The Role of Early CT Coronary Angiography in the Evaluation, Intervention and Outcome of Patients Presenting to the Emergency Department With Suspected or Confirmed Acute Coronary Syndrome.
Phase: NA
Conditions: Acute Coronary Syndrome
Sponsor: University of Edinburgh

 
 
 
 
RAPID CTCA Protocol             Page 1 of 29            Version 7         24/02/2020 
 
Study Protocol 
The RAPID-CTCA Trial 
(Rapid Assessment of Potential Ischaemic Heart Disease with CTCA) 
 
The role of early CT Coronary Angiography in the evaluation, intervention and outcome of patients 
presenting to the Emergency Department with suspected or confirmed Acute Coronary Syndrome 
 
Co-sponsors 
University of Edinburgh & NHS Lothian, ACCORD,  
The Queen’s Medical Research Institute 
47 Little France Crescent, Edinburgh, EH16 4TJ. 
Funder 
Funded by the National Institute for Health Research 
Health Technology Assessment Programme.  
Funding Reference Number 
13/04/108 
ISRCTN Number 
ISRCTN19102565 
ClinicalTrials.gov Identifier 
NCT02284191 
Chief Investigator 
Prof Alasdair Gray 
REC Number 
14/SS/1096 
Version Number and Date 
Protocol version 7 (24/02/2020)   
    COORDINATING CENTRE 
Lead Investigator 
Professor Alasdair J Gray 
Emergency Medicine Research Group 
(EMeRGE) 
Department of Emergency Medicine 
Royal Infirmary of Edinburgh 
51 Little France Crescent 
Edinburgh, EH16 4SA  
Tel: 0131 242 1340 
Fax: 0131 242 1339  
Email: alasdair.gray@ed.ac.uk 
Co-sponsor Representative 
Dr Fiach O’Mahony* 
Clinical Research Facilitator 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Tel: 0131 242 9418 
Fax: 0131 242 9447 
Email: fiach.o’mahony@ed.ac.uk  
Trial Management 
Ms Kat Oatey   
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh EH16 4UX  
Tel: 0131 651 9913  
 
Email: rapid.ctca@ed.ac.uk  
Trial Statistician 
Professor Steff Lewis  
Edinburgh Clinical Trials Unit 
Usher Institute 
The University of Edinburgh 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh EH16 4UX  
Tel: 0131 651 9956 
Email: steff.lewis@ed.ac.uk  
 
   

 
 
 
 
RAPID CTCA Protocol             Page 2 of 29            Version 7         24/02/2020 
 CO-APPLICANTS 
 
Professor Steve Goodacre  
University of Sheffield 
School of Health and Related Research 
(ScHARR) 
Regent Court 
30 Regent Street 
S1 4DA 
Tel: 0114 222 0842  
Email: s.goodacre@sheffield.ac.uk  
 
Professor David Newby  
Centre for Cardiovascular Science  
University of Edinburgh 
Chancellor’s Building 
Royal Infirmary 
49 Little France Crescent 
Edinburgh, EH16 4SB 
Tel: 0131 242 6515  
Email: d.e.newby@ed.ac.uk 
 
Surgeon Captain Jason Smith (Royal Navy) 
Emergency Medicine 
Derriford Hospital 
Derriford Road 
Plymouth, PL6 8DH 
Tel: 01752 437 629 
Email: jasonesmith@nhs.net 
 
Dr Alan Fletcher  
Acute Medicine 
Sheffield Teaching Hospitals NHS 
Foundation Trust 
Northern General Hospital 
Herries Road, Sheffield, S5 7AU 
Tel: 07799 067 573 Email: 
alan.fletcher@sth.nhs.uk 
 
Professor Carl Roobottom 
Medical Imaging  
Peninsula Medical School 
University of Plymouth 
Derriford Hospital 
Plymouth 
PL6 8DH 
Tel: 01752 792 185  
Email: carl.roobottom@nhs.net 
 
Professor Robert Storey 
Department of Cardiovascular Science 
University of Sheffield 
Sheffield 
S10 2RX 
Tel: 0114 226 1124  
Email: r.f.storey@sheffield.ac.uk 
 
Dr Graham McKillop 
Radiology 
NHS Lothian Health Board 
Royal Infirmary 
51 Little France Crescent 
Edinburgh, EH16 4SA 
Tel: 0131 242 3744  
Email: 
graham.mckillop@nhslothian.scot.nhs.uk 
 
Dr Praveen Thokala 
Health Economics and Decision Science 
University of Sheffield 
School of Health and Related Research 
Regent Court 
30 Regent Street 
S1 4DA 
Tel: 0114 220 7784 
Email: p.thokala@sheffield.ac.uk 
All the persons named above have contributed as Authors to this protocol, with the exception of       
those marked * 
 
 
 
 
 

 
 
 
 
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CONTENTS 
LIST OF ABBREVIATIONS………………………………………………………………………..………….4 
PROFESSIONAL SUMMARY…………………………………………………………………………….......6 
LAY SUMMARY…………………………………………………………………………………………………7 
1 
INTRODUCTION ..........................................................................................................8 
1.1 
BACKGROUND AND RATIONALE ......................................................................8 
2 
STUDY OBJECTIVES ................................................................................................ 11 
2.1 
OBJECTIVES..................................................................................................... 11 
2.1.1 
Primary Objective ............................................................................................ 11 
2.1.2 
Secondary Objectives ..................................................................................... 11 
2.2 
ENDPOINTS ...................................................................................................... 11 
2.2.1 
Primary Endpoint ............................................................................................. 11 
2.2.2 
Secondary Endpoints ...................................................................................... 11 
3 
STUDY DESIGN ......................................................................................................... 12 
4 
STUDY POPULATION ............................................................................................... 12 
4.1 
NUMBER OF PARTICIPANTS ........................................................................... 12 
4.2 
INCLUSION CRITERIA ...................................................................................... 12 
4.3 
EXCLUSION CRITERIA ..................................................................................... 13 
4.4 
CO-ENROLMENT .............................................................................................. 13 
5 
PARTICIPANT SELECTION AND ENROLMENT ...................................................... 13 
5.1 
IDENTIFYING PARTICIPANTS ......................................................................... 13 
5.2 
CONSENTING PARTICIPANTS ........................................................................ 14 
5.3 
SCREENING FOR ELIGIBILITY ........................................................................ 15 
5.4 
RANDOMISATION ............................................................................................. 15 
5.4.2. Intervention Allocation ..................................................................................... 15 
5.4.3. Compliance and withdrawal of Study Participants ........................................... 16 
6. 
STUDY ASSESSMENTS ............................................................................................ 16 
7. 
DATA COLLECTION ................................................................................................. 18 
8. 
STATISTICS AND DATA ANALYSIS ........................................................................ 18 
9. 
ADVERSE EVENTS ................................................................................................... 19 
9.1. DEFINITIONS ......................................................................................................... 19 
9.2. IDENTIFYING AEs AND SAEs ............................................................................... 20 
9.4 ASSESSMENT OF AEs AND SAEs ........................................................................ 21 
9.4.1. Assessment of Causality ................................................................................... 21 
9.5 REPORTING OF SAEs/SARs.................................................................................. 21 
9.6 FOLLOW UP PROCEDURES.................................................................................. 22 
10 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ................................. 22 
10.1 TRIAL MANAGEMENT GROUP ............................................................................ 22 
10.3 DATA MONITORING COMMITTEE ....................................................................... 22 
11 
GOOD CLINICAL PRACTICE .................................................................................... 22 
11.1 ETHICAL CONDUCT ............................................................................................. 22 
11.2 INVESTIGATOR RESPONSIBILITIES ................................................................... 23 
11.2.1 Informed Consent ............................................................................................ 23 
11.2.2 Study Site Staff ................................................................................................ 23 

 
 
 
 
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11.2.3 Data Recording ................................................................................................ 23 
11.2.4 Investigator Documentation ............................................................................. 23 
11.2.5 GCP Training ................................................................................................... 23 
11.2.6 Confidentiality .................................................................................................. 23 
11.2.7 Data Protection ................................................................................................ 23 
12  
STUDY CONDUCT RESPONSIBILITIES ................................................................... 24 
12.1 PROTOCOL AMENDMENTS ................................................................................ 24 
12.2 PROTOCOL VIOLATIONS AND DEVIATIONS ..................................................... 24 
12.3 STUDY RECORD RETENTION ............................................................................. 24 
12.4 END OF STUDY .................................................................................................... 24 
12.5 INSURANCE AND INDEMNITY ............................................................................. 24 
13  
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ........................ 25 
13.1 AUTHORSHIP POLICY ......................................................................................... 25 
13.2 PUBLICATION ....................................................................................................... 25 
13.3 PEER REVIEW ...................................................................................................... 25 
14  
REFERENCES .................................................................................................. 25 
 
LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - 
Joint office for University of Edinburgh and NHS Lothian 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
AHA 
American Heart Association 
AKI 
Acute Kidney Injury 
AR 
Adverse Reaction 
CAD 
Coronary Artery Disease 
CHB 
Complete Heart Block 
CI 
Chief Investigator 
CKD 
Chronic Kidney Disease 
CT 
Computerised Tomography 
CTCA 
Computerised Tomography Coronary Angiography 
CTU 
Clinical Trials Unit 
CRF 
Case Report Form 
CV 
Curriculum Vitae 
ECTU 
Edinburgh Clinical Trials Unit 
ECG 
Electrocardiogram 
ED 
Emergency Department 
 
