Chief Investigator: 
Prof Nicholas L Mills 
 
 
On behalf of the High-STEACS Trial Investigators  
 
 
 
Funders: 
 
 
 
British Heart Foundation 
 
 
 
 
 
Abbott Diagnostics 
 
 
 
 
Sponsor: 
 
 
 
University of Edinburgh  
NHS Lothian Health Board  
 
ClinicalTrials.gov Identifier:  
NCT01852123 
 
REC Number:  
 
 
12/SS/0115 
 
Trial Start Date: 
 
 
10 June 2013 
Trial Finish Date: 
 
 
02 March 2018 
Trial Report Date: 
 
 
02 September 2018 
  
Correspondence Address and Main Centre: 
 
Professor Nicholas L Mills  
Room SU225, Chancellor's Building, University of Edinburgh, Royal Infirmary, Little 
France, Edinburgh, EH16 4SB, UK. 
Tel: +44 (0) 131 242 6517 
Fax: +44 (0) 131 242 6379 Email:  
nick.mills@ed.ac.uk  

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COORDINATING CENTRE 
Chief Investigator 
Prof Nicholas L Mills 
Room SU225, Chancellor's Building, 
University of Edinburgh, Royal 
Infirmary, Little France, Edinburgh, 
EH16 4SB, UK. 
Tel: +44 (0) 131 242 6517 
Fax: +44 (0) 131 242 6379 
Email: nick.mills@ed.ac.uk  
Co-Sponsor Representative 
Marise Bucukoglu 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Tel: 0131 242 9262 
Fax: 0131 242 9447 
Email: marise.bucukoglu@ed.ac.uk  
Trial Manager 
Chris Tuck 
Edinburgh Clinical Trials Unit, 
University of Edinburgh 
Level 2, Nine Edinburgh Bioquarter, 
Edinburgh, EH16 4UX  
Tel: +44 (0) 131 651 9907 
Email: chris.tuck@ed.ac.uk  
Trial Statistician 
Prof Christopher Weir  
Edinburgh Clinical Trials Unit, 
University of Edinburgh 
Level 2, Nine Edinburgh Bioquarter, 
Edinburgh, EH16 4UX   
Tel: +44 (0) 131 651 9957 
Email: christopher.weir@ed.ac.uk 
 

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PARTICIPATING SITES 
NHS Lothian  
(Royal Infirmary of Edinburgh, 
Western General Hospital, St John’s 
Hospital) 
Principal Investigator 
Prof Nicholas L Mills 
Room SU225, Chancellor's Building, 
University of Edinburgh, Royal 
Infirmary, Little France, Edinburgh, 
EH16 4SB, UK. 
Tel: +44 (0) 131 242 6517 
Fax: +44 (0) 131 242 6379 
Email:  nick.mills@ed.ac.uk  
NHS Greater Glasgow and Clyde 
(Glasgow Royal Infirmary, Western 
Infirmary and Gartnavel General 
Hospital, Southern General Hospital, 
Victoria Infirmary, Paisley Alexandra 
Hospital, Inverclyde Royal Hospital, 
Vale of Leven General Hospital)               
Principal Investigator 
Professor Colin Berry 
Department of Cardiology, Western 
Infirmary, G11 6NT 
Tel: +44 (0) 141 211 2000 
Email: colin.berry@glasgow.ac.uk  
Sub study 1 RIE & WGH 
Prof Nicholas L Mills 
Room SU225, Chancellor's Building, 
University of Edinburgh, Royal 
Infirmary, Little France, Edinburgh, 
EH16 4SB, UK. 
Tel: +44 (0) 131 242 6517 
Fax: +44 (0) 131 242 6379 
Email:  nick.mills@ed.ac.uk 
Sub study 1 RAH 
Dr Iain Findlay 
Department of Cardiology, Royal 
Alexandra Hospital, PA 
Tel: 
Email: iain.findlay@ggc.scot.nhs.uk 
 
Sub study 2 & 3 RIE 
Prof Nicholas L Mills 
Room SU225, Chancellor's Building, 
University of Edinburgh, Royal 
Infirmary, Little France, Edinburgh, 
EH16 4SB, UK. 
Tel: +44 (0) 131 242 6517 
Fax: +44 (0) 131 242 6379 
Email:  nick.mills@ed.ac.uk 
Sub study 1 GRI 
Dr Donogh Maguire 
Emergency Department, Glasgow Royal 
Infirmary, 84 Castle Street, Glasgow,  
G4 0ET 
Tel: 0141 211 4000 
Email: donogh.maguire@ggc.scot.nhs.uk 
 
 

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Contents: 
 
 
Section 
 
Pages 
 
1. 
 
2. 
 
3. 
 
4. 
 
5. 
 
6. 
 
7. 
 
8. 
 
9. 
 
10. 
 
11. 
 
12. 
 
13. 
 
Protocol Approval 
 
Investigator Statement 
 
Summary 
 
Background 
 
Study Objectives 
 
Trial Design 
 
Data Analysis and Statistical Considerations 
    
Expected Results 
 
 Safety Reporting 
 
Study Monitoring 
    
Ethical and Regulatory Issues 
 
References 
 
Appendices 
  
 
5 
 
6 
 
7 
 
8 
 
14 
 
15 
 
21 
 
27 
 
28 
 
29 
 
30 
 
31 
 
33 
 

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1 
Protocol Approval 
 
High-sensitivity Troponin in the Evaluation of patients with Acute Coronary 
Syndrome (HighSTEACS): A randomised controlled trial 
 
Signatures 
 
Prof Nicholas Mills 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Prof Christopher Weir 
 
 
 
Trial Statistician 
Signature 
 
Date 
 
 
 
 
 

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2 
Investigator Statement 
 
High-sensitivity Troponin in the Evaluation of patients with Acute Coronary 
Syndrome (HighSTEACS): A randomised controlled trial 
 
 
I agree to conduct the study according to this protocol, the principles of 
International Conference on Harmonisation Tripartite Guidelines for Good 
Clinical Practice (ICH GCP) and the applicable regulatory requirements.  Any 
changes in procedure will only be made if necessary to protect the safety, rights or 
welfare of the patients. 
 
I agree to take responsibility for the conduct of the study and ensure that all other 
staff involved are adequately informed about the protocol and amendments and 
their study related duties and functions. 
 
 
Signatures 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
 
 
 
 
Name of Investigator (please print) 
 
 
 
 
 
 
 
 

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Summary 
 
We have recently demonstrated that lowering the diagnostic threshold for troponin is 
associated with a halving in the rate of recurrent myocardial infarction and death in 
patients redefined with myocardial infarction. We here propose to determine whether 
further lowering the diagnostic threshold for myocardial infarction using a novel high-
sensitivity cardiac troponin assay will continue to improve outcomes in patients with 
suspected acute coronary syndromes. If increased sensitivity does not impinge on the 
specificity of the diagnosis of myocardial infarction, then these assays will improve 
patient outcome through better targeting of therapies for coronary heart disease. 
However, if increased sensitivity leads to poor specificity, then patients may be 
misdiagnosed and given inappropriate cardiac medications with potentially detrimental 
outcomes. In 10 secondary and tertiary care hospitals across Scotland, we will 
undertake a cluster randomised controlled trial of the implementation of a novel high-
sensitivity troponin assay in approximately 15,000 patients presenting with suspected 
acute coronary syndromes. The primary end-point will be the one-year rate of death or 
recurrent myocardial infarction. This will establish whether the introduction of high-
sensitivity assays into routine clinical practice is detrimental or beneficial to patient 
management and outcome; a fundamental and critical assessment for the modern 
definition of acute myocardial infarction.  

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Background 
 
Coronary heart disease is the commonest cause of death in the United Kingdom. There 
are 124,000 patients admitted with acute myocardial infarction per annum in the UK, 
and despite significant improvements in the management of coronary disease over the 
last 20 years, the 30-day mortality remains unacceptably high.  
The risks associated with myocardial infarction lead to large numbers of patients self-
presenting or being referred by primary care to the Emergency Department with 
undifferentiated chest pain of suspected cardiac origin. These patients are responsible 
for 5 per cent of all presentations to the Emergency Department and 40 per cent of 
unplanned hospital admissions [Goodacre et al., 2005]. This therefore represents a 
major burden on scarce health care resource. Approaches to improve the accurate 
identification of patients with acute myocardial infarction would therefore be welcome 
and potentially of major benefit to patients and the NHS. 
Definition of myocardial infarction 
Myocardial infarction has, for many years, been defined by the clinical history, 
electrocardiogram and a rise in serum creatine kinase as evidence of myocardial 
necrosis. Recent improvements in the sensitivity of assays to detect myocardial necrosis 
required a more precise definition. The Global Task Force for the Universal Definition 
of Myocardial Infarction and the National Academy of Clinical Biochemistry now 
recommend that any detectable increase in cardiac troponin above the 99th percentile of 
a healthy reference population should be used to diagnose myocardial infarction 
[Thygesen et al., 2007; Morrow et al., 2007]. This statement was based on expert 
consensus rather than evidence from randomised controlled trials and the guidelines 
have not been universally adopted. The diagnostic threshold recommended by the 
Global Task Force has been implemented in fewer than 1 in 3 hospitals in Europe 
[Collinson et al., 2011a] and none in North America where the Food and Drug 
Administration have yet to approve the use of high-sensitivity troponin assays. 
The use of out dated diagnostic thresholds for troponin continues to be widespread and 
lowering this threshold remains a highly contentious issue in clinical practice [Mills et 
al., 2011c; Bauer et al., 2009]. Progressively lowering the threshold of plasma troponin 
concentration in order to define increasing numbers of patients with myocardial 
infarction may not be appropriate because of the potential to reduce specificity and 
increase false positive diagnoses of myocardial infarction, with raised troponin levels 
occurring in a range of common presentations including septicaemia, pulmonary 
embolism, and cardiac and renal failure [McFalls et al., 2011]. This could lead to an 
increase in unnecessary hospital admissions, misplaced investigations and treatment, 
and may be detrimental to patient care. 
 
