Duration of Dual Anti-Platelet Therapy in Acute Coronary Syndrome
Phase: PHASE4
Conditions: Acute Coronary Syndrome, Coronary Artery Disease
Sponsor: University of Edinburgh

 
 
Study Title 
Duration of Dual Anti-Platelet Therapy in  
Acute Coronary Syndrome  
The DUAL-ACS Trial 
 
Document Title 
  UK Protocol 
 
Document Version and Date  
  Version 6.0 22 July 2022 
 
NCT Number 
  NCT03252249 
 
 

 
CR007-T01v2.1 
Page 1 of 39 
 
 
Study Protocol 
 
 
 
Duration of Dual Anti-Platelet Therapy in  
Acute Coronary Syndrome  
The DUAL-ACS Trial 
 
UK Protocol 
 
Co-sponsors 
University of Edinburgh & NHS Lothian 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
British Heart Foundation 
Funding Reference Number 
SP/17/12/32960 
Chief Investigator 
Professor David Newby  
REC Number 
18/YH/0013 
Sponsor Reference 
AC16104 
Clinical Trials.gov  reference NCT03252249 
EudraCT Number 
2016-003596-22 
Version Number and Date 
Version 6.0 22 July 2022   

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COORDINATING CENTRE 
 
Chief Investigator 
 
Professor David Newby 
Centre of Cardiovascular Science 
Chancellor’s Building 
49 Little France Crescent 
Edinburgh EH16 4SB  
 
Tel: 0787 616 3699                                
Fax: 0131 242 6379                               
Email: d.e.newby@ed.ac.uk 
 
Co-sponsor Representative 
 
Dr Fiach O’Mahony 
Research Governance & QA Office  
Queens Medical Research Institute  
47 Little France Crescent  
Edinburgh  EH16 4TJ 
 
Tel: 0131 2429418 
Email: Fiach.O’Mahony@ed.ac.uk 
 
Trial Manager 
 
Dr Laura Forsyth 
Edinburgh Clinical Trials Unit 
Usher Institute, 
University of Edinburgh  
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh  
EH16 4UX   
 
Tel: 0131 651 9912 
 
Email: laura.forsyth@ed.ac.uk 
Trial Statistician 
 
Professor John Norrie 
Edinburgh Clinical Trials Unit  
Usher Institute, 
University of Edinburgh  
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh  
EH16 4UX   
 
Tel: 0131 651 7895 
Email: j.norrie@ed.ac.uk 
 

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CONTENTS 
1. 
INTRODUCTION .............................................................................................. 9 
1.1 
META-ANALYSES ................................................................................. 10 
1.2 
BLEEDING AND TOTAL MORTALITY ................................................... 11 
1.3 
REDUCING ATHEROTHROMBOTIC EVENTS ..................................... 11 
1.4 
PILOT DATA: ONE-YEAR MORTALITY FOLLOWING MYOCARDIAL 
INFARCTION IN SCOTLAND ................................................................ 12 
1.5 
ELECTRONIC HEALTH RECORDS FOR MAJOR CLINICAL TRIALS .. 13 
1.6  
IMPORTANCE ....................................................................................... 14 
1.7 
SCIENTIFIC PRINCIPLES UNDERLYING THE PROPOSED 
RESEARCH ........................................................................................... 14 
1.8  
RATIONALE FOR THE TRIAL ............................................................... 15 
2. 
STUDY OBJECTIVES .................................................................................... 16 
2.1 
STUDY ENDPOINTS ............................................................................. 16 
3 
STUDY DESIGN ............................................................................................. 17 
4. 
STUDY POPULATION ................................................................................... 17 
4.1 
NUMBER OF PARTICIPANTS ............................................................... 17 
4.2 
INCLUSION CRITERIA .......................................................................... 17 
4.3  
EXCLUSION CRITERIA ......................................................................... 17 
4.4 
CO-ENROLMENT .................................................................................. 17 
5 
PARTICIPANT SELECTION AND ENROLMENT .......................................... 18 
5.1 
IDENTIFYING PARTICIPANTS ............................................................. 18 
5.2 
CONSENTING PARTICIPANTS ............................................................ 18 
5.3 
SCREENING FOR ELIGIBILITY ............................................................ 18 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .......................... 18 
5.5 
RANDOMISATION ................................................................................. 18 
5.5.1 
Randomisation Procedures ................................................................. 18 
5.5.2 
Treatment Allocation ........................................................................... 19 
5.5.3 
Methods to Ensure Blinding ................................................................ 19 
5.5.4 
Discontinuation of the Investigational Medicinal Product ..................... 19 
5.6 
WITHDRAWAL OF STUDY PARTICIPANTS ......................................... 19 
6 
INVESTIGATIONAL MEDICINAL PRODUCTS .............................................. 20 
6.1. 
STUDY DRUGS ..................................................................................... 20 
6.2. 
PARTICIPANT COMPLIANCE ............................................................... 20 
6.3. 
OTHER MEDICATIONS ......................................................................... 20 
6.3.1 
Prohibited Medications ........................................................................ 20 
7 
STUDY ASSESSMENTS ................................................................................ 21 
7.1 
OUTCOME ASSESSMENTS AND DATA COLLECTION ....................... 21 
7.2 
COMPLIANCE ....................................................................................... 21 
8. 
DATA COLLECTION ..................................................................................... 21 
8.1 DATA MANAGEMENT ................................................................................ 21 
8.1.1 Personal Data ........................................................................................ 21 