 
 
 
 
 

 
 
 
 
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LIST OF ABBREVIATIONS (continued) 
 
GCP 
Good Clinical Practice 
GTN 
Glyceryl Trinitrate 
HTA 
Health Technology Assessment 
ICA 
Invasive Coronary Angiography 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IHD 
Ischaemic Heart Disease 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
MACE 
Major Adverse Cardiac Event 
MAU 
Medical Assessment Unit 
MI 
Myocardial Infarction 
PACS 
Picture Archiving and Communication System 
PI 
Principal Investigator 
PMG 
Project Management Group 
QA 
Quality Assurance 
QALY 
Quality-adjusted life year 
REC 
Research Ethics Committee 
R&D 
Research and Development 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVT 
Supra ventricular tachycardia 
TSC 
Trial Steering Committee 
TMF 
Trial Master File 
UAR 
Unexpected Adverse Reaction 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia 
 
 
 
 
 
 
 

 
 
 
 
RAPID CTCA Protocol             Page 6 of 29            Version 7         24/02/2020 
SUMMARY 
Professional Summary 
Design: Open parallel group randomised controlled trial of early computed tomography coronary 
angiography (CTCA) in patients presenting with suspected/confirmed acute coronary syndrome (ACS) 
to Emergency Departments (ED), Cardiology Departments, and Medical Assessment Units (MAU). 
 
Setting: ~35 EDs, acute medical services, radiology, and cardiology departments in tertiary and district 
general hospitals in the UK. 
 
Target population: Inclusion criteria are patients ≥18 years with symptoms mandating investigation for 
suspected or confirmed ACS with at least one of: 1. ECG abnormalities e.g. ST segment depression 
>0.5 mm; 2. History of ischaemic heart disease (where the clinician assessing patient confirms history 
based on patient history or available records); 3. Troponin elevation above the 99th centile of the normal 
reference range or increase in high sensitivity troponin meeting European Society of Cardiology criteria 
for ‘rule-in’ of myocardial infarction.  Exclusion criteria:  1. Signs, symptoms, or investigations supporting 
high-risk ACS: ST elevation MI; ACS with signs or symptoms of acute heart failure or circulatory shock; 
Crescendo episodes of typical anginal pain; Marked or dynamic ECG changes e.g. ST depression of >3 
mm; Clinical team have scheduled early invasive coronary angiography on day of trial eligibility 
assessment. 2. Patient inability to undergo CT: Severe renal failure (serum creatinine >250 µmol/L or 
estimated glomerular filtration rate <30 mL/min); Contrast allergy; Beta blocker intolerance (if no 
alternative heart rate limiting agent available/suitable) or allergy; Inability to breath hold; Atrial fibrillation 
(where mean heart rate is anticipated to be greater than 75 beats per minute after beta blockade).  3. 
Patient has had invasive coronary angiography or CTCA within last 2 years and the previous 
investigation revealed obstructive coronary artery disease, or patient had either investigation within the 
last 5 years and the result was normal. 4. Previous recruitment to the trial; 5. Known pregnancy or 
currently breast feeding; 6. Inability to consent; 7. Further investigation for ACS would not in the patient’s 
interest, due to limited life expectancy, quality of life or functional status; 8. Prisoners 
 
Health technologies being assessed: Early use of ≥64-slice CTCA as part of routine assessment 
compared to standard care.  
 
Measurement of costs/outcomes: Primary end-point will be one-year all-cause death or subsequent type 
1 or type 4b MI at one year, measured as time to first such event. Secondary endpoints: 
Key Secondary Endpoints : 1. Coronary Heart Disease (CHD) death or subsequent non-fatal MI; 2.  
Cardiovascular Disease (CVD) death or subsequent non-fatal MI; 3. Subsequent non-fatal MI; 4. 
Coronary Heart Disease death; 5. Cardiovascular death; 6. All-cause death. Other Endpoints; Coronary 
Heart Disease (CHD) death or subsequent non-fatal MI (type 1 or 4b);Subsequent Non-fatal MI (type 1 
or 4b); Non-cardiovascular death; Invasive coronary angiography; Coronary revascularisation;  
Percutaneous coronary intervention; Coronary artery bypass graft; Proportion of patients prescribed 
ACS therapies during index hospitalisation; Proportion of patients discharged on preventative treatment 
or have alteration in dosage of preventative treatment during index hospitalisation; Length of stay for 
index hospitalisation; Representation or rehospitalisation with suspected ACS/recurrent chest pain 
within 12 months after index hospitalisation; Chest pain symptoms up to 12 months; Patient satisfaction 
at 1 month; Clinician certainty of presenting diagnosis after CTCA;  Quality of Life (measured by EQ-
5D-5L up to12 months).  Adverse Events and Serious Adverse Events; Proportion of patients with 
alternative cardiovascular diagnoses identified on CTCA; Proportion of patients with non-cardiovascular 
diagnosis identified on CTCA; Radiation exposure from CTCA as trial intervention. Cost effectiveness: 
Estimated in terms of the lifetime incremental cost per quality-adjusted life year (QALY) gained. 
 
Sample size: one-year all-cause death or subsequent MI for this patient group is ~20% (Mills et al, 
2011). The original aim was to recruit 2424 evaluable patients (1212 per arm) to have 90% power to 
detect a 20% vs.15% difference in one-year death or subsequent type 1 MI or type 4b MI rate, 2-sided 
P<0.05. With a ~3% drop out rate, the sample size will be 2,500 patients.  The revised aim is to recruit 
at least 1720 patients (not allowing for missing data), at least 1735 with expected loss to follow up rates, 

 
 
 
 
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which would provide the trial the opportunity to detect a 3.4% ARR at the current primary event rate of 
6.8% with 80% power, 2-sided P<0.05. 
Lay Summary 
 
Coronary artery disease (CAD) occurs when narrowing develops in the blood vessels supplying the 
heart. If the blood vessels become blocked, the patient may develop a critical lack of blood and oxygen 
getting to the heart muscle or an acute coronary syndrome (ACS) and be at risk of a heart attack, heart 
failure and death. Around 700,000 people attend hospital emergency (also known as A&E) departments 
(EDs) each year with chest pain mainly for assessment for suspected ACS. 
 
Standard assessment involves using a tracing of the heart (electrocardiogram, ECG) and a blood test 
to measure the level of a protein released from heart cells called troponin. If both tests are normal, then 
the patient is at low risk of a bad outcome and can often be discharged home. If either test is positive, 
the patient is at intermediate (medium) or high risk and requires admission to hospital. While in hospital, 
patients may require invasive coronary angiography. This test accurately identifies blockage in the 
coronary blood vessels that can then be treated but involves passing a tube or catheter into the heart 
and therefore carries significant risks.  
 
High-risk patients are usually investigated with invasive coronary angiography while they are in hospital 
because there is a substantial chance of finding a blocked artery that can then be unblocked and kept 
open. Medium-risk patients are sometimes investigated with invasive coronary angiography but may not 
undergo this investigation because the risks may not justify the potential benefits. However, medium-
risk patients have a 20%-risk of developing a serious heart problem over the following months. This 
could be reduced if their heart disease was more accurately investigated and appropriate treatment 
including long term medicines provided. Also, troponin testing is becoming more sensitive, increasing 
the amount of patients who are given a diagnosis of ACS but small rises in this blood test may not reflect 
CAD or a blocked heart artery. If this results in more invasive coronary angiograms and more use of 
powerful anti-clotting medication, this may increase the risk to patients and costs for the NHS without 
significant benefit.  
 
Computerised Tomography coronary angiography (CTCA) involves using a CT scan to identify 
blockages in the coronary arteries. It is slightly less accurate at identifying obstruction than invasive 
coronary angiography but has much fewer risks. It could therefore be used to improve the investigation 
of medium-risk patients. It could be used to identify patients with significant blockage who require 
invasive coronary angiography, allowing treatment of the obstruction and reducing the risk of serious 
heart problems. It could also identify patients without significant obstruction who don’t have a blockage 
and could therefore be discharged home, avoiding unnecessary tests and medication. However, 
although the ability of CTCA to detect obstruction is well known, it is unclear whether using CTCA leads 
to more appropriate use of coronary angiography and medication, a reduced risk of serious heart 
problems and improved patient outcomes.  
 
The aim is to undertake a research study of CTCA in patients admitted to hospital with suspected or 
confirmed ACS in the group of patients who are at medium risk, excluding high-risk patients needing 
immediate coronary angiography and very low-risk patients who can be discharged home without further 
investigation. 
 
Patients who are suitable will be given information about the study and asked to sign a consent form. 
Patients will be allocated to either receive CTCA as part of their assessment or receive standard 
assessment without this test. We will then follow up patients for one year to determine the rate of bad 
outcomes (such as heart attack or death), quality of life, patient satisfaction, the use of diagnostic tests 
or treatments, and health care costs. The study will be undertaken by an experienced team of UK 
researchers involved in previous successful trials in patients with chest pain. The team includes experts 
in emergency medicine, cardiology, radiology, acute medicine, statistics, and economics. 