The Global Task Force addressed the potential for more sensitive troponin assays to 
reduce clinical specificity by proposing a classification system for myocardial 
infarction based on the aetiology of myocardial necrosis [Thygesen et al., 2007]. Type 
I myocardial infarction is defined as a spontaneous myocardial infarction with ischemia 
due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or 
dissection. Type II myocardial infarction is defined as myocardial ischemia secondary 
to either increased oxygen demand or decreased supply (e.g. coronary artery spasm, 
coronary 
embolism, 
anaemia, 
arrhythmia, 
hypertension 
or 
hypotension). 

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Differentiating between primary and secondary causes of myocardial injury is not 
straightforward and therefore this classification system has not been adopted in clinical 
practice.  
Implementation of a contemporary sensitive troponin assay in NHS Lothian 
Following improvements in assay performance, we replaced our conventional troponin 
assay with a contemporary sensitive troponin assay. The validation and subsequent 
implementation of the ARCHITECT STAT troponin I assay provided us with an 
opportunity to assess the impact of a more sensitive assay on the management and 
clinical outcome of patients with suspected acute coronary syndrome [Mills et al., 
2011a].  
Sensitive troponin assays improve clinical outcomes 
In our cohort of 2,092 patients, lowering the diagnostic threshold from 200 to 50 ng/L 
with the ARCHITECT STAT troponin I assay increased the incidence of myocardial 
infarction by 29%. During the validation phase of this study only values at or above the 
diagnostic threshold of 200 ng/L from the previous generation of assay were reported 
to clinicians. Perhaps surprisingly patients with troponin concentrations greater than 
200 ng/L had better clinical outcomes than those with small undisclosed increases in 
plasma troponin concentrations of 50-200 ng/L. These latter patients were 2-3 times 
more likely to have an adverse outcome in comparison to those with more marked 
elevation in troponin.  
Implementation of the sensitive assay and lowering the diagnostic threshold to 50 ng/L 
was associated with a more than halving of death and recurrent myocardial infarction 
in patients who would otherwise not have been classified as having sustained an acute 
myocardial infarction. In this group of patients improvements in clinical outcome were 
associated with more referrals to a cardiologist (74% versus 44%), and greater use of 
dual anti-platelet therapy (58% versus 27%) and coronary angiography (46% versus 
20%)(P<0.001 for all). To our knowledge, this is the first time that the introduction of 
a new assay into clinical practice has changed management and reduced cardiovascular 
mortality. Whilst important, these observations were derived from a single tertiary 
centre using a troponin assay that is not able to achieve the necessary precision to use 
the 99th percentile of a normal reference population as the diagnostic threshold.  
Lowering the threshold for diagnosis of myocardial infarction 
The Global Task Force for the Universal Definition of Myocardial Infarction and the 
National Academy of Clinical Biochemistry recommends the 99th percentile as the 
diagnostic threshold where assay precision can be demonstrated with a coefficient of 
variation (CV) of ≤10% at this concentration. Whilst the ARCHITECT STAT troponin 
I assay was clearly superior to our previous conventional troponin assay it was unable 
to meet these precision criteria and therefore we selected a diagnostic threshold above 
the 99th percentile where the CV is ≤10% in order to minimise the risk of false positive 
results and making an inappropriate diagnosis of myocardial infarction.  
In exploratory analysis from the same cohort, we assessed the relationship between 
troponin concentration, assay precision and clinical outcome [Mills et al., 2011b; under 
revision]. We demonstrate that patients with troponin concentrations above the 99th 
percentile (12 ng/L according to manufacturer), but below our revised diagnostic 
threshold (50 ng/L), were more likely to be dead or readmitted with recurrent 
myocardial infarction compared to those with troponin concentrations in the normal 
range of <12 ng/L (13% versus 3%, adjusted OR 2.3, 95% CI 1.3-4.0, P=0.004; Figure 
1). Although patients with troponin concentration 12 to 49 ng/L were older and more 

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likely to have established ischaemic heart disease or cardiovascular risk factors than 
those patients with a troponin concentration in the normal reference range, plasma 
troponin concentration remained an independent predictor of clinical outcome even 
after adjustment for these clinical characteristics and despite reduced assay precision 
below the diagnostic threshold (CV up to 28.9%). Our findings are consistent with 
recent studies of patients with acute coronary syndrome participating in randomized 
clinical trials where troponin concentrations above the 99th percentile measured from 
stored sample were associated with poorer outcomes [Eggers et al., 2009; Lindahl et 
al., 2010]. Importantly, our study population comprised consecutive “real-world” 
patients admitted with suspected cardiac chest pain rather than a homogeneous group 
of patients with a clinical diagnosis of acute coronary syndrome on optimal therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lowering the diagnostic threshold to the 99th percentile will identify more patients at 
risk of recurrent events, but would potentially increase the number of patients diagnosed 
with myocardial infarction by a further 46% from 752 to 1,104 of 2,092 patients 
admitted with suspected acute coronary syndrome. This will have major implications 
for health care resources, public health targets, government statistics, and on the 
employment prospects and insurance policies of our patients. Will lowering the 
threshold further and reclassification of patients with suspected acute coronary 
syndrome as myocardial infarction alter clinical outcome? 
In our original study patients admitted during the validation phase of our contemporary 
sensitive assay with an undisclosed troponin concentration of 50 to 200 ng/L had a high 
event rate of 39% at one year [Mills et al., 2011a]. In comparison patients with 
undisclosed troponin concentrations 12 to 50 ng/L are at lower risk with a one-year 
event rate of 13%. Therefore there may be less to gain from the reclassification and 
treatment of these patients for myocardial infarction. Additional discussion on this point 
is included in the attached manuscript under revision. The need for prospective 
randomised controlled trials to determine whether the use of high-sensitivity troponin 
assays with greater analytical precision at the 99th percentile will translate into 
improvements in clinical outcomes was highlighted by authorities in the field including 
the Editor of Heart, Dr Adam Timmis, during the open peer review of this manuscript.  
Figure 1: Association between cardiac 
troponin concentration and odds of death 
or recurrent myocardial infarction relative 
to odds at the mean troponin (9 ng/L, black 
line) among patients with troponin 
concentrations below the diagnostic 
threshold of 50 ng/L (red line). The 99th 
percentile for a healthy reference population 
is 12 ng/L (blue line). Estimates were 
obtained from a generalized additive model 
using a cubic smoothing spline (df=3, 
P=0.005 for non-linearity). A rug plot 
illustrates the density of the data for given 
value of troponin. 
  
Troponin I (ng/mL)
Odds Ratio for death or recurrent myocardial infarction 
0.00
0.01
0.02
0.03
0.04
0.05
0.5
1
2
4
8
16
mean troponin
99th percentile
10% CV
Troponin I concentration, ng/L 
0 
10 
30 
40 
50 
20 