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8.1.2 Transfer of Data ..................................................................................... 22 
8.1.3 Data Processor ...................................................................................... 22 
8.1.4 Data Controller ....................................................................................... 22 
9. 
STATISTICS AND DATA ANALYSIS ............................................................ 22 
9.1 
PROPOSED SAMPLE SIZE .................................................................. 22 
9.2  
SAMPLE SIZE CALCULATION .............................................................. 23 
9.3 
PROPOSED ANALYSES ....................................................................... 23 
10. 
PHARMACOVIGILANCE ............................................................................... 24 
10.1 
DEFINITIONS ........................................................................................ 24 
10.2 
RECORDING AND REPORTING AEs, ARs, SAEs AND SARs ............. 25 
10.2.1 Assessment of Seriousness ................................................................ 25 
10.2.2 Assessment of Causality ..................................................................... 25 
10.2.3 Assessment of Expectedness ............................................................. 26 
10.2.4 Assessment of Severity ....................................................................... 26 
10.3 
REPORTING OF SUSARs ..................................................................... 27 
10.4 
REGULATORY REPORTING REQUIREMENTS ................................... 27 
10.5  
FOLLOW UP PROCEDURES ................................................................ 28 
10.6  
PREGNANCY ........................................................................................ 28 
11 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ..................... 28 
11.1 
TRIAL MANAGEMENT GROUP ............................................................ 28 
11.2 
TRIAL STEERING COMMITTEE. .......................................................... 28 
11.3 
DATA MONITORING COMMITTEE. ...................................................... 28 
11.4 
INSPECTION OF RECORDS ................................................................ 29 
11.5 
RISK ASSESSMENT ............................................................................. 29 
11.6 
BENEFIT and RISK BALANCE .............................................................. 29 
11.7 
STUDY MONITORING AND AUDIT ....................................................... 29 
12 
GOOD CLINICAL PRACTICE ........................................................................ 30 
12.1 
ETHICAL CONDUCT ............................................................................. 30 
12.2 
REGULATORY COMPLIANCE .............................................................. 30 
12.3 
INVESTIGATOR RESPONSIBILITIES ................................................... 30 
12.3.1 Informed Consent ................................................................................ 30 
12.3.2 Study Site Staff ................................................................................... 31 
12.3.3  Data Recording ................................................................................... 31 
12.3.4 Investigator Documentation ................................................................. 31 
12.3.5  GCP Training ...................................................................................... 31 
12.3.6  Confidentiality ..................................................................................... 31 
12.3.7  Data Protection ................................................................................... 32 
13. 
STUDY CONDUCT RESPONSIBILITIES ....................................................... 32 
13.1 
PROTOCOL AMENDMENTS ................................................................. 32 
13.2 
PROTOCOL NON COMPLIANCE .......................................................... 32 
13.2.1 Definitions ........................................................................................... 32 
13.2.2 Protocol Waivers ................................................................................. 32 
13.2.3 Management of Deviations and Violations........................................... 33 
13.3 
URGENT SAFETY MEASURES ............................................................ 33 
13.4 
SERIOUS BREACH REQUIREMENTS .................................................. 33 
13.5 
STUDY RECORD RETENTION ............................................................. 33 