 
 
 
 
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1 
INTRODUCTION 
1.1 
BACKGROUND AND RATIONALE 
Scale of the problem 
Ischaemic heart disease (IHD) including myocardial infarction (MI) continues to be a major cause of 
mortality in the UK. In 2011, 5% of deaths in England were as a consequence of acute MI and 13% 
were directly related to IHD [Office for National Statistics, 2012]. Approximately 700,000 patients present 
annually to Emergency Departments (ED) with chest pain in England and Wales, resulting in around 
350,000 emergency chest pain admissions [Goodacre S, 2005]. The vast majority of these patients 
present and are subsequently admitted for evaluation of suspected ACS. Chest pain admissions have 
doubled in the last decade accounting for approximately 5% of all emergency admissions (the 
commonest reason for acute hospital admission), whilst those for angina or ACS have fallen, see figure 
1, [Health and Social Care Information Centre (HSCIC), 2012; Hospital Episode Statistics, 2012]. 
Therefore, the majority of patients admitted for suspect ACS are discharged with the condition not being 
diagnosed. However, confirmed ACS remains a common diagnosis and associated with major adverse 
outcomes. One fifth of patients with ACS are re-hospitalised for suspected recurrent ACS or heart failure 
within 6 months of index admission [Goldberg R et al, 2004]. Mortality remains high with a 6-month 
mortality of around 20% [Das R et al, 2006]. These events may be the consequence of their index event 
or due to further myocardial ischaemia. They can be reduced by pharmacological and coronary 
revascularisation interventions [Fox K et al, 2007; Wallentin L et al, 2009]. The prompt diagnosis and 
treatment of ACS is therefore critically important. 
 
Current diagnostic pathways for suspected ACS 
Due to the consequences of inadvertent discharge of a patient with ACS and the limitations of initial 
clinical assessment, most patients with suspected ACS will require diagnostic investigation and a short 
hospital admission. This assessment and evaluation period in the United Kingdom is based on national 
guidelines [NICE, 2012; SIGN, 2013] and includes serial cardiac biomarkers, typically troponin I or T, 
and 12-lead ECGs. Current troponin assays do not reach maximal sensitivity until 12 hours after chest 
pain onset. Patients with an elevated troponin who present with a suspected ACS will have sustained 
an acute MI according to the Universal Definition of MI [Thygesen K, 2012].  Subsequent assessment, 
to further delineate IHD especially if troponin testing is negative, is inconsistent in the UK, resulting in 
many patients being discharged from hospital with “troponin negative” chest pain and no clear alternative 
diagnosis. This leads to many patients and clinicians being unclear what to do in the event of the patient 
having recurrent symptoms since coronary artery disease has not been unequivocally excluded. 
 
The role of additional investigations 
Exercise ECG testing is not widely used for the further delineation of CAD in UK emergency care settings 
[Dunham M et al, 2010]. When used it is typically in the context of a standardised assessment alongside 
biomarker testing on a chest pain unit. These units are widespread in the United States but have only 
been established in a few centres in the UK in the light of a cluster-randomised trial that failed to show 
evidence of benefit [Goodacre S et al, 2007]. European Society of Cardiology guidelines recommend 
using a stress test (typically exercise ECG) to select patients for further investigation with coronary 
angiography [Hamm C et al, 2011], while NICE guidance does not recommend using exercise ECG in 
the context of suspected ACS [NICE, 2012]. However, a systematic review of 54 observational studies 
incorporating 19,874 patients with clinical MI indicates that pre-discharge stress testing provides limited 
additional prognostic information to guide patient management [Shaw L et al, 1996].  All forms of non-
invasive stress testing demonstrate similar sensitivities and specificities for the prediction of future 
cardiac events.  Although the negative predictive value is high (~94%), the positive predictive value is 
low (<10% for cardiac death and <20% for cardiac death or MI). 
 
Invasive coronary angiography (ICA) is recommended by the European Society of Cardiology [Hamm 
C et al, 2011] in confirmed ACS or those patients believed to be at high risk of obstructive coronary 
disease but is costly and associated with a small but significant major complication rate, including death 
[British Cardiovascular Intervention Society, 2012]. It often requires the transfer of patients between 
hospitals in the UK as only around 35% of acute hospitals have on-site revascularisation facilities [British 
Cardiovascular Intervention Society, 2012].  It is unknown how many patients receive unnecessary ICA 
but it is likely to be significant and a potentially increasing number, if all patients with a raised troponin 
and chest pain receive coronary angiography. Some patients with confirmed ACS do not receive ICA 
due to limited availability, belief that troponin elevation is due to an alternative condition or other reasons 
for a decision to pursue non-invasive management. In the RITA-3 trial of patients presenting with a non-

 
 
 
 
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ST elevation ACS [Fox K et al, 2002], those undergoing invasive investigation were managed with 
medical therapy in 43%, percutaneous coronary intervention in 35% or coronary artery bypass graft 
surgery in 22%. On this basis, patients with an ACS could be investigated by CTCA with onward referral 
for percutaneous coronary intervention or coronary artery bypass graft surgery limited to patients with 
clear treatable coronary obstruction. Indeed, CTCA has similar discriminatory value in determining the 
need for coronary revascularization as ICA [Miller J et al 2008]. 
 
The potential impact of improved diagnosis 
A recent large observational study [Mills N et al, 2011; Mills N et al, 2012] revealed that changing the 
diagnostic threshold of troponin reported to treating clinicians had a significant effect on patients with 
suspected ACS whose troponin level was in the range between old and new reported diagnostic 
thresholds: 3-month (27% to 11%) and 12-month (39% to 21%) death or subsequent  MI rates were 
dramatically improved. Associated changes in coronary interventions and preventative medication 
confirm a causal pathway between increased diagnosis and improved outcomes. Coronary angiography 
and revascularisation rates went from 20% to 46% and 16% to 20% respectively. Primary and secondary 
prevention drug prescription rate also increased e.g. dual antiplatelet therapy administration increased 
from 27 to 58%. We, therefore, believe that there remains the potential for further significant incremental 
improvement in outcome if CTCA is widely adopted as part of the early assessment of ACS. 
 
CT Coronary Angiography in chest pain assessment 
Without doubt there is a need for novel interventions as part of the evaluation of suspected or confirmed 
ACS that enable the following: 1. better identification of ACS; 2. better risk stratification of ACS; 3. better 
case selection for ICA in patients with ACS; 4. provide information to tailor subsequent management 
and improve outcomes. CTCA could potentially fulfil all of these requirements. 
 
CTCA is quicker, simpler, substantially cheaper and more readily delivered than ICA and should 
translate into a highly effective and safe imaging strategy. A recent systematic review of 21 diagnostic 
accuracy studies of CTCA reported a pooled sensitivity of 99% and specificity of 89% for detection of 
CAD [Mowatt G et al, 2008]. A recent HTA-funded meta-analysis of eight diagnostic cohort studies of 
CTCA in suspected ACS [Goodacre S, 2013] reported sensitivity of 94% (95% predictive interval 61–
99%) and specificity of 87% (95% predictive interval 16–100%), but decision-analysis modelling was 
unable to draw reliable conclusions about effectiveness and cost-effectiveness of CTCA in suspected 
ACS. Three recent US trials investigating CTCA in patients with chest pain presenting to the ED promote 
its use and widespread adoption [Goldstein J, 2011; Hoffman U, 2012; Litt H et al, 2012]. Meta-analyses 
of 4 trials [D’Ascenzo F et al, 2012; Hulten E et al, 2013] conclude that CTCA is safe, cost effective and 
reduces length of stay in the US health care system. However, the event rates in these studies are low 
with no difference between trial arms. Moreover, the participants had relatively long hospital stays, and 
many additional tests compared with UK practice.  CTCA enables non-invasive anatomical quantification 
of CAD.  This allows accurate identification of patients that may benefit from coronary revascularisation 
[Miller J et al, 2008] and more accurately target patients for primary or secondary therapies, thus 
improving clinical outcomes. In those patients without disease, it may reduce hospital stay, recurrent 
hospitalisation and improve patient satisfaction due to clarity around the absence of CAD.  However, if 
CTCA use results in an increase in ICA as a result of false positive or equivocal results in low-risk 
patients, it may increase the cost and risk without clinical benefit. This risk-benefit dilemma needs 
evaluation so that benefit can be proven or refuted before widespread adoption across the NHS. 
 
The rationale for this trial 
This research is likely to have a significant impact on this large and important group of patients 
presenting with suspected or confirmed ACS to NHS hospitals. If the trial is positive, those patients with 
CAD will receive an early and accurate anatomical characterisation of coronary arteries by CTCA 
allowing targeting of ICA to those patients that are most likely to require revascularisation and facilitating 
early optimisation of primary and secondary preventive medicines. These interventions will save lives 
and reduce the burden of undiagnosed ischaemic heart disease. In patients with non-obstructive CAD 
or normal coronary arteries, it is likely to facilitate earlier discharge and prevent unnecessary ICA with 
the attendant risks. In terms of NHS benefit, this research is likely to lead to more optimal use of scarce 
expensive resources, reduced duration of hospital stay at the time of index presentation, and 
subsequent reduced hospitalisation. The early effective use of primary and secondary prevention will 
lead to lower long-term cardiovascular events. 
 