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Additional studies have further shown the benefits of serial changes in high sensitive 
troponin and early diagnosis of myocardial infarction [Keller et al 2011c] providing 
further evidence of the role of troponin in accurate and rapid assessment of patients 
with acute coronary syndrome and possibly facilitating rapid discharge. 
Impact of sensitive troponin assays on clinical specificity 
Many clinicians are concerned that the use of progressively lower diagnostic thresholds 
will result in patients being misdiagnosed with myocardial infarction and that small 
troponin elevations will also be caused by other pathologies. This may lead to 
inappropriate hospital admission, misdiagnosis, initiation of potentially detrimental 
therapies and poorer clinical outcomes for patients.  
In a further analysis of patients admitted during the validation and implementation of 
our contemporary sensitive troponin I assay we identified consecutive patients in whom 
peak troponin concentrations were between 50 to 200 ng/L irrespective of presenting 
symptom (manuscript in preparation). Two independent cardiologists reviewed all 
patient records and classified patients according to the universal definition of 
myocardial infarction as type 1 (primary myocardial ischemia) or type 2 (secondary 
myocardial ischemia). Disagreements were resolved following in-depth case note and 
source file review until a consensus was achieved. We identified 922 patients with peak 
cardiac troponin concentrations between 50 to 200 ng/L during the 6-month validation 
(n=525; reported as troponin ‘negative’) and implementation phases (n=397; reported 
as troponin ‘positive’). These patients were classified as having type 1 myocardial 
infarction in 28% (n=275) and type 2 myocardial infarction in 72% (n=666). So for 
every patient with a spontaneous type 1 myocardial infarction identified using a 
sensitive troponin assay we identified nearly three patients with secondary myocardial 
ischemia and a clear alternative clinical diagnosis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interestingly although patients with type 2 myocardial infarction had worse clinical 
outcomes compared to patients with type 1 myocardial infarction (Figure 2), this was 
primarily driven by death (28%) rather than recurrent myocardial infarction (6%). 
Following implementation of the sensitive assay, referrals to cardiology increased in 
patients with type 2 myocardial infarction (19% to 34%, P<0.001) as did requests for 
Figure 2. Survival free from death 
or recurrent myocardial infarction 
in patients with type 1 and type 2 
myocardial infarction. Patients 
with undisclosed increases in 
cardiac troponin with type 1 or type 
2 myocardial infarction had similar 
clinical outcomes during the 
validation period. Following 
implementation of the sensitive 
assay death and recurrent 
myocardial infarction was reduced 
in patients with type 1 myocardial 
infarction (31% vs 17%, P=0.009), 
but did not change in patients with 
type 2 myocardial infarction (36% 
vs 29%, P=0.09).  
 

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cardiac echocardiography (12% to 23%, P<0.001) and the use of coronary angiography 
(1% to 6%, P<0.001). Despite more extensive investigation in patients with type 2 
myocardial infarction, clinical outcomes (recurrent myocardial infarction and all cause 
mortality) were similar whether they were managed as troponin ‘negative’ during the 
validation phase or troponin ‘positive’ following implementation. Reduced clinical 
specificity for primary myocardial infarction will be an even greater challenge with the 
next generation of high-sensitivity troponin assays and even lower diagnostic 
thresholds. As such, prospective studies with a formal assessment of cost-effectiveness 
are essential.  
Conventional, contemporary sensitive, high-sensitivity and ultra-sensitive cardiac 
troponin assays 
The use of conventional troponin assays lead to patients being classified as troponin 
‘negative’ or ‘positive’ with clear therapeutic options, but assay imprecision required 
higher diagnostic thresholds with an increased risk of clinically important false negative 
results. The current generation of contemporary sensitive troponin assays improve the 
early diagnosis of myocardial infarction [Reichlin et al., 2009; Keller et al., 2009] and 
clinical outcome in patients with suspected acute coronary syndrome [Mills et al., 
2011b]. Indeed in a recent randomised controlled trial of point-of-care testing in the 
emergency room (RATPAC trial) troponin measured on admission was as effective as 
a multiple biomarker strategy or serial measurements to rule out acute myocardial 
infarction [Collinson et al., 2011b].  
At present few contemporary sensitive assays are able to achieve the recommended 
precision (co-efficient of variation <10%) to use the 99th percentile of a normal 
reference population as the diagnostic threshold in clinical practice. There is only one 
commercially available high-sensitivity assay troponin assay (high-sensitivity troponin 
T assay; Roche Diagnostics, Basel, Switzerland) that has been approved for clinical use 
in Europe. This assay has greater analytical sensitivity than contemporary sensitive 
assays and is able to detect cardiac troponin at lower concentrations such that troponin 
is measureable in about 50% of apparently healthy persons [Keller et al., 2011]. 
However, the high-sensitivity troponin T assay appears to have similar sensitivity and 
specificity for the diagnosis of acute myocardial infarction compared to current 
contemporary sensitive troponin I assays [Reichlin et al., 2009]. The latest development 
in assay technology involves magnetic nanoparticle-based immunoassays coupled with 
single-molecule counting and permits cardiac troponin to be accurately quantified in 
>98% of healthy persons at concentrations <1 ng/L [Sabatine et al., 2009]. These ultra 
sensitive assays are an interesting research tool, but the platform does not permit the 
rapid throughput necessary to make clinical decisions in the emergency department.  
 
ARCHITECT STAT high-sensitive troponin I assay 
The prototype ARCHITECT STAT high-sensitive troponin I assay (Abbott Diagnostics) 
is a two-step assay that offers increased precision for measuring very low plasma 
troponin concentrations and can quantify troponin concentrations in 98% of healthy 
persons (personal communication, Dr Fred Apple) with a limit of detection of 1 ng/L 
and 10% co-efficient of variation <5.5 ng/L [Matias et al., 2010]. Using this assay the 
mean±standard deviation concentration of a healthy reference population is 1.6±3.1 
ng/L with the 99th percentile of 16 ng/L. Whilst this prototype assay is likely to be 
marketed as a ‘high-sensitivity’ assay it is able to detect troponin across the complete 
reference range of a healthy population with sensitivity comparable to the leading ultra-

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sensitive research assay [Sabatine et al., 2009]. This assay therefore has the sensitivity 
and precision to report absolute measurements of troponin and a normal reference 
range, rather than an arbitrary threshold based on limited assay performance. Critically 
it can be delivered within 60 minutes of sample collection using the existing 
ARCHITECT platform, which is already used by more than fifty NHS hospitals across 
the United Kingdom and in all of the participating centres in the proposed trial.  
High-sensitivity cardiac troponin and the early rule out of myocardial infarction 
Until recently NICE guidelines have recommended measuring cardiac troponin on 
presentation and 10-12 hours after the onset of symptoms to coincide with the peak in 
circulating troponin concentration (Skinner et al., 2010). This allows the assessment of 
infarct size, and will minimise the risk of missing a small myocardial infarct. However, 
it requires the majority of patients to be admitted to hospital for serial testing placing 
pressure on already overcrowded emergency departments and medical admissions 
units.  
 
Recently, NICE reviewed the available evidence comparing high-sensitivity cardiac 
troponin assays with standard troponin assays for the early rule out of myocardial 
infarction 
[NICE 
Diagnostic 
Guidance 
D15 
available 
at 
https://www.nice.org.uk/guidance/dg15]. They conclude that the use of high-sensitivity 
troponin on presentation and at 3 hours was both clinically effective and a cost-effective 
strategy compared to admission of patients for standard troponin testing at 10-12 hours, 
and recommended the use of high-sensitivity cardiac troponin assays in the National 
Health Service.  
 
A number of areas of uncertainty were identified. First, whilst most studies have shown 
that high-sensitivity cardiac troponin measured at 3 hours has good negative predictive 
value for myocardial infarction (Keller et al., 2011, Cullen et al., 2013, Reichlin et al., 
2012), these studies were based on retrospective analysis of small cohorts. Second, 
many studies selected low-risk patients and therefore the findings may not be 
generalizable across all patients presenting with suspected acute coronary syndrome 
(Cullen et al., 2013, Collinson et al., 2012a). Third, no study used the high-sensitivity 
assay as the reference standard, and therefore the adjudication of the diagnosis of 
myocardial infarction was based on peak troponin testing using a standard assay. This 
will overestimate both the sensitivity and negative predictive value of the high-
sensitivity assay measured at 3 hours (Shah et al., 2013). Finally, few studies have not 
been large enough to address important subgroups of patients, such as those who present 
early and within 3 hours of the onset of their symptoms. 
 
In view of these uncertainties, NICE diagnostic guidance recommended careful audit 
of patient outcomes following implementation of high-sensitivity assays and early rule 
out pathways.   
 
 
 
 
 
 
 
 
 

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5 
Study Objectives 
 
In both secondary and tertiary care hospitals across Scotland, we will undertake a 
stepped wedge cluster randomised controlled trial of the implementation of the 
ARCHITECT STAT high-sensitive troponin I assay. The main objective of this study 
is to determine whether identifying the 99th percentile of a normal reference population 
as the diagnostic threshold for myocardial infarction is appropriate in patients with 
suspected acute coronary syndrome. There is the potential for both major patient benefit 
as well as harm in this approach. If the increased sensitivity does not impinge on the 
specificity of the diagnosis of myocardial infarction, then the next generation of high-
sensitivity assays will confer large healthcare benefits and improve patient outcome 
through better targeting of therapies for coronary heart disease. However, if the 
increased sensitivity leads to poor specificity, then patients will be misdiagnosed with 
myocardial infarction, inappropriately given cardiac medications and potentially have 
adverse and detrimental outcomes. This may also lead to mismanagement of the patient 
due to a lack of recognition and treatment of the true underlying cause of their 
symptoms. 
In addition, there will be an exploratory objective to look at efficacy and safety of the 
implementation of the high-sensitive troponin I assay stratified by age, sex, diagnostic 
threshold (sex-specific, uniform), diagnostic classification (type 1-5 myocardial 
infarction, myocardial injury), and renal function. We will also examine the association 
between patient characteristics, clinical diagnoses and all primary and secondary 
outcomes in the study population using a variety of statistical (including Bayesian) and 
machine learning approaches. 
 