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13.6 
END OF STUDY .................................................................................... 34 
13.7 
INSURANCE AND INDEMNITY ............................................................. 34 
14. 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ............ 35 
14.1 
AUTHORSHIP POLICY ......................................................................... 35 
14.2 
PUBLICATION ....................................................................................... 35 
14.3 
DATA SHARING .................................................................................... 35 
14.4  
PEER REVIEW ...................................................................................... 35 
15. 
REFERENCES ............................................................................................... 36 
 
 
 

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PROTOCOL APPROVAL SIGNATURE PAGE 
 
Duration of Dual Anti-Platelet Therapy in Acute Coronary Syndrome  
The DUAL-ACS Trial 
 
 
Signatures 
 
 
Professor David Newby 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Professor John Norrie 
 
 
 
Trial Statistician 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Dr Fiach O’Mahony 
 
 
 
Sponsor(s) 
Representative 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator  
Signature 
 
Site  
 
Date 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & 
Development  
Joint Office for University of Edinburgh and NHS Lothian 
AE 
Adverse Event 
AR 
Adverse Reaction 
BCIS 
British Cardiovascular Society Intervention 
CRF 
Case Report Form 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NHS 
National Health Service 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
UAR 
Unexpected Adverse Reaction 

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SUMMARY 
 
Despite substantial evidence supporting the use of dual anti-platelet therapy in 
patients with acute coronary syndrome, there remains major uncertainty regarding 
the optimal duration of therapy. Recent evidence suggests that shorter durations 
of dual anti-platelet therapy are superior because the avoidance of 
atherothrombotic events is counterbalanced by the greater risks of excess major 
bleeding with apparent increases in all-cause mortality with longer durations. We 
here propose an international randomised controlled trial of 18,318 patients with 
type 1 myocardial infarction allocated to differing durations of dual anti-platelet 
therapy. We will use electronic health record linkage to track duration of therapy 
and clinical outcomes in a real-world, real-time, efficient and highly cost-effective 
trial. This has the potential to define treatment duration, settle a major outstanding 
international controversy, and influence modern cardiology practice across the 
world.  
 
It was planned that 18,318 participants would be recruited to the trial but 
recruitment in the UK was halted after 4,576 patients because the funder felt the 
trial was undeliverable due to the current challenging environment.  

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1. 
INTRODUCTION 
 
Coronary heart disease is the commonest cause of death worldwide. The World 
Health Organisation estimates that 3.8 million men and 3.4 million women die from 
coronary heart disease each year. Since 1990, more people have died from 
coronary heart disease than any other cause. In the United Kingdom, coronary 
heart disease is also the single biggest killer. It is responsible for nearly one in six 
deaths for men and one in ten for women: three times more women die from 
coronary heart disease than breast cancer. Indeed, 73,000 people die in the United 
Kingdom every year: one person every 7 minutes. Death rates are particularly high 
in Scotland, especially in areas of social deprivation. Deaths are sudden and 
unheralded, increasing the distress of those left behind. Coronary heart disease 
also has a devastating effect on peoples’ lives not just from the large numbers of 
those who die from it. Disability-adjusted life years, a measure of “healthy years of 
life lost”, can be used to indicate the burden of disease rather than the resulting 
deaths. The World Health Organisation estimates that coronary heart disease is 
responsible for 10% of disability-adjusted life years in low-income and 18% in high-
income countries. In the United Kingdom, 2.3 million people are living with coronary 
heart disease [BHF, 2012]. 
 