 
 
 
 
RAPID CTCA Protocol             Page 10 of 29            Version 7         24/02/2020 
If the trial is negative, the results will prevent widespread NHS adoption of an ineffective technology 
that, if implemented unnecessarily without significant patient outcome benefit, would substantially 
increase NHS costs and expose patients to unnecessary investigation with radiation exposure and 
potential anxiety related to a false positive diagnosis. 
 
Additionally, the increasing use of high sensitivity troponin will result in many more patients who have 
elevated troponin measurements; some of these patients will not have ACS. CTCA will enable local 
screening of these patients and only select patients for ICA that will directly benefit from this intervention. 
 
To reiterate, it is imperative that CTCA is proven to improve clinical and cost outcomes before 
widespread adoption in the NHS. A positive or indeed a negative trial is equally important and valuable 
to the NHS. 
 
Evidence explaining why this research is needed now 
HTA evidence synthesis 
A Health Technology Assessment (HTA) comprehensive systematic review in 2008 assessed the role 
of 64-slice multidetector computed tomography as an alternative to ICA [Mowatt G et al, 2008]. In 
keeping with previous analyses [Schroeder S et al, 2008], it confirmed the excellent accuracy of 
multidetector computed tomography in the identification of CAD. However, this systemic review 
highlighted several areas that need further research and highlighted, amongst other things, the need to 
evaluate the usefulness of multidetector CTCA in patients with suspected CAD.  
 
A recent evidence synthesis [Goodacre S et al, 2013] evaluated the diagnostic and prognostic accuracy, 
and cost-effectiveness of CTCA in suspected ACS. This evidence review showed that CTCA has good 
diagnostic accuracy for coronary artery obstruction: sensitivity, 94% (95% predictive intervals 61-99%); 
specificity, 87% (95% predictive intervals 16-100). Coronary artery obstruction on CTCA predicted 
MACE with a relative risk of 3.1 (0.3-18.7) or 5.8 (0.6-24.5) depending upon how indeterminate scans 
were classified. Economic analysis was subject to substantial uncertainty but CTCA was likely to be 
cost-effective if subsequent MACE was >2% (£30,000/QALY threshold) or >2.9% (£20,000/QALY 
threshold). The review suggests further research regarding the effect of testing and treatment on MACE 
is needed. 
 
National Institute of Clinical Excellence 
The NICE guidelines [NICE, 2012] identified areas of evidence uncertainty including the investigation of 
the cost-effectiveness of CTCA as a first-line test in patients with troponin-negative ACS. A subsequent 
NICE commissioned review suggests that CTCA is cost effective [NICE, 2013] 
 
Recent randomised controlled trials and meta-analysis 
Three recent US trials investigating CTCA in patients with chest pain presenting to the ED promote its 
use and widespread adoption [Goldstein J et al, 2011; Hoffman U et al, 2012; Litt H et al, 2012]. Meta-
analyses of 4 trials [D’Ascenzo F et al, 2012; Hulten E et al, 2013] conclude that CTCA is safe, cost 
effective and reduces length of stay in low-risk patients in the US health care system. The event rates 
in these studies are low, with long hospital stays, and many additional tests compared with UK practice. 
The event rate in troponin negative patients is likely to fall further, with sensitive troponin use, negating 
any small benefit of additional investigation in this negligible risk group. 
 
Early CTCA needs investigation in intermediate-risk ACS patients where improved and optimal targeting 
of interventions, including coronary revascularisation, and primary and secondary preventive therapy is 
likely to improve diagnosis and longer term outcome. The clinical and cost effectiveness of early CTCA 
in suspected or confirmed ACS must be clearly demonstrated before adoption of the technology into 
routine NHS practice given its cost, risk and uncertainty of benefit. A positive or negative trial is equally 
important to the NHS. 
 
 

 
 
 
 
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2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 
Primary Objective 
This study aims to investigate the effect of early CTCA in patients with suspected or confirmed ACS 
presenting to the ED, MAU, or cardiology, upon interventions, event rates and health care costs in a 
pragmatic clinical trial and economic evaluation up to 1 year after the trial intervention. The primary 
objective will be to investigate the effect of the intervention by comparing all-cause death or subsequent 
non-fatal type 1 or type 4b MI at one year.  
2.1.2 
Secondary Objectives 
1. The proportion of patients receiving coronary angiography and revascularisation at index 
hospitalisation and during 12-month follow up. 
2. The proportion of patients representing or readmitted to hospital with suspected ACS/recurrent chest 
pain up to one year after index presentation. 
3. The use of cardiovascular treatment during index hospitalisation and preventative therapies on 
discharge. . 
4. Length of stay at index hospitalisation. 
5. The use of NHS resource including hospitalisation and other investigations and interventions. 
6. The proportion of patients with symptoms, morbidity and mortality up to one year. 
7. Quality of life.  
8. The incremental cost per QALY gained by providing CTCA compared to current standard practice. 
2.2 
ENDPOINTS 
2.2.1 
Primary Endpoint 
The primary end-point will be all-cause death or subsequent non-fatal type 1 or type 4b MI at one year, 
measured as time to first such event. MI will be defined according to the most recent Universal Definition 
[Thygesen K, 2012] and will be adjudicated by two independent cardiologists blinded to the intervention.   
 
2.2.2 
Secondary Endpoints 
 
Key Secondary Endpoints  
 
1. Coronary Heart Disease (CHD) death or subsequent non-fatal MI;  
2.  Cardiovascular Disease (CVD) death or subsequent non-fatal MI;  
3. Subsequent Non-fatal MI; 
4. Coronary Heart Disease death;  
5. Cardiovascular death; 
6. All-cause death. 
 
Other Endpoints  
 
 
Coronary Heart Disease (CHD) death or subsequent non-fatal MI (type 1 or 4b); 
 
Subsequent Non-fatal MI (type 1 or 4b); 
 
Non-cardiovascular death; 
 
Invasive coronary angiography;  
 
Coronary revascularisation;  
 
Percutaneous coronary intervention; 
 
Coronary artery bypass graft;  
 
Proportion of patients prescribed ACS therapies during index hospitalisation; 
 
Proportion of patients discharged on preventative treatment or have alteration in dosage of 
preventative treatment during index hospitalisation; 
 
Length of stay for index hospitalisation;  
 
Representation or rehospitalisation with suspected ACS/recurrent chest pain within 12 months 
after index hospitalisation; 

 
 
 
 
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 
Chest pain symptoms up to 12 months; 
 
Patient satisfaction at 1 month; 
 
Clinician certainty of presenting diagnosis after CTCA;  
 
Quality of Life (measured by EQ-5D-5L up to12 months).  
 
Adverse Events and Serious Adverse Events:  
 
 
Proportion of patients with alternative cardiovascular diagnoses identified on CTCA;  
 
Proportion of patients with non-cardiovascular diagnosis identified on CTCA ; 
 
Radiation exposure from CTCA as trial intervention. 
 
Cost effectiveness:  
 
 
Estimated in terms of the lifetime incremental cost per quality-adjusted life year (QALY) gained.  
3 
STUDY DESIGN 
 
RAPID-CTCA is an open prospective parallel group randomised controlled trial of CTCA and standard 
care or standard care only in patients presenting to the ED, MAU, or cardiology with suspected or 
confirmed ACS. Recruitment will take place in ~35 NHS tertiary and district hospitals (with and without 
on-site invasive coronary angiography facilities) with emergency departments, acute medical, radiology 
and cardiology services. Participants will be randomised to CTCA and standard care, or standard care 
only.  Participants allocated CTCA will receive the scan during the initial admission or if discharged, as 
an ambulatory patient within 72 hours of randomisation (see section 5.4.2).  All participants will be 
followed up for one year and be asked to complete questionnaires at baseline, 1, 6 and 12 months to 
assess quality of life, angina symptoms and NHS services usage.   
4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
 
Our original sample size calculation was based on an estimated one-year death or subsequent MI rate 
for this patient group of ~20% [Mills N et al, 2011]. 2424 evaluable patients were, therefore, required 
(1212 per arm) to have 90% power to detect a 20% vs.15% difference in one-year death or subsequent 
MI rate, 2-sided P<0.05. With a 3% drop out rate, the sample size would have been 2,500 patients. 
However, on review, after recruiting and following up the first 716 participants the overall event rate was 
6.8% (95% confidence interval 5.2% to 8.9%). In addition, we were recruiting at a significantly lower rate 
than originally predicted. As part of an extension application the above information was used to calculate 
a variety of sample sizes for a range of event rates (6%, 6.8% and 8%) and effect sizes (Relative Risk 
0.5, 0.6, 0.75) with 80% and 90% power. The only plausible sample size option given recruitment rates 
with associated trial fatigue and potential for loss of clinical equipoise, event rates and funding was to 
deliver a trial of at least 1720 patients (not allowing for missing data), at least 1735 with expected loss 
to follow up rates, which would provide the trial the opportunity to detect a 3.4% ARR at the current 
primary event rate of 6.8% with 80% power, 2-sided P<0.05. 
4.2 
INCLUSION CRITERIA 
 
Patient ≥18 years with symptoms mandating investigation for suspected or confirmed ACS with at least 
one of: 
 
 
ECG abnormalities e.g. ST segment depression >0.5 mm; 
 
 
History of ischaemic heart disease (where the clinician assessing patient confirms history based on 
patient history or available records); 

 
 
 
 
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 
Troponin elevation above the 99th centile of the normal reference range or increase in high sensitivity 
troponin meeting European Society of Cardiology criteria for ‘rule-in’ of myocardial infarction  
(NB troponin assays will vary from site to site; local laboratory reference standards will be used). 
 