 
 
5.1 
Original Hypothesis 
 
Implementation of the ARCHITECT STAT high-sensitive troponin I assay will 
reduce myocardial infarction or death at one year in patients with suspected acute 
coronary syndrome. 
 
 
 

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6 
Trial Design 
 
 
Design: Prospective stepped wedge cluster randomised controlled trial  
There will be three equal 6-month study phases in the stepped wedge design: validation, 
randomisation, and implementation (see section 13). The ARCHITECT STAT high-
sensitive troponin I assay will be run in parallel with the existing contemporary 
sensitive troponin I assay (standard care) throughout the study. During the validation 
phase, 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. In the randomisation phase, participating centres will be 
randomised 1:1 to introduce the high-sensitivity assay or continue with the existing 
diagnostic thresholds (standard care). Centres will be matched by number of admissions 
and type of health care provider (secondary and tertiary care). Thereafter all centres will 
implement the high-sensitivity assay for at least 6 months.  
The stepped wedge design allows each participating centre to act as its own control and 
permits adjustment for seasonal differences in the incidence of acute myocardial 
infarction and temporal changes in clinical outcome due to advances in clinical practice. 
It is neither practical nor advantageous to randomise individual patients in this trial. 
The use of a cluster-randomised design permits the inclusion of all patients with 
suspected acute coronary syndrome, prevents selection bias and limits the potential for 
confusion amongst clinicians who would otherwise be required to simultaneously 
assess patients using different diagnostic criteria for acute myocardial infarction. We 
will also assess the appropriateness of sex-specific thresholds using the high-sensitivity 
assay prior to the start of the study. 
Following a recommendation from the trial steering committee the 6-month 
implementation phase will be extended for those sites randomised to early 
implementation until all sites have completed the study protocol. This will provide 
additional information on the impact of seasonality on the primary end-point.  
Setting: Multi-centre trial in 10 acute secondary and tertiary hospitals throughout 
Scotland (see Appendix). 
Primary end-point:  Event-free survival (myocardial infarction or cardiovascular 
death) at one year 
Secondary efficacy end-points:  
i) 
Duration of stay  
ii) Myocardial infarction  
iii) Unplanned coronary revascularisation  
iv) Cardiovascular death (any; cardiac; non-cardiac) 
v) All-cause death 
vi) Hospitalization for heart failure 
vii) Ischaemic stroke 
 
Secondary safety end-points: 
i) 
Major and minor haemorrhage  
ii) Recurrent hospitalization excluding acute coronary syndrome 
iii) Cardiovascular death excluding acute coronary syndrome 
iv) Non-cardiovascular death  

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An increase in the correct identification of patients with myocardial infarction is likely 
to lead to improved outcomes as we have demonstrated in our previous study [Mills et 
al, 2011a]. However, we will also need to monitor for an increase in false positive 
diagnoses of myocardial infarction. The two principal safety hazards of a misdiagnosis 
of myocardial infarction are likely to relate to excess bleeding events (especially during 
the index admission) and a failure to investigate and treat a potentially serious 
alternative diagnosis. These hazards will be captured by specifically looking for 
bleeding events, and recurrent hospitalizations or deaths due to conditions not 
attributable to index or recurrent myocardial infarctions. We plan to follow up the study 
population at 3 and 5 years to capture relevant efficacy and safety outcomes.   
 
Troponin assays:  
The ARCHITECT STAT high-sensitive troponin I assay will be compared with the 
previous generation ARCHITECT STAT assay that is currently used for routine clinical 
testing in each of the 10 participating centres. All participating centres currently report 
the lowest concentration where the assay coefficient of variation is ≤10% when assessed 
under local laboratory conditions in accordance with international guidelines [Thygesen 
et al, 2007].  
ARCHITECT STAT troponin I assay (standard care) 
Limit of detection 10 ng/L  
10% co-efficient of variation 42 ng/L (Greater Glasgow) and 50 ng/L (Lothian) 
Diagnostic threshold 42 ng/L (Greater Glasgow) and 50 ng/L (Lothian) 
ARCHITECT STAT high-sensitive troponin I assay  
Limit of detection 1 ng/L  
10% co-efficient of variation <5 ng/L 
Proposed diagnostic threshold 16 ng/L (99th percentile of healthy reference population) 
During the validation period both assays will be run in parallel and all sites will 
continue to report cardiac troponin using the standard assay and existing diagnostic 
thresholds. This period will permit the ARCHITECT STAT high-sensitive troponin I 
assay to be evaluated on each ARCHITECT platform within all of the participating 
centres. Analytical precision will be determined using a series of quality control 
standards and pooled serum.  
Prior to randomisation sensitivity and specificity for the diagnosis of myocardial 
infarction will be determined in the cohort of patients admitted to the Royal Infirmary 
Edinburgh and Western Infirmary Glasgow. Two independent cardiologists will review 
clinical data including troponin concentrations measured using the standard assay, 
whilst unaware of troponin concentrations from the high-sensitivity assay. Patients will 
be classified as acute myocardial infarction, unstable angina, cardiac chest pain due to 
non-coronary pathology (e.g. tachyarrhythmia), non-cardiac chest pain (clear 
alternative diagnosis), or symptoms of unknown origin. Disagreements will be resolved 
following in-depth case note and source file review and adjudicated by a third 
cardiologist. We will also explore whether high-sensitivity cardiac troponin is useful in 
the diagnosis or rule out of other conditions associated with myocardial injury (e.g. 
pulmonary embolism).  
For the high-sensitivity assay we will systematically evaluate the impact of the 
following variables on sensitivity and specificity: i) a sex-specific normal reference 
range and diagnostic thresholds [Apple et al., 2010], ii) absolute change in troponin 

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concentration (admission to 6 or 12 hours), iii) relative change in troponin concentration 
(admission to 6 or 12 hours) [Reichlin T et al., 2011]. The normal reference range and 
diagnostic threshold for the trial will be agreed across all sites prior to randomisation 
and sensitivity analysis (i-iii) will be used to guide clinical advice issued during the 
introduction of the high-sensitivity assay at each participating centre.  
Study population:  
At each participating centre, we will identify all patients with suspected acute coronary 
syndrome who have cardiac troponin I measured as part of their routine clinical 
assessment. The Community Health Index (CHI) number, date and time of sample, 
presence or absence of chest pain, and absolute troponin concentration will be extracted 
from the ARCHITECT database in each participating centre. All patients with a history 
of suspected acute coronary syndrome as recorded by the requesting clinician who have 
valid paired cardiac troponin I measurements on both the contemporary and high-
sensitivity assay during the index presentation will be allocated a unique study number 
and will comprise the study population. Patients who are not resident in Scotland will 
be excluded as follow-up via routinely collected sources will not capture the primary 
outcome for these individuals. Excess clinical samples that would otherwise be 
discarded (surplus) will be anonymously stored for future evaluation and audit of 
biomarkers. The results of these assays will not be used to alter clinical management. 
All samples will be anonymised and linked by a unique non identifiable ID. 
One of the major strengths of this approach is that we will identify all patients with 
suspected acute coronary syndrome, rather than limiting our findings to a selected group 
who may not be representative of the broad range of patients presenting to acute NHS 
hospitals. 
 
Data collection and record linkage: 
CHI is a population register containing details of all Scottish residents registered with 
a General Practitioner and will be used to link all data sources. The Scottish Morbidity 
Record (SMR) will be used to identify the discharge diagnosis of all study participants 
including whether patients were classified as having unstable angina (ICD-10 codes 
I20) or myocardial infarction (I21 and I22). These data are routinely collected by the 
Information Services Division (ISD) of NHS National Services Scotland and are 
considered some of the best health service data in the world combining high quality, 
consistency, national coverage and the ability to link data to allow individual patient-
based analysis and follow up. ISD Scotland data quality is assessed regularly with the 
accuracy and completeness of coding compared to source documents demonstrating 
that ICD-10 codes for coronary heart disease (I20-25) are 94.2% accurate and 99.2% 
complete.  
As in our previous studies [Mills et al, 2011a; Mills et al, 2011b], additional clinical 
information will be obtained through the TrakCare software application (InterSystems 
Corporation, Cambridge, MA, USA); an Electronic Patient Record (EPR) system used 
in Lothian for 6 years and in all participating centres prior to the start of the trial. 
Programmers at NHS Lothian and Edinburgh University will develop a standardised 
pro forma for the assessment of patients with chest pain to replace the current generic 
admission form that will be implemented across all participating sites. This pro forma 
will include data fields that the admitting or discharging clinician will be required to 
complete, with the majority of data fields populated from drop-down menus. The 
following data will be captured: time of onset of symptoms, time of hospitalisation, 