A ruptured or eroded coronary atherosclerotic plaque is the underlying cause of an 
acute coronary syndrome. This plaque heals in combination with therapeutic 
interventions, such as dual anti-platelet therapy, statins and coronary 
revascularisation. The greatest “at risk” period is during this early phase of plaque 
instability and healing, with recurrent event rates peaking in the first month. By 
three months, the plaque has usually stabilised and subsequent event rates return 
to the background rates seen in patients with stable coronary heart disease [CURE, 
2001; Bhatt et al, 2006]. Indeed, beyond three months, recurrent events commonly 
occur on ‘non-culprit’ plaques at other sites within the coronary circulation [Stone 
et al, 2011]. Therefore, from first principles, the first three months are the most time 
critical for interventions to reduce recurrent cardiovascular events after an acute 
coronary syndrome. This is consistent with event rates seen in all clinical trials of 
patients with acute coronary syndrome: an initial (0-3 months) time-varying high 
event rate that reverts to a consistent linear lower event rate from 3 months 
onwards (Table 1) [CURE, 2001; Chen et al, 2005; Bhatt et al, 2006; Wiviott et al, 
2007; Fox et al, 2008; Wallentin et al 2009]. 
 
When used in addition to aspirin, the CURE [CURE, 2001] and COMMIT-CCS 
[Chen et al, 2005] trials demonstrated reductions in cardiovascular events with 
clopidogrel, and the TRITON [Wiviott et al, 2007] and PLATO [Wallentin et al, 2009] 
trials demonstrated superior efficacy of prasugrel and ticagrelor above clopidogrel. 
However, these trials have included considerable variations in the duration of dual 
anti-platelet therapy: from 1 to 15 months. This in itself has generated confusion 
regarding the duration of dual anti-platelet therapy. Given the early cardiovascular 
hazards, the biggest absolute reductions in events with dual antiplatelet therapy 
are seen in the first 3 months after an acute coronary syndrome [CURE, 2001; 
Wiviott et al, 2007; Wallentin et al, 2009] (Table 1). The CHARISMA [Bhatt et al, 
2006] (Table 1) and PEGASUS [Bonaca et al, 2015] trials assessed the potential 
benefits of long-term maintenance dual anti-platelet therapies in patients without a 

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recent (>12 months) acute coronary syndrome and demonstrated reductions in 
cardiovascular events. However this came at a cost. Both trials reported increases 
in major bleeding events and a neutral effect on overall mortality. For major and 
serious bleeding (including fatal bleeds), the average number needed to harm per 
month is 900 for the CURE trial [CURE, 2001] and 2333 for the CHARISMA trial 
[Bhatt et al, 2006]. More contemporary trials show similar balances for benefit and 
harm. In the DAPT trial [Mauri et al, 2014], the number needed to treat to avoid a 
major adverse cardiovascular events was 1124 per month and the number needed 
to harm from major bleeding was 666 per month. For the PEGASUS trial [Bonaca 
et al, 2015], this was 2927 and 2590 respectively. For all of these trials, the risk of 
major bleeding exceeded the prevention of myocardial infarction without affecting 
all-cause mortality. 
 
Table 1. 
Temporal Relationship with the Clinical Benefits of Clopidogrel Therapy 
 
It is important to highlight that populations included in randomised controlled trials 
have lower rates of bleeding and non-cardiovascular death than the general 
population (Table 2) because patients with any history of bleeding or major 
comorbidity were specifically excluded from such trials. The introduction of dual 
antiplatelet therapy into routine clinical practice and the inclusion of a broader 
population of patients with acute coronary syndrome runs the risk of exaggerated 
harm without necessarily conferring greater benefit. The critical clinical question is: 
what is the optimal duration of dual anti-platelet therapy in a broad unselected 
population of patients with acute coronary syndrome? Does the excess bleeding 
risk negate the avoidance of atherothrombotic events? 
 
1.1 
META-ANALYSES 
Recent meta-analyses of trials using dual anti-platelet therapy in patients receiving 
intracoronary stents (including patients with acute coronary syndrome) have 
compared short