4.3 
EXCLUSION CRITERIA 
1. Signs, symptoms, or investigations supporting high-risk ACS:  
o 
ST elevation MI;  
o 
ACS with signs or symptoms of acute heart failure or circulatory shock; 
o 
Crescendo episodes of typical anginal pain; 
o 
Marked or dynamic ECG changes e.g. ST depression of >3 mm  
o 
Clinical team have scheduled early invasive coronary angiography on day of trial eligibility 
assessment.  
 
2. Patient inability to undergo CT:  
o 
Severe renal failure (serum creatinine >250 µmol/L or estimated glomerular filtration rate 
<30 mL/min); 
o 
Contrast allergy; 
o 
Beta blocker intolerance (if no alternative heart rate limiting agent available/suitable) or 
allergy; 
o 
Inability to breath hold; 
o 
Atrial fibrillation (where mean heart rate is anticipated to be greater than 75 beats per minute 
after beta blockade). 
 
3. Patient has had invasive coronary angiography or CTCA within last 2 years and the previous 
investigation revealed obstructive coronary artery disease, or patient had either investigation within 
the last 5 years and the result was normal.  
 
4. Previous recruitment to the trial; 
 
5. Known pregnancy or currently breast feeding;   
 
6. Inability to consent; 
 
7. Further investigation for ACS would not in the patient’s interest, due to limited life expectancy, quality 
of life or functional status; 
 
8. Prisoners 
 
4.4 
CO-ENROLMENT 
Co-enrolment will be permitted with non-interventional studies that involve data collection only.  Co-
enrolment with another interventional trial may be allowed provided this is not expected to place an 
undue burden upon participants and their families and will not compromise the primary end-point of 
either trial.  Consideration will also be given to the total exposure to ionising radiation should additional 
studies require further exposure. Co-enrolment will only be permitted with agreement of the Chief 
Investigators of both studies. 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
The research nurses, where it is locally agreed that they are part of the clinical care team, will identify 
patients using triage information and clinical or electronic records in the Emergency Department, 
Cardiology Department or the Medical Assessment Unit. In this case, it is anticipated they would identify 
patients and make the first approach. Any member of the clinical team who has received general and 
trial specific training and is on the delegation log may also identify patients in this way. 

 
 
 
 
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If research nurses are not considered to be part of the direct care team locally, activities carried out prior 
to consent (including identification) will be carried out by a member of the direct care team. 
 
Where research nurses are not considered to be part of the care team, the research nurse should ask 
a member of the direct care team to identify suitable patients and ask permission from the patient to be 
approached by the research nurse to discuss participation. 
 
There will be no additional trial specific screening tests performed. The patient will receive routine acute 
clinical assessment including, as a minimum, a 12-lead ECG, vital signs measurement (pulse rate, non-
invasive blood pressure, respiratory rate, conscious level, oxygen saturations and skin prick blood 
sugar) and admission routine blood tests including troponin and renal function. The results of these will 
inform trial eligibility and the patient may be approached as soon as these are available (normally in the 
first 2 hours after presentation). Patients may be approached up to 24 hours after presentation. This 
time period has been chosen as it allows the longest period for recruitment where the patient could be 
deemed to be receiving acute assessment i.e. up to the point where a 12-hour troponin result is being 
used by routine clinicians for acute decision making.  Patient and clinician will be unaware of treatment 
allocation until after screening, consent and randomisation. 
 
5.2 
CONSENTING PARTICIPANTS 
 
Potentially eligible participants who are willing to take part in the study will be asked to provide written 
informed consent. Consent will be obtained by trained members of the clinical team or members of the 
research team who have been delegated this responsibility. The Investigator is responsible for the 
delivery of processes to ensure informed consent is obtained before any protocol specific procedures 
are carried out.  The decision of a patient to participate in clinical research is voluntary and should be 
based on a clear understanding of what is involved.   
The patient (and if present and appropriate their accompanying relative) will be given a Patient 
Information Sheet, which will explain the aims of the trial and the potential risks and benefits of the study 
treatments. If necessary, a summary sheet will be provided first to provide a brief outline of the study 
and allow potential participants to decide whether or not they wish to proceed and before the full Patient 
Information Sheet is provided.   
 
The patient (and if appropriate the accompanying relative) will be given enough time to consider the trial 
and ask questions regarding their participation in the trial. At most this could be an hour but may be only 
10-15 minutes. Potential participants must receive adequate oral and written information.  The oral 
explanation to the patient will be performed by the clinical research nurse or a trained and delegated 
member of the clinical team and must cover all the elements specified in the Participant Information 
Sheet and Consent Form. The patient must be given every opportunity to clarify any points they do not 
understand and, if necessary, ask for more information.  The patient must be given sufficient time to 
consider all the information provided.  It should be emphasised that the patient may withdraw their 
consent to participate at any time without loss of benefits to which they otherwise would be entitled. The 
participant will be informed and agree to their medical records being inspected by representatives of the 
sponsor(s). 
The Investigator or delegated member of the trial team and the participant will sign and date the Informed 
Consent Form(s) to confirm that consent has been obtained.  The original consent form will be filed in 
the Investigator Site File (ISF), the participant will receive a copy of this document and a copy filed in 
the participant’s medical notes. 
 
Capacity will be assessed by the Principal Investigator (PI) or a clinician responsible for the treatment 
of the participant. This assessment of capacity will be documented in the participant’s medical records.  
The trial excludes patients who have “life threatening features” and therefore this will effectively exclude 
patients who lack temporary capacity due to their current illness. Patients with permanent incapacity will 
not be recruited. 
 

 
 
 
 
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5.3 
SCREENING FOR ELIGIBILITY 
 
All patients aged ≥18 years of age with suspected or confirmed ACS will be screened for eligibility.  
Ineligible and non-recruited patients will receive standard medical care.  
Female patients of childbearing potential i.e. women who have experienced menarche, are pre-
menopausal, have not been sterilised should be asked if they are pregnant prior to entry into the trial.  
If the patient is unsure, they should be given an hCG pregnancy test to confirm before randomisation.  
 
An anonymised log will be kept for patients who were screened for the study and those who were 
subsequently found to be ineligible or who were not recruited.  This data should be entered onto the e-
CRF for central monitoring purposes.  Further guidance about screening can be found in the RAPID-
CTCA Screening guidelines.   
 
5.4 
RANDOMISATION 
 
5.4.1. 
Randomisation Procedures 
After assessment for eligibility and consent, the clinical research nurse or a delegated member of the 
clinical team will collect the baseline data necessary to complete the pre-randomisation information on 
RAPID-CTCA Admission CRF. Randomisation will be carried out using a web-based randomisation 
service (managed by the Edinburgh Clinical Trials Unit) that ensures allocation concealment. 
Randomisation will be carried out within 24 hours of arrival at the hospital. Once a patient is randomised, 
s/he will remain in the study and have all outcomes recorded regardless of compliance with randomised 
pathway allocation, unless s/he specifically withdraws consent to have data stored.  Consented patients 
will be randomised on a 1:1 basis to CTCA in addition to standard care or standard care alone and will 
be stratified by study site. 
 
5.4.2. 
Intervention Allocation 
CTCA results will be available to the clinical team to support acute clinical decision making. It is 
anticipated that the provision of immediate CTCA with early reporting is likely to be variable across the 
centres. The intervention will be delivered by routine clinical staff. It is anticipated that 60-70% of patients 
will be recruited between 8.00 am and 6.00 pm and would be eligible for immediate CTCA [Goodacre S 
et al, 2011]. Patients recruited to the study and randomised to CTCA should receive a CTCA as soon 
as feasible, and normally on the day of, or day following randomisation providing this does not 
significantly delay routine processes of care including discharge.  Where a clinical decision is made to 
discharge the participant before the scan takes place, they should be asked to return for ambulatory 
CTCA within 72 hours. The patient should receive clinical review in the ED, MAU or cardiology after the 
CTCA, and the CTCA result should be available to support this clinical decision making.  Discharged 
patients will receive an appointment card detailing study contact details, the date, time, and location of 
their CTCA.   
 
The results of the CTCA are likely to direct subsequent management. A guideline has been developed 
which will be available to clinicians to guide subsequent management dependent on the CTCA result. 
[Appendix 1].  A template GP letter is available to clinicians if they wish to use this to inform the GP 
about non-obstructive disease identified by the CTCA which may require secondary prevention being 
implemented by the GP.  
 
Other interventions 
All other management and admission or discharge decisions will be at the discretion of the treating 
clinicians. Sites will be requested not to use CTCA as part of the routine investigation of ACS and this 
will be closely monitored.  
 
Blinding 
This is an open trial. The patient, recruiting and treating clinicians and radiologist will not be blinded to 
the intervention including results. Outcome assessors, however, will be blinded to the intervention. 
 