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patient demographics (e.g. age and sex, cardiovascular risk factors, medical therapy on 
admission), GRACE score, heart rate, blood pressure, management in the Emergency 
Department, referral to cardiology, and discharge location. Any change to medical 
therapy will be extracted from the patients’ standardised electronic discharge summary. 
12-lead electrocardiograms will be obtained from a digital archive, the MUSE 
Cardiology Information System (GE Healthcare Clinical Systems Ltd., Herts, UK) in 
all participating centres. Reports from diagnostic coronary angiography, percutaneous 
and surgical coronary revascularisation will be extracted from the TOMCAT database 
(Cardiovascular Information Management System, Philips, Amsterdam, Netherlands) 
in the tertiary centres for NHS Greater Glasgow & Clyde (Golden Jubilee National 
Hospital, NHS Golden Jubilee National Hospital) and NHS Lothian (Royal Infirmary 
of Edinburgh). The use of a dedicated admission pro forma and identical platforms 
(ARCHITECT, TrakCare, MUSE, TOMCAT) for routine data collection in all 
participating centres will ensure a high degree of standardisation across sites and 
minimise missing data.  
In the two largest tertiary centres in Scotland with excellent clinical research 
infrastructure (Royal Infirmary of Edinburgh and Western Infirmary of Glasgow) and 
the largest district general hospital (Royal Alexandra Hospital, Paisley), dedicated 
research nurses will validate routine data sources. Patients will be identified and 
located from the ARCHITECT platform on a daily basis. All patients with chest pain 
in whom troponin was measured on admission or 6-12 hours after symptom onset will 
be identified. Clinical characteristics, risk factors, investigations and management will 
be obtained from hospital records during the admission.  
Sub-study 1: Clinical- and cost-effectiveness of high-sensitivity troponins 
 
The costs of a high-sensitivity troponin assay are small and its introduction may reduce 
duration of stay, unnecessary diagnostic investigations, recurrent admissions, and 
deaths. In contrast, the more sensitive assay may reduce specificity and increase the use 
of unnecessary cardiac investigations and treatments. It is therefore essential that cost-
effectiveness analysis will measure the incremental cost per quality adjusted life year 
(QALY) gained using the high-sensitivity assay, compared to the standard assay. 
Patients admitted to the two largest tertiary centres in Scotland (Royal Infirmary of 
Edinburgh and Glasgow Royal Infirmary) and the largest district general hospital 
(Royal Alexandra Hospital, Paisley), will be asked to give consent for inclusion into a 
sub-study that will permit storage of plasma and serum and will require the completion 
of an EQ-5D health survey during the index admission and after 1 and 12 months of 
follow up.  
In consented patients, excess serum (surplus) from routine clinical blood sampling on 
admission and 6 or 12 hours will be frozen and stored. Additional blood samples will 
be obtained between admission and 6 hours post presentation (maximum of 40 mL 
sample volume on no more than four blood draws). Plasma and serum will be prepared 
and stored for future analysis to quantify troponin, novel biomarkers of myocardial 
ischemia and for further biochemical profiling. A whole blood sample will be obtained 
for DNA extraction and genotyping. Strategies for the diagnosis and rule out of 
myocardial infarction will be explored in the sub-study and validated across the main 
study population where possible. To explore issues around the certainty of diagnosis, 
we will ask clinicians and patients to rate their perception of whether their chest pain is 
due to myocardial infarction before the results of troponin tests are available. 

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Patients can be co-recruited into other studies and included in our study population. 
Clinicians and other researchers will be informed of recruitment to the High-STEACS 
sub-study through the electronic patient record systems. This will allow researchers to 
take into consideration any additional burden placed on the patient through co-
enrollment onto subsequent studies. 
In situations where individuals have capacity to consent, but are unable to read the 
patient information sheet (e.g. visual impairment) or are unable to write, consent will 
be witnessed by an independent person and witness signature obtained to confirm that 
all information about the study was conveyed and that the patient gave their consent 
to take part. 
 
Measurement of costs and outcomes:  
Within trial economic analysis of resource costs and health outcomes will be conducted 
on an intention-to-treat basis. Efficacy and safety outcomes will be determined via 
record linkage with the Scottish Morbidity Register by the Information Services 
Division (ISD) Scotland. Fatal and non-fatal primary and secondary end-points will be 
verified through source data and patient hospital records.  
Safety endpoints will be monitored throughout the main study and form part of routine 
reports. The Trial Management Team, the Trial Steering Committee (TSC) and the data 
monitoring committee (DMC) will oversee safety monitoring throughout the study. 
Death from a cardiovascular cause will be defined as death from all cardiovascular 
causes and any death without another known cause [Wallentin et al, 2009]. Myocardial 
infarction will be defined according to international guidelines when there is evidence 
of myocardial necrosis in a clinical setting consistent with myocardial ischemia 
[Thygesen et al, 2007]. In brief, a diagnosis of myocardial infarction will be made 
where a rise and fall of cardiac troponin above the diagnostic threshold (standard care 
= 10% CV; intervention = 99th percentile of a reference population) is demonstrated in 
the presence of symptoms of myocardial ischemia, ECG changes consistent with 
myocardial ischemia, and/or evidence of new loss of viable myocardium from cardiac 
imaging. Major and minor haemorrhage will be defined from linked data using criteria 
based on the American College of Cardiology Foundation/American Heart Association 
Task Force on Clinical Standards [ACCF/AHA Task force, 2013]. 
In the sub-set of consented patients, we will determine one-year cumulative costs of in-
patient investigation and management, and evaluate self-reported health at baseline and 
at 1 and 12 months of follow up using the EQ-5D health survey. Patients will complete 
the Seattle Angina Questionnaire at 1 and 12 months to capture patient reported 
outcome. The EQ-5D score, will be combined with survival times to enable estimation 
of QALYs for all patients up to one year following randomisation. Multiple imputation 
will be used to address missing values. Longer run modeling of incremental costs and 
health outcomes will estimate the distribution of costs and QALYs calculated over the 
expected patient lifetimes.  
 
Sub-study 2: Patient reported outcomes  
The high-sensitivity cardiac troponin assay may allow us to rule out myocardial 
infarction earlier and support the discharge of patients who have not had a myocardial 
infarction directly from the Emergency Department. In sub study 2 we will explore 
patient perceptions around discharge. Patients who have had myocardial infarction 

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ruled out as a possible diagnosis will be invited to participate in sub-study 2 
(Appendix 3). 
 
Consented patients will be visited in their own home (or a place of their choosing) 
approximately one week after discharge. In-depth interviews surrounding their 
experience of discharge from hospital following this episode of chest pain will be 
conducted and audiotaped. Follow up investigations ordered for these patients and 
their outcomes at 1 year will be recorded. This sub study will help guide the 
introduction of early discharge protocols into clinical practice by considering patient 
perceptions around discharge.  
 
Sub-study 3: High-sensitivity cardiac troponin and the early rule out of 
myocardial infarction 
In addition to the evaluation of the implementation of the high-sensitivity assay as part 
of the main study, we propose a sub-study to evaluate the efficacy and safety of a 
pathway to rule out myocardial infarction on presentation. During the final 6-months 
of the implementation phase of the main trial, sites will continue to follow the standard 
chest pain pathway with troponin testing at 12 hours using the high-sensitivity assay 
(standard care). Participating centres will then implement an early rule out pathway 
(intervention) based on National Institute of Clinical Excellence (NICE) 
[https://www.nice.org.uk/guidance/dg15] and European Society of Cardiology 
guidelines where troponin will be measured on presentation and myocardial infarction 
ruled out if troponin concentrations are <5 ng/L with further testing at 3 hours if 
indicated (Appendix 4). Implementation will be stepped using a similar approach to the 
main trial over the next 6-month period. After this 6 month period we will continue to 
identify patients across all sites for a further 6 months.  
 
 
 
 
 
 

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7 
Data Analysis and Statistical Considerations 
 
The trial results will be reported in accordance with the CONSORT guidelines and, 
where possible, the clinical profile of non-recruited and ineligible patients will be 
recorded.  
 
Statistical analysis:  
The analysis will take account of the cluster-randomised nature of the stepped wedge 
design.  The primary end-point of 12-month event-free survival (reinfarction and 
cardiovascular death) will be compared before and after implementation of the high-
sensitivity assay using a logistic regression generalized linear mixed model. Primary 
endpoint survival times will also be summarised descriptively using Kaplan-Meier 
survival curves and analysed formally using a Cox proportional hazards model 
incorporating a site level random effect and fixed effects for assay and covariate effects. 
The proportional hazards assumption will be verified by plotting log-cumulative hazard 
versus log-time for the high sensitive and standard care troponin assay groups. Model 
validity will be further explored using plots of Cox-Snell and Martingale residuals. 
Secondary efficacy endpoint (i), duration of stay, will be analysed using Kaplan-Meier 
survival curves and a Cox proportional hazards model as above, with death in hospital 
being treated as a censoring event. Secondary efficacy endpoints (ii)-(vii) and safety 
outcomes will be analysed using the same methods as used for the primary efficacy 
endpoint. The statistical methods will be documented in full in a detailed statistical 
analysis plan.Pre-specified exploratory subgroup analyses are planned to determine 
efficacy and safety stratified by age, sex, diagnostic threshold (sex-specific, uniform), 
diagnostic classification (type 1-5 myocardial infarction, myocardial injury), and renal 
function.  
 