Follow up 

 
 
 
 
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Patients will be followed up using routine clinical notes and research contact with the patient by phone, 
email or post. A 3% loss to follow up (patient withdrawal and inability to retrieve data for the primary 
outcome from routine NHS records) is built into the sample size calculation for the primary outcome; all 
patients will be analysed for the primary outcome on an intention-to-treat basis. At Trusts where it is not 
possible to routinely get this data from the NHS records, the research team at site will attempt to contact 
the participant and/or their GP by telephone to gather the 12-month follow up data.  All patients will be 
followed for 1 year.    
 
5.4.3. 
Compliance and withdrawal of Study Participants 
Study participants are free to withdraw from the trial at any time. Reasons, if given, will be recorded and 
data collected up to that time point may be used in the final analyses, unless the patient specifically 
requests that their data are not used.  If the patient withdraws consent to have their data stored, then 
this will be documented on the trial CONSORT flow diagram as ‘withdrawn’ and their data will not be 
used in the final analyses. Patients may withdraw from participation in active follow up but data will 
continue to be collected unless the patient requests otherwise. The patient may be willing to give a 
reason for withdrawal, but this is not obligatory. 
 
Crossover  
Any patient in the control group that has a CTCA as part of routine care within 30 days of randomisation 
will be defined as a crossover and does not need to be recorded as a deviation.  
 
Non-adherence 
This will be defined as to have occurred in any participant not receiving a reported CTCA if randomised 
to it within 72 hours of the randomisation and this would be recorded as a deviation. This allows 
ambulatory CTCA to be delivered when appropriate.  
 
Individual site retention, crossover and non-adherence will be monitored and reviewed at the Project 
Management Group and Trial Steering Committees meetings. 
6. 
STUDY ASSESSMENTS 
Patients will be screened, consented, recruited and randomised in the ED, Cardiology or MAU of 
participating centres within 24 hours of arrival to the hospital. All patients will receive standard acute 
clinical assessment including a presentation 12-lead ECG and troponin measurement.  
 
CTCA will be delivered and reported by a trained radiologist or cardiologist within an established 
radiology service as soon as possible, ideally within 2 hours of procedure and reported and 
communicated immediately to the treating clinician. 
 
Patients randomised to standard care will receive the standard management for patients with suspected 
or confirmed ACS at that NHS hospital site. The only difference will be the early use of CTCA in the 
intervention arm and the subsequent impact on patient care after the result is provided to the clinician 
for clinical decision making. Local chest pain management guidelines will be collected, or confirmation 
obtained from PI that CTCA us not currently in routine use for eligible patients (including change in 
practice, during the period of the trial).  
 
CTCA delivery 
The technology being assessed is 64 slice or greater multidetector CT scanners enabled to perform 
ECG-gated cardiac studies. The examination may include a non-contrast ECG-triggered acquisition for 
calcium scoring (if part of local protocol) and a post-contrast ECG-gated acquisition covering the whole 
of the heart and the root of the aorta. 
 
Patients must be able to hold their breath for >20 seconds. The intervention will be for no longer than 
30 minutes and the patient will be observed for a period of 30 minutes afterwards.  
 
Radiation reduction techniques will be employed and, where appropriate, intravenous or oral beta 
blockade (or alternative heart rate limiting agent) will be used to reduce heart rate (target of <70 /min) 
enabling significant radiation dose saving protocols.   

 
 
 
 
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Due to the variation in conversion factors used by sites to convert dose-length product (DLP) to effective 
dose in mSv, radiation dose will be routinely reported for the trial as DLP. A DLP to mSv conversion 
factor of 0.014 mSv/mGy/cm will be used for trial reporting in line with recent publications in this area of 
research.  
 
A typical participant with a heart rate below 70 beats per minute in sinus rhythm and a BMI <25 should 
have a DLP ≤ 686 mGy.cm and cases exceeding this will be considered to be a protocol deviation. 
Deviations will be reviewed by a Radiologist/Cardiologist in the central trials team and any cases which 
have an impact on patient safety or study outcomes will instead be reported as a protocol violation.  For 
other participants, without the typical characteristics stated above, DLP values ≥686 mGy.cm are 
anticipated as part of routine clinical practice (for example, due to the need for continuous retrospectively 
gated scanning in some participants with arrhythmia).  For such participants, any DLP which exceeds 
1500 mGy.cm will be considered to be a protocol deviation.  Deviations will be reviewed by a 
Radiologist/Cardiologist in the central trials team and any cases which have an impact on patient safety 
or study outcomes will instead be reported as a protocol violation.  
 
All participating centres will be required to verify that their CTCA imaging protocol complies with the 
doses outlined in the research protocol prior to recruitment and patient doses will be recorded and 
monitored as part of the study. Iodine based contrast agent will be administered intravenously using the 
standard local procedure at each site.  The use of GTN for coronary artery dilatation will be used at the 
discretion of individual centres.  
 
Further guidance can be found in the trial CT coronary angiography guidance document. 
 
CTCA result reporting 
 
CTCA will be usually reported by a trained radiologist or cardiologist at recruiting centres as soon as 
possible, ideally within 2 hours and communicated immediately to the treating clinician. 
 
The clinical report detailing the results should be reported according to the Society of Cardiovascular 
CT guidelines, with the use of the AHA coronary artery segment model and will include both the calcium 
score if calculated and the presence of cardiac and non-cardiac findings. Stenoses will be quantified as: 
no significant coronary artery disease (estimated stenosis <10%), mild non-obstructive disease 
(estimated stenosis of 10-49%), moderate non-obstructive disease (estimated stenosis of 50-70%), or 
obstructive coronary artery disease (estimated stenosis of >70%).  
 
The research Scan Report should also be completed by the radiologist/cardiologist and will record 
scanner technology, acquisition protocol, dose length product and patient characteristics.  
 
 A proportion of CTCA reporting may be delivered remotely using remote access technology by a core 
group of readers. Transfer of image data is simple and a well-established process within the UK for out-
of-hours reporting.   Secure electronic transfer via the national PACS system (with required 
permissions) will allow reporting using voice recognition dictation either direct to the host radiology 
information system or via e-mail direct to the referring centre.  
 
QA reporting of CTCA scans  
A proportion of scans will be re-reported by experts independent to the trial site and blinded to the 
initial report to measure inter-observer reliability. The first 10 scans carried out at each site will undergo 
this process, as detailed in the working practice document ‘Dual Quality Assurance Reporting of CTCA 
Scans’.   
 
CTCA for future research 
The scans sent for QA reporting will be retained for future research.  Additional scans will be collected 
from sites willing to provide these for this research repository.  
 
Impact of technology on care pathway 
A trial guideline on the management of trial participants depending on CTCA result is listed in appendix 
1. This will, however, not be mandated as this is a pragmatic trial investigating the impact of the 
diagnostic intervention on practice and clinical outcomes.  

 
 
 
 
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Current alternative investigation strategies and standard care arm 
Investigation guidelines and strategies for each centre will be collected and the use of CTCA will be 
monitored during the trial. Each centre will be requested not to use CTCA in the routine assessment of 
suspected or confirmed ACS during trial recruitment and should inform the trials team about any 
changes to local practice. 
7. 
DATA COLLECTION 
Data collection for primary, secondary and safety clinical outcomes 
Data will be collected by the research team from routinely available NHS hospital records or trial specific 
documentation and will include the following categories: eligibility criteria, consent and baseline 
demographics, comorbidities, regular treatment, ECG results, vital signs, blood results, admission and 
discharge diagnoses, cardiology and other relevant investigations or interventions, length of stay, repeat 
hospitalisations and adverse events. Detail will also be collected on the trial intervention including timing, 
details of the procedure including dose, reporting clinician, report including incidental findings, and any 
adverse events as a result of the intervention. 
 
Collection of cost and health outcome data 
Length of stay and major adverse cardiac events will be recorded from telephone contact of patients, 
hospital and primary care records, and deaths from the Central Registry Office or equivalent. At 
baseline, 1, 6 and 12 months, quality of life and angina symptoms will be measured using the EQ-5D-
5L and ROSE questionnaires by direct patient interview, postal or email survey with telephone follow up 
for non-responders after two mailings two weeks apart.  
8. 
STATISTICS AND DATA ANALYSIS 
Statistical Analysis 
The trial will be reported on an intention-to-treat basis. The primary outcome is defined as first event of 
all cause death or subsequent non-fatal MI type 1 or 4b. Time to primary outcome is defined as time 
from randomisation to primary outcome. Patients discontinuing the study (for any reason) prior to 
reaching primary outcome will have their time to primary outcome censored at the last contact date. The 
relationship between intervention and the primary outcome will be analysed using Cox proportional 
hazard regression adjusted for study site (used to stratify the randomisation), baseline GRACE score, 
and previous CAD. The results will be expressed as a hazard ratio with the corresponding 95% 
confidence intervals and p-value. The individual elements of the composite primary outcome will be 
reported separately. Subgroup analysis on the primary outcome is planned for age, sex, baseline 
GRACE score, previous CAD, baseline ECG result, baseline troponin concentration, and presentation 
to a study site with or without on-site invasive coronary angiography facilities. These will be assessed 
by examining the effect of entering the treatment by subgroup interaction into the Cox regression model. 
Secondary outcomes will be analysed using appropriate methods: logistic regression for binary 
outcomes and linear regression for normally distributed continuous outcomes, adjusted as described 
above. Continuous outcomes that are not normally distributed will be analysed using appropriate 
nonparametric techniques.  Every effort will be made to minimise missing data, and our primary analysis 
will be a complete case analysis. If there is a sufficient level of missing data for it to affect our 
conclusions, a multiple imputation analysis will be undertaken, using clinically appropriate variables, as 
a sensitivity analysis. Significance testing will use a hierarchical approach – for the primary outcome  
and the key secondary outcomes, statistical significance will be declared if the outcome in question, and 
all prior outcomes listed, have p<0.05.  P-values will be reported for all other outcomes but will not be 
declared to be significant. 
 
A full statistical analysis plan will be written during the trial and finalised prior to database lock. 
 
Economic analysis 
Economic evaluation will assist policy makers to decide whether multidetector computed tomography 
scanning represents a cost-effective use of NHS resources. Cost-effectiveness analysis will be used to 
estimate the incremental costs and quality adjusted life years (QALYs). The economic analysis will 
include a) within-trial cost effectiveness analysis (i.e. comparing the observed costs and QALYs of the 

 
 
 
 
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intervention and control groups during the trial period), and b) analysis of the long-term cost 
effectiveness of CTCA, by adapting an existing decision analytic model [Goodacre S et al, 2013; Thokala 
P et al, 2012],  
 
In the within trial cost-effectiveness analysis, incremental cost per QALY gained by using CTCA 
compared to standard care will be estimated by calculating the area under the curve for health utility 
using the EQ-5D-5L and health service costs up to one year. Quality of life will be measured using the 
EQ-5D-5L at baseline and 1, 6 and 12 months after index admission. All health care consumption and 
costs will be estimated from a health care perspective using patient self-reported questionnaires, and 
from hospital records. Costs will be attributed to the need for (i) continued hospitalisation, (ii) additional 
invasive or non-invasive imaging, (iii) drug therapy, and (iv) rehospitalisation for myocardial ischaemia. 
Resource use will be measured for each patient in the trial and multiplied by national average costs to 
provide the estimated cost per patient.  
 
Long term cost-effectiveness will be estimated by adapting an existing model, developed for as part of 
a previous HTA evidence synthesis project [Goodacre S et al, 2013; Thokala P et al, 2012]. The model 
used published sources to capture the life expectancy, annual costs and corresponding annual utilities, 
based on whether they had MI at initial hospital attendance and whether they suffered reinfarction. The 
data from the trial will be input into the model which estimates the lifetime QALYs and costs of surviving 
patients. The results will be reported as the incremental cost effectiveness ratio (ICER) of CTCA arm 
compared to usual care. 
Sensitivity analyses will explore the potential impact of parameters upon costs, QALYs and ICERs. 
Parameter uncertainty will be included in probabilistic sensitivity analysis based on Monte Carlo 
simulation. Cost effectiveness acceptability curves (CEACs) will be plotted to identify the probability of 
the CTCA arm being cost effective compared to standard care for a range of threshold values for an 
additional QALY.  
9. 
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definitions detailed below.   
All adverse events (AE) meeting the criteria outlined in section 9.2.1 must be reported in detail on the 
Adverse Events CRF.  Participants undergoing CTCA will be instructed to contact their Investigator after 
consenting to join the trial if any symptoms develop from consent until 10 days after joining the study. 
Participants in the standard care arm that go on to receive a scan should also have any relevant AEs 
recorded.  
In the case of an AE, the Investigator should initiate the appropriate management according to their 
medical judgment.  Participants with AEs present at the last visit must be followed up until resolution of 
the event. 
9.1. DEFINITIONS 
Adverse Event (AE) 
Any untoward medical occurrence in a study participant, which does not necessarily have a causal 
relationship with the study intervention. 
Adverse Reaction (AR) 
Any untoward and unintended response that has occurred due to the intervention. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
Any AE or AR that: 
 
results in death of the study participant 
 
is life-threatening* 
 
requires inpatient hospitalisation^ or prolongation of existing inpatient hospitalisation 

 
 
 
 
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 
results in persistent or significant disability or incapacity 
 
consists of a congenital anomaly or birth defect 
 
results in any other significant medical event not meeting the criteria above 
* Life-threatening in the definition of an SAE or SAR refers to an event where the participant was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might have caused 
death if it were more severe. 
^ Any hospitalisation that was planned prior to randomisation will not meet SAE criteria. Any 
hospitalisation that is planned post randomisation, will meet the SAE criteria. 
9.2. IDENTIFYING AEs AND SAEs 
All AEs and SAEs that meet the reporting criteria in sections 9.2.1 and 9.2.2 will be recorded from the 
time a participant signs the consent form to take part in the study until 10 days afterwards. . Patients 
who have consented to the trial will be asked to contact the research team if they experience any 
untoward effects within these 10 days. 
AEs and SAEs may also be identified via information from support departments e.g. laboratories or the 
patient record.  These will be reported to the investigator within 7 days of identification.  
Any AEs or SAEs out-with the given definitions will not be recorded during the study.   
 
9.2.1 
Adverse Events relating to CT Scanning 
 
The following Adverse Events can be attributed to the application of CTCA and should be recorded as 
an AE (and reported as an SAE if appropriate):  
 
 
Contrast related anaphylaxis/allergy requiring treatment, requiring critical care admission or 
resulting in cardiac arrest or death.  
 
Contrast related AKI or Acute on CKD 
 
Side effects or complications related to beta blocker (or alternative HR-limiting medication) or 
Glyceryl Trinitrate premedication. 
 
No other AEs out-with this definition will be recorded on the CRF. 
 
9.2.2 SAE reporting and exemptions 
All SAEs that meet the definition given in section 9.1 should be reported to the Sponsor unless they 
meet the exemption criteria below. SAEs should be reported from consent until 10 days afterwards.  
These events are anticipated to occur in this patient group and will not be reported to the Sponsor but 
will be collected in the CRF for all participants: 
 
Malignant arrhythmia – CHB requiring pace maker; VT/VF/SVT requiring cardioversion or     
 defibrillation 
 
Cardiac Arrest  
 
Death 
 
ICU admission 
 
Procedure related MI, coronary artery dissection, pseudo aneurysm 
 
9.3. RECORDING AEs AND SAEs. 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g. 
hospital notes, laboratory and diagnostic reports) related to the event.  The Investigator will then record 
all relevant information in the CRF and on the SAE form (if the AE meets the criteria of serious). 

 
 
 
 
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9.4 ASSESSMENT OF AEs AND SAEs 
Each AE must be assessed for seriousness, causality, severity and expectedness by the PI or another 
suitably qualified physician in the research team who is trained in recording and reporting AEs and who 
has been delegated this role. 
The Chief Investigator (CI) may not downgrade an event that has been assessed by an Investigator as 
an SAE or SAR but can upgrade an AE to an SAE or SAR if appropriate. 
The Investigator will make an assessment of seriousness (as defined in section 9.1). 
9.4.1. Assessment of Causality 
The Investigator will make an assessment of whether the AE is likely to be related to the study 
intervention according to the following definitions: 
Unrelated: where an event is not considered to have occurred as a result of the study intervention. 
Possibly Related: The nature of the event, the underlying medical condition, concomitant medication 
or temporal relationship make it possible that the AE has a causal relationship to the study intervention. 
Where there are two assessments of causality (e.g. between PI and CI), the causality assessment by 
the Investigator cannot be downgraded. In the case of a difference of opinion, both assessments are 
recorded and the ‘worst case’ assessment is used for reporting purposes. 
9.4.2. Assessment of Expectedness 
 If the AE is judged to be related to the study intervention, the Investigator will make an assessment of 
expectedness. 
Expected: The type of event is expected in line with the study intervention. 
Unexpected: The type of event was not listed in the protocol or related documents/literature as an 
expected occurrence. 
9.4.3. Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record this on the CRF or 
SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not interfering 
with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday activities. 
Severe: an event that prevents normal everyday activities. 
Note: the term ‘severe’, used to describe the intensity, should not be confused with ‘serious’ which is a 
regulatory definition based on participant/event outcome or action criteria.  For example, a headache 
may be severe but not serious, while a minor stroke is serious but may not be severe. 
9.5 REPORTING OF SAEs/SARs 
Once the Investigator becomes aware that an SAE has occurred in a study participant, the information 
will be reported to the ACCORD Research Governance & QA Office immediately or within 24 hours. 
If the Investigator does not have all information regarding an SAE, they should not wait for this additional 
information before notifying ACCORD.  The SAE report form can be updated when the additional 
information is received. 
The SAE report will provide an assessment of causality and expectedness at the time of the initial report 
to ACCORD according to Sections 9.4.2, Assessment of Causality and 9.4.3, Assessment of 
Expectedness. 
The SAE form will be transmitted by fax to ACCORD on +44 (0)131 242 9447 or may be transmitted by 
hand to the office or submitted via email to Safety.Accord@ed.ac.uk. Only forms in a pdf format will be 
accepted by ACCORD via email. 
Where missing information has not been sent to ACCORD after an initial report, ACCORD will contact 
the investigator and request the missing information.  