Exploratory data analyses will examine the association between patient characteristics, 
clinical diagnoses and all primary and secondary outcomes in the study population. 
Analyses will be conducted using a variety of statistical (including Bayesian) and 
machine learning approaches. In combination, these approaches will allow us to 
develop clinical decision support tools to aid in diagnosis, risk prediction and 
management of patients with suspected acute coronary syndrome. 
 
Full methods for exploratory analyses will be documented in separate statistical 
analysis plans. 
 
 
Power calculations: 
Over a 12-month period (2008-2009), 2,092 patients were admitted at the Royal 
Infirmary of Edinburgh with chest pain and suspected acute coronary syndrome [Mills 
et al, 2011a; Mills et al, 2011b]. Of these, 1,383 patients had troponin concentrations 
below the current diagnostic threshold of 50 ng/L and 350 of these patients were found 
to have an undisclosed increase in plasma troponin within the range of 12-50 ng/L. At 
12 months, 47/350 (13%) patients with an undisclosed troponin rise were dead or 
readmitted with myocardial infarction compared to 31/1,033 (3%) of those with normal 
troponin concentrations of <12 ng/L. Implementation of the previous generation of 
troponin assay reduced 12-month death and recurrent myocardial infarction from 39 to 
21% (OR 0.42, 95%CI 0.24-0.84, P=0.013). We estimate that patients identified with 

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the high-sensitivity assay will derive similar benefit, but given the lower event rate in 
this group (13%), we have powered the prospective trial to detect a 3% absolute risk 
reduction. 
In the proposed study, 10 sites will contribute patients during three 6-month phases: the 
validation phase (standard care), randomisation phase (standard care/intervention) and 
implementation phase (intervention).  For each site we can calculate the difference in 
proportions, between standard care and intervention, of the primary outcome during the 
12 months following hospital admission. This difference in proportions will be 
approximately normally distributed with a standard deviation that depends on the 
primary outcome event rate under standard care and the number of patients recruited by 
the site.  ISD data for the financial year 2008-2009 were used to estimate site 
recruitment during each 6-month phase [Appendix 2]. Based on an average site 
recruitment of 525 patients with suspected acute coronary syndrome during each 6-
month phase, a 2.1% absolute risk reduction would be detectable with 80% power, 
while the power would be over 95% for detection of a change in absolute risk of 3%. 
 
Sub study 1: Clinical- and cost-effectiveness analysis  
 
Statistical analysis: 
Data from sub study 1 will allow evaluation of strategies for diagnosis of type 1 MI and 
for prediction of a major adverse cardiac event (MACE) at 30 days. 
 
Type I MI diagnosis 
12hr troponin will be used to define the gold-standard diagnosis of type I MI. 
The sensitivity, specificity, and positive and negative predictive value of five strategies 
will be evaluated: 
1. 3hr troponin >99th percentile 
2. Admission troponin >99th percentile 
3. 1 or 2 
4. 1 or 2 plus a 20% increase (“delta”) from admission to 3hrs 
5. 20% increase (“delta”) from admission to 3hrs 
In addition, diagnostic performance of a range of admission and “delta” cut-points will 
be explored using ROC curve methodology. 
 
Prediction of MACE at 30 days 
The same strategies will be evaluated as for type I MI diagnosis.   
 
Subgroup analysis 
The performance of each diagnostic/prognostic strategy will also be described within 
the subgroups: 
• Admission within 3hrs of onset (Yes/No) 
• Age (over 65 years/not over 65 years) 
• Pre-existing coronary disease (Yes/No) 
Sample size: 
 
Pilot data indicate that about 20% of the population under study will have a final 
diagnosis of type I MI based on the peak or 12 hr troponin concentration.  Realistic 

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estimates for recruitment over a period of 12 months indicate that it will be possible to 
enrol up to 1500 participants in the sub-study. The table below indicates the precision 
with which the sensitivity and specificity could be estimated – as defined by 95% 
confidence interval width – for a range of overall sample sizes (1000-1500) and levels 
of sensitivity and specificity (95-99%). 
 
Overall 
sample 
size 
N with type I MI
Sensitivity
Sensitivity 
95% CI 
width 
N without 
type I MI 
Specificity
Specificity 
95% CI 
width 
1000
200
95%
+/-3.0%
800
95%
+/-1.5%
1000
200
99%
+/-1.4%
800
99%
+/-0.7%
1500
300
95%
+/-2.5%
1200
95%
+/-1.2%
1500
300
99%
+/-1.1%
1200
99%
+/-0.6%
 
For the purposes of providing an overview, the confidence intervals considered use 
the normal approximation to the binomial distribution.  In the actual study analysis, 
exact intervals will be used since the levels of sensitivity and specificity attained are 
expected to be close to 100% for some of the strategies being evaluated. 
From analysis of pilot study data we will estimate the pairwise correlations among the 
troponin-based diagnostic strategies listed above. These will be used to inform further 
sample size calculations to determine the precision with which differences in 
sensitivity and/or specificity between a given diagnostic strategy and a reference 
strategy could be estimated in the sub-study. 
 
 
 

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Sub study 2: Patient reported outcomes  
 
A mixed methods approach will be adopted for the analysis of data from sub study 2 
(Appendix 3). 
 
Sample size: 
Eighty patients will be included in Sub study 2: 
   
10 female patients aged <65 years
Patients selected from those 
discharged after the result of a 
troponin taken at 12 hours 
10 female patients aged >65 years
10 male patients aged <65 years
10 male patients aged >65 years  
10 female patients aged <65 years
Patients selected from those 
discharged after the result of a 
troponin taken on presentation 
10 female patients aged >65 years
10 male patients aged <65 years
10 male patients aged >65 years  
  
The numbers selected will help provide a range of views from the patient population, 
through this stratified sample. The object is to uncover the widest range of views held 
by the participants in the two patient groups. When no new meanings are emerging 
from the in-depth interviews, theoretical saturation will have been reached. It is 
anticipated that the proposed sample sizes will provide enough participants to capture 
all relevant themes. No formal power calculations are required for this qualitative 
approach. Qualitative research aims for depth rather than breadth. Based on previous 
qualitative studies the overall sample size will allow for exploration of similarities and 
differences within and between the patient groups.   
 
 

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Sub-study 3: High-sensitivity cardiac troponin and the early rule out of 
myocardial infarction 
 
Statistical analysis 
Primary efficacy end-point:  Length of hospital stay, defined as the length of time 
from initial presentation to the Emergency Department until final discharge from 
hospital  
 
Primary safety end-point: Type 1 or type 4b myocardial infarction or cardiac death 
after discharge and within 30 days of index presentation  
 
Statistical analysis 
 
The primary efficacy outcome will be analysed using a linear mixed-effects regression 
model, adjusting for hospital site, season, time of patient presentation since start of 
study (in days), and an indicator variable for whether the early rule out pathway has 
been actually implemented or not. Season will feature in the model as a four category 
factor variable, with three indicator dummy variables for Spring (March April May), 
Summer (June July August) and Autumn (Sept Oct Nov); relative to Winter (Dec Jan 
Feb), which is the reference category. Hospital site will be included as a random effect 
in the model, and the length of stay outcome will be log-transformed prior to analysis 
to reduce the influence of extreme outliers and ensure that the model assumptions are 
valid. Results will be expressed as geometric mean factors with two-sided 95% 
confidence intervals. It is possible that a very small proportion of patients with long 
hospital stays of over 3 months might not have been discharged by the time of the final 
analysis; in which case, these patients will be excluded from the primary efficacy 
analysis, but the number and percentage of these patients will be reported.  
 
If the primary efficacy outcome analysis is statistically significant at the two-sided 5% 
level, then we will proceed to perform a non-inferiority analysis on the primary safety 
outcome. This will involve fitting a logistic mixed-effects regression model, adjusting 
for hospital site (as a random effect), season (defined as for the primary efficacy 
analysis), time of patient presentation since start of study (in days), and an indicator 
variable for whether the new intervention pathway has been implemented or not. A one-
sided 95% confidence interval will be reported and a one-sided 5% significance 
threshold will be used. If the upper limit of the one-sided 95% confidence interval lies 
below the 0.5% non-inferiority margin; then non-inferiority of the intervention will be 
established. If non-inferiority is shown, then the primary safety outcome results will be 
assessed for superiority by interpreting the upper limit of the 95% confidence interval. 
If the upper limit of the 95% confidence interval lies below 0% (or 1 on the odds ratio 
scale) then superiority of the intervention will be concluded with respect to the primary 
safety outcome. 
 
For the primary analysis, the data will be analysed according to the actual timing of 
the introduction of the new pathway rather than the randomised time the new pathway 
was to be introduced (if different). 
 
 
Sample size: 
 

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Based on simulation methods, the total sample size of 38,994 patients will provide 99% 
power at the two-sided 5% level of significance to detect a realistic true difference of 
at least 60 minutes in arithmetic mean length of stay (primary efficacy endpoint).  
Again, based on simulation methods, a sample size of 38,994 patients ensures that there 
is 90% power to demonstrate non-inferiority assuming an event rate of 0.4% for the 
primary safety end-point (type 1 or type 4b myocardial infarction or cardiac death from 
discharge to 30 days), a one-sided 95% confidence interval is constructed for the 
difference, and a non-inferiority margin of 0.5% in favor of standard care. The 0.4% 
event rate assumption comes from initially reported observations in the validation phase 
of the HighSTEACS trial. 
The overall power to detect a statistically significant difference for the primary efficacy 
endpoint and demonstrate non-inferiority for the primary safety endpoint is 89%. 
 
 
  
 
 

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8. 
Expected Results 
 
Based on our previous studies we expect the ARCHITECT STAT high-sensitive 
troponin I assay to reclassify up to 17% of all patients admitted with suspected acute 
coronary syndrome: a potential 46% increase in the diagnosis of myocardial infarction. 
We anticipate that clinical outcomes will improve in those patients reclassified as 
myocardial infarction due to greater use of effective therapies for the treatment of 
coronary artery disease. It is likely that this improvement in outcome will be at the 
expense of more patients identified with elevated cardiac troponin concentrations with 
non-cardiac causes of chest pain. The use of cardiac medication and investigations in 
this group is likely to increase, but may not improve clinical outcomes.  
These findings will represent the first evidence from a randomised controlled trial to 
evaluate the appropriateness of the universal definition of myocardial infarction and to 
assess its impact on clinical outcomes. One of the major strengths of the trial design is 
that we will capture all patients with suspected acute coronary syndrome presenting to 
both secondary and tertiary care hospitals rather than a highly selected sub-population 
of consented patients managed in a regional cardiac centre. This large and unique data 
set will provide us with an opportunity to critically evaluate whether it is appropriate to 
base the diagnosis of myocardial infarction on a statistical assumption about the normal 
distribution of troponin from an unrelated reference population. Using this novel high 
sensitive assay we will quantify troponin in >98% of study participants and therefore 
will be able to examine the true relationship between troponin concentration and clinical 
outcome to define the optimal clinical threshold or parameters that identify patients who 
would benefit from treatment for myocardial infarction.  
 
National guidelines now recommend the use of high-sensitivity cardiac troponin assays 
to rule out of myocardial infarction earlier in patients with suspected acute coronary 
syndrome. These assays will allow earlier testing with serial measurements performed 
in the Emergency Department and will permit use of lower thresholds such that 
myocardial infarction may be safely ruled out on presentation. This trial will determine 
whether the introduction of early rule out pathways into routine clinical practice is safe. 
 
We anticipate that implementation of a novel high-sensitivity cardiac troponin assay 
and an early rule out pathway will be associated with major cost savings, and our 
findings will form the basis of future guidelines for the assessment of patients with 
suspected acute coronary syndrome. 
 
 
 

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9 
Safety Reporting 
 
Safety endpoints will be monitored throughout the main study and form part of 
routine reports. The Trial Management Team, the Trial Steering Committee (TSC) 
and the data monitoring committee (DMC) will oversee safety monitoring throughout 
the study. Individual adverse events will not be monitored as part of the main study.  
In the event of any safety concerns being reported to the trial team, these will be 
recorded and reported to the Sponsor and the Trial Steering Committee within the 
appropriate regulatory timeframes. 
 
 

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10 
Study Monitoring 
 
10.1 
Trial Steering Committee 
 
The committee will include representatives from the grant applicants, trial management 
and four individuals not directly involved in the trial. A member of a relevant consumer 
(patient) group as well as a representative of the British Heart Foundation (BHF) will 
be invited to be members of the committee. 
 
10.2 
Trial Management Group 
 
The trial management group will meet regularly and consists of the grant applicants, 
the trial manager, and research team. 
 
10.3 
Data Monitoring Committee 
 
The main study involves linkage of records from existing patient records and does not 
require data entry. A data monitoring committee will oversee the data management and 
record linkage processes throughout the study.  
 
10.4 
End-point adjudication committee 
An endpoint adjudication committee will also be set up to adjudicate the study 
endpoints and validate documented endpoints. 
 
 
 
 

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11 
Ethical and Regulatory Issues 
 
The High-STEACS study protocol V 1.0 was approved by the Scotland A Research 
Committee on 14th August 2012 (Ref: 12/SS/0115). NHS Lothian Research and 
Development Approval (2012/R/CAR/17) has been obtained and is in progress in NHS 
Greater Glasgow and Clyde. 
 
 
 

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12 
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measuring the clinical management and outcomes of patients with acute coronary 
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Biochem. 2010;43(12):1034-6. 
Apple FS, Collinson PO. Analytical characteristics of high-sensitivity cardiac 
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Bauer A, Gawaz M. Sensitive cardiac troponin assays. N Engl J Med 2009;361:2575. 
Collinson P, van Dieijen-Visser MP, Pulkki K, et al. Evidence-based laboratory 
medicine: how well do laboratories follow recommendations and guidelines? The 
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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 
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2011b. Nov 10. [Epub ahead of print] 
Eggers KM, Jaffe AS, Lind L, Venge P, Lindahl B. 2009. Value of cardiac troponin I 
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High-Sensi ve Troponin in the Evalua on of pa ents with Acute Coronary 
Syndrome (HighSTEACS): A randomised controlled trial  
Bri sh Heart Founda on Special Project Grant 
Randomisa on* 
High-sensi ve assay 
Standard care 
Follow up 
Valida on* 
Standard care 
Standard care 
0 
6 
18 
30 
All sites 
(n=10) 
5 sites 
5 sites 
Ter ary sites 
(n=2) 
* During the valida on and randomisa on phases of the study both the standard and high sensi vity assays will be run in 
parallel. During the valida on phase and following randomisa on in those sites randomised to standard care, only results of 
the standard assay will be made available with clinical decisions based on exis ng diagnos c thresholds. 
Iden fica on and characterisa on of  all pa ents with troponin 
measured as rou ne care and chest pain with suspected acute 
coronary syndrome in ter ary sites with dedicated Clinical Research 
Facili es 
 
Consent into cost-effec veness sub-study   
Iden fica on of all pa ents with troponin measured  
as rou ne care and chest pain with ICD-10 codes (I20, I21, I22) to  
define pa ents with confirmed acute coronary syndrome 
Record linkage with the Sco
sh Morbidity 
Register, corroborated through source data, 
pa ent hospital records and with event 
commi ee adjudica on  
 
Record linkage with the Sco
sh Morbidity 
Register, corroborated through source data, 
pa ent hospital records and with event 
commi ee adjudica on  
n = 15,000 
n = 6,000 
months 
High-sensi ve assay 
Follow up 
12 
High-sensi ve assay 
Implementa on 
 
13 Appendices 
 
Appendix 1 
 
 

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Extension of implementation phase (HighSTEACS) 
 
 
2013 
2014 
2015 
2016 
Site  
J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F 
A 
Early
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
        
  
  
  
  
  
  
  
  
  
B 
Early
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C 
Early
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
D 
Late
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
E 
Late
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
F 
Late
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
G 
Late
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
H 
Early
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
I 
Late
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
J 
Early
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 

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Recruitment and follow up timescales: HighSTEACS and sub studies 
 
 
2013 
2014 
2015 
2016 
 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
HighSTEACS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2016 (cont) 
2017 
2018 
2019 
 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
J 
J 
A 
S 
O 
N 
D 
J 
F 
M 
A 
M 
HighSTEACS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sub study 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEY: 
 
Recruitment 
Follow up 
Previous pathway 
Introduction 
Evaluation 
 
 

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Appendix 2 
 
Number of hospitalisations with chest pain (ICD code R7), myocardial infarction (I21, I22) 
and unstable angina (I20), and number of troponin assays performed on the ARCHITECT 
platform in all participating centres for the financial year 2008-2009. 
Participating 
centre 
 
Chest pain 
MI 
UA  
TnI/annum 
Vale of Leven General Hospital 
 
455 
132 
72 
2,548 
Inverclyde Royal Hospital 
 
980 
135 
175 
5,486 
Royal Alexandra Hospital 
 
1,371 
178 
380 
7,675 
Glasgow Royal Infirmary 
 
1,791 
227 
349 
10,026 
Victoria Infirmary 
 
1,670 
315 
112 
9,349 
Southern General Hospital 
 
1,274 
163 
99 
7,132 
Western Infirmary/ Gartnavel 
 
1,867 
187 
302 
10,451 
Western General Hospital 
 
379 
103 
115 
2,121 
St John's Hospital 
 
1,001 
211 
286 
5,604 
Royal Infirmary of Edinburgh  
 
2,051 
864 
588 
11,482 
TOTAL 
 
12,839 
2,515 
2,478 
71,874 
Source:  ISD Scotland, SMR01 (Inpatient/Day cases) linked database as at 26 February 2011.  
MI = myocardial infarction; UA = unstable angina; TnI = troponin I  

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Appendix 3  
Sub study 2 outline 
 
A qualitative investigation of patients’ views on and experiences of discharge in suspected acute coronary 
syndrome before and after implementation of early rule out strategies 
 
Background 
The HighSTEACS study is assessing the impact of the introduction of a new high-sensitivity troponin assay on 
the clinical management of acute coronary syndrome and on clinical outcomes. These new high-sensitivity 
troponin assays are able to detect lower levels of cardiac troponin and have the potential to allow rule out of 
myocardial infarction on presentation, rather than at 12 hours with a conventional assay. High-sensitivity assays 
will therefore support the introduction of early discharge protocols for patients with chest pain. In this 
qualitative sub-study, we will explore patients’ perceptions and experiences of standard and early discharge 
protocols. 
 