 
 
 
 
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All reports faxed to ACCORD and any follow up information will be retained by the Investigator in the 
Investigator Site File (ISF). 
9.6 FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator will follow each 
participant until resolution or death of the participant.  Follow up information on an SAE will be reported 
to the ACCORD office. 
AEs still present in participants at the last study visit will be monitored until resolution of the event or 
until no longer medically indicated. 
10 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
The Edinburgh CTU will be responsible for trial management including: organisation of management 
group meetings, organisation of the steering committee and data monitoring committee, contracting with 
other organisations, preparation of REC and R&D applications, standard operating procedures, 
provision of the randomisation system, database development, data management, data analysis, writing 
the report and dissemination of findings.   
10.1 TRIAL MANAGEMENT GROUP 
The trial will be led by Alasdair Gray and coordinated by an experienced ECTU trial manager and 
emergency medicine research nurse coordinator with support from ECTU. A project management group 
(PMG) comprising the applicants and relevant members of the ECTU team will be formed. The 
Academic and Clinical Central Office for Research & Development (ACCORD) in Edinburgh will provide 
Sponsorship and monitoring oversight for the project and the trial will be conducted in line with the 
relevant Sponsor SOPs which are http://www.accord.ed.ac.uk/standardopprocs/CRSOPs.html.  
 
A Delegation Log will be prepared for each site, detailing the responsibilities of each member of staff 
working on the trial.   
 
10.2 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established to oversee the conduct and progress of the study. 
The terms of reference of the Trial Steering Committee, the draft template for reporting and the names 
and contact details are detailed in the TSC charter.  
10.3 DATA MONITORING COMMITTEE 
A Data Monitoring Committee will be composed of independent members and at a minimum will include 
a statistician, a cardiologist, a radiologist and an emergency or acute medicine physician. The Peto-
Haybittle rule will be used by the Data Monitoring Committee as a guideline on the primary endpoint to 
trigger discussions on stopping the trial. Importantly the decision to stop the trial will not rely on p-values 
alone and will consider whether the results are convincing to the clinical community and patients. 
 
 
10.4 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and audits on behalf 
of the sponsor and REC review.  In the event of an audit or monitoring, the Investigator agrees to allow 
the representatives of the sponsor direct access to all study records and source documentation. 
11 
GOOD CLINICAL PRACTICE 
11.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of Good Clinical Practice (GCP). 
A favorable ethical opinion will be obtained from the appropriate REC and local R&D approval will be 
obtained prior to commencement of the study. 

 
 
 
 
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11.2 INVESTIGATOR RESPONSIBILITIES 
The PI is responsible for the overall conduct of the study at the site and compliance with the protocol 
and any protocol amendments.  In accordance with the principles of GCP, the following areas listed in 
this section are also the responsibility of the PI.  Responsibilities may be delegated to an appropriate 
member of study site staff.   
11.2.1 Informed Consent 
The Principal Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out and this process should be carried out as detailed in section 5.2 of 
the protocol.    
11.2.2 Study Site Staff 
The Investigator must be familiar with the intervention, protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately informed about 
the intervention, protocol and their trial related duties. 
11.2.3 Data Recording 
The PI is responsible for the quality of the data recorded in the CRF at each Investigator Site. The source 
data plan identifies which source data correspond to CRF data and states which data are recorded 
directly into the CRF. 
11.2.4 Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular essential documents 
to the ACCORD Research Governance & QA Office, including but not limited to: 
 
An original signed Investigator’s Declaration (as part of the Clinical Trial Agreement 
documents); 
 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it is accurate and 
current. 
The ACCORD Research Governance & QA Office will ensure all other documents required by GCP are 
retained in a Trial Master File (TMF), where required, and that appropriate documentation is available 
in local ISFs. 
11.2.5 GCP Training 
Principal Investigators at each site should hold evidence of GCP training and ensure their staff are aware 
of the guidelines.  All staff on the delegation log should have appropriate and relevant training in the 
research tasks that they undertake.   
11.2.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a manner 
designed to maintain participant confidentiality.  All records must be kept in a secure storage area with 
limited access.  Clinical information will not be released without the written permission of the participant.  
The Investigator and study site staff involved with this study may not disclose or use for any purpose 
other than performance of the study, any data, record, or other unpublished, confidential information 
disclosed to those individuals for the purpose of the study.  Prior written agreement from the sponsor or 
its designee must be obtained for the disclosure of any said confidential information to other parties. 
11.2.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements of the 
Data Protection Act 1998 and General Data Protection Regulation (GDPR) with regard to the collection, 
storage, processing and disclosure of personal information and will uphold the Act’s core principles. 
Access to collated participant data will be restricted to those clinicians treating the participants, 
representatives of the sponsor(s).  
Computers used to collate the data will have limited access measures via user names and passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 

 
 
 
 
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12  
STUDY CONDUCT RESPONSIBILITIES 
12.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate hazard to 
the participant in the case of an urgent safety measure, must be reviewed and approved by the Chief 
Investigator.   
Amendments to the protocol must be submitted in writing to the appropriate REC and local R&D for 
approval prior to participants being enrolled into an amended protocol. 
12.2 PROTOCOL VIOLATIONS AND DEVIATIONS 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and therefore 
will not be implemented, except where necessary to eliminate an immediate hazard to study participants. 
If this necessitates a subsequent protocol amendment, this should be submitted to the REC and local 
R&D for review and approval if appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the sponsors 
every 6 months. Each protocol violation will be reported to the sponsor within 3 days of becoming aware 
of the violation. 
12.3 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 5 years from the protocol defined end of study 
point.  When the minimum retention period has elapsed, study documentation will not be destroyed 
without permission from the sponsor. 
12.4 END OF STUDY 
The end of study is defined as 15 months after the recruitment of the last participant.  
The Investigators and/or the trial steering committee and/or the co-sponsor(s) have the right at any time 
to terminate the study for clinical or administrative reasons.  
The end of the study will be reported to the REC within 90 days, or 15 days if the study is terminated 
prematurely.  The Investigators will inform participants of the premature study closure and ensure that 
the appropriate follow up is arranged for all participants involved. 
A summary report of the study will be provided to the REC within 1 year of the end of the study. 
12.5 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
 
The Protocol has been designed by the Chief Investigator and researchers employed by the 
University and collaborators.  The University has insurance in place (which includes no-fault 
compensation) for negligent harm caused by poor protocol design by the Chief Investigator 
and researchers employed by the University. 
 
Sites participating in the study will be liable for clinical negligence and other negligent harm to 
individuals taking part in the study and covered by the duty of care owed to them by the sites 
concerned.  The co-sponsors require individual sites participating in the study to arrange for 
their own insurance or indemnity in respect of these liabilities. 
 
Sites which are part of the United Kingdom's Nation Health Service will have the benefit of 
NHS Indemnity. 

 
 
 
 
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13  
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS 
The protocol for this trial will be submitted for publication and the trial results will be submitted for 
publication even if this trial stops early. If successfully completed the main paper from this project will 
be submitted for publication in a leading international general medical journal. 
 
The main outputs will be provided to guideline developing bodies (including NICE, SIGN and the 
European Society of Cardiology), key professional organisations (such as the College of Emergency 
Medicine) and patient representative organisations (such as the British Heart Foundation). 
13.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.  On completion of the study, 
the study data will be analysed and tabulated, and a study report will be prepared in accordance with 
the funders requirements. The authors for this project are listed in the trial’s writing committee and 
publication policy document.  
13.2 PUBLICATION 
The clinical study report will be used for publication and presentation at scientific meetings. Investigators 
have the right to publish orally or in writing the results of the study. 
Summaries of results will also be made available to Investigators for dissemination within their centres 
(where appropriate and according to their discretion). 
13.3 PEER REVIEW 
The trial has been reviewed by the Edinburgh Clinical Trials Unit executive group, the NIHR national 
cardiovascular group and HTA reviewers. 
14  
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Appendix 1 - Management guideline for trial intervention arm 
 
CTCA result 
Troponin 
result 
 
Trial treatment recommendation 
Obstructive Disease: Stenosis ≥70%
 
 
Positive 
or 
Negative 
1. 
ACS 
and 
secondary 
preventative 
therapies; 
2. 
Invasive 
Coronary 
Angiography 
± 
revascularisation. 
Moderate Non-obstructive Disease: 
Stenosis 50-69%  
 
  
Positive 
 
 
 
1. 
ACS 
and 
secondary 
preventative 
therapies;  
2. Consider Invasive Coronary Angiography 
if 
uncertainty 
about the presence of 
obstructive coronary artery disease or 
functional testing. 
Moderate Non-obstructive Disease: 
Stenosis 50-69%  
 
Negative 
1. Secondary preventative therapies; 
2. Consider Invasive Coronary Angiography 
if 
uncertainty 
about the presence of 
obstructive coronary artery disease or 
functional testing. 
Mild Non-obstructive Disease: 
Stenosis <50% 
 
Positive 
 
1. 
Consider 
ACS 
and 
secondary 
preventative therapies. 
2. Consider alternative cause of chest pain 
and troponin rise  
Mild Non-obstructive Disease: 
Stenosis <50% 
 
Negative 
1. Discharge with no further follow up; 
2. 
Consider 
secondary 
preventative 
therapies. 
Normal (no evidence of CAD)  
 
Discharge with no further follow up.