The majority of patients with chest pain will have normal troponin values and are informed they have “non-
cardiac chest pain”, or “unexplained chest pain”. Patients with unexplained chest pain suffer from increased 
anxiety, use more hospital services, and have functional status that are comparable to those patients with 
coronary heart disease. Studies exploring the information needs of patients with unexplained chest pain have 
highlighted themes of “lack of focus on individual problems”,“unanswered questions”, and “unmet information 
needs”. Before adopting an early discharge protocol we need to understand the patients’ beliefs, perceptions 
and experiences related to attending hospital with chest pain. It is these beliefs and concerns that are likely to 
drive repeat attendance if these are not tackled during their index admission.  These studies will determine the 
patients’ view and acceptability of an early discharge protocol. We will identify whether these views differ by 
age and between men and women. We anticipate that an early discharge protocol for all patients may increase 
patient anxiety. Our findings will help identify ways to support patients following early discharge, and lead to 
clinical guidance tools that will reduce the risk of inappropriate discharge or reattendance. 
 
Research Methods: This study will utilize a mixed methods approach. Patients with suspected acute coronary 
syndrome in whom myocardial infarction has been ruled out will be recruited from the Emergency Department 
and Medical Assessment Areas of the Royal Infirmary Edinburgh, Western General Hospital Edinburgh, and St 
John’s Hospital Livingston before (n=40; phase 1) and after (n=40; phase 2) implementation of the early 
discharge protocol. Patients will not be made aware that discharge may be occurring at an earlier time point 
than conventional treatment so as not to potentially load any anxiety. Patients will be stratified by age and 
gender with 10 subjects in each group (males ≤65 and >65 years; females ≤65 and >65 years based on the mean 
age of presentation with suspected acute coronary syndrome). Patient’s co-morbid illness, social support and 
levels of anxiety will be recorded quantitatively using a visual analogue scale completed on discharge and at the 
home visit approximately 1 week later, and a Hospital Anxiety and Depression scale (HAD) validated for use in 
NCCP patients. Follow up investigations arranged for this group of patients, and their outcomes at 1 year will 
also be recorded. The qualitative component of the study will use a phenomenological approach that explores 
lived experience, revealing both what is experienced and how it is experienced.  In- depth interviews will be 
conducted, with participant consent, in the week following discharge. Interviews will be recorded and 
transcribed and an analytical framework developed. Transcripts will be read multiple times in order to develop 
relevant codes and analytical themes. The interview schedule will be developed after a thorough literature 
review has been conducted and tested through pilot interviews. A preliminary scoping of the literature suggests 
four interrelated themes, but we shall remain alert to themes emerging from the patients’ accounts. Based on 
previous studies and a literature review I will explore four themes 
• Patients’ beliefs of the cause of chest pain  
• Patients’ experiences of how a cardiac cause has been ruled out  
• The interrelationship between health care seeking behaviour, self-care and social support  
• Patients’ experience of standard of care 
 
 

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Recruitment 
Patients attending the Royal Infirmary of Edinburgh (Emergency Department or Primary Assessment Area), the 
Western General Hospital Edinburgh (Acute Receiving Unit), or St John’s Hospital Livingston (Emergency 
Department) for assessment of suspected acute coronary syndrome will be offered the opportunity to participate 
in the additional qualitative study by Emergency Department clinical staff. After reading the information sheet, 
patients will be asked if they would be happy to be contacted by phone or e-mail at least twenty four hours later 
to discuss taking part in the interview study, and if so to arrange a suitable time for the interview to take place. 
This information will be recorded on a screening log. Those agreeing to take part in the study will then be 
telephoned on the day before or the morning of the interview to see if they are still happy to take part. Patient 
consent will be gained prior to the interview commencing. 
 
Study procedures 
Consenting patients will be visited in their own home (or place of their choosing) approximately one week after 
discharge. In-depth interviews surrounding their experience of discharge from hospital following an episode of 
chest pain will be conducted and audio recorded. Follow up investigations ordered for these patients and their 
outcomes at 1 year will be recorded. 
 
Data management 
All data will be gathered, stored, and transferred in a manner which is safe, ensures accuracy, maintains 
participant confidentiality yet remains accessible to research staff. Data will be anonymised as soon as 
practicable and electronic devices used for data collection will have appropriate security settings enabled to 
prevent unauthorised access. Any file transfers will be conducted using encryption technology (for example for 
professional transcription). Identifying participant details will be held separately in a secure filing cabinet. 
NVivo will be used for data curation and analysis. 
 
Transcription will be conducted by a reputable organisation used by the University of Edinburgh which adheres 
to strict guidance, including confidentiality. Instructions will be given so that the data can be anonymised 
during transcription. Each transcript will have a unique identifier and a version number before being uploaded 
to NVivo. 
 
All electronic data collected for the study will be stored in a designated shared drive. The data folder will only 
be accessible to the research team. Data stored on external media (e.g. audio digital recorders, pen drives) will 
be transferred to the relevant shared folder as soon as practicable. After 5 years the audio recordings will be 
destroyed. 
 
All hard copy data will be stored in a locked filing cabinet in a secure office. Under no circumstances will paper 
records be left unattended in a public area with anyone outside the research team. 
 
Summary: Our findings will help identify ways to support patients following early discharge, and lead to 
clinical guidance tools that will reduce the risk of inappropriate discharge or reattendance.  
 
 
 

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39 
Chest pain and suspected acute coronary syndrome (ACS)
Review of pre-hospital and departmental 
ECG by senior staff within 10 mins
Immediate IV access and bloods including 
high-sensitivity cardiac troponin (hs-cTnI)
Cardiac monitoring
Non-diagnostic
ST-segment elevation
ST-depression/T-wave inversion
Bleep 5834 for em ergency PCI
•
Aspirin 300 mg 
•
Clopidogrel 600 mg 
•
Heparin 5,000 units IV 
(if not anti-coagulated)
•
Sub-lingual nitrate or analgesia
•
Consider Tirofiban IV bolus 
Admit and hs-cTnI at 6 hours
Senior review or cardiology referral
•
Aspirin 300 mg 
•
Sub-lingual nitrate or analgesia
•
Consider Clopidogrel 300 mg 
•
Consider Fondaparinux 2.5 mg 
SC
(if not anti-coagulated)
•
CXR as indicated
•
Consider Aspirin 300 mg 
•
Sub-lingual nitrate or analgesia
•
CXR as indicated
Review baseline hs-cTnI 
<5 ng/L*
>16 ng/L (women)
>34 ng/L (men)
≥5 ng/L AND
≤16 ng/L (women)
≤34 ng/L (men)
CHANGE <3 ng/L
AND
≤16 ng/L (women)
≤34 ng/L (men)
≤16 ng/L (women)
≤34 ng/L (men)
Myocardial infarction ruled out
A) Clear alternative diagnosis
Treat as appropriate
B) Atypical chest pain or recent 
negative investigations
Reassure patient low cardiac risk, 
advice and GP follow up
C) Typical cardiac pain on 
exertion with no previous 
investigations
Reassure, aspirin 75mg od and 
GTN spray, consider referral to 
the RACPC 
Myocardial injury or Infarction
Arrange for admission, senior 
medical review and repeat hs-
cTnI testing at 6 hours 
A) Consider other causes of 
m yocardial injury (e.g. heart 
failure, arrhythmia, sepsis, 
pulmonary embolism)
B) If diagnosis of type 1 
m yocardial infarction confirmed:
•
Clopidogrel 300 mg
•
Fondaparinux 2.5mg SC
•
Sub-lingual nitrate
hs-cTnI 3 hours from presentation
>16 ng/L (women)
>34 ng/L (men)
CHANGE ≥3 ng/L
AND
≤16 ng/L (women)
≤34 ng/L (men)
Admit and hs-cTnI 6 hours from presentation
>16 ng/L (women)
>34 ng/L (men)
New horizontal or downsloping 
ST-depression ≥2mm or deep symmetrical 
T-wave inversion in 2 adjacent leads 
≥2mm in 2 adjacent chest leads 
or >1mm in 2 adjacent limb leads
or new LBBB
or >2mm ST depression V1-V3 (posterior)
Myocardial infarction ruled out
Senior medical review or referral 
to cardiology 
Myocardial injury or Infarction
Referral to cardiology for 
in-patient assessment 
EMERGENCY DEPARTMENT  AND PAA
HOSPITAL ADMISSION
Rapid rule out of myocardial infarction
Lothian protocol version 4.0; 12 November 2015
* In all patients with chest pain for <2 hours repeat hs-cTnI at 3 hours
 
Appendix 4.  Early rule out pathway for patients with suspected acute coronary syndrome (NHS 
Lothian)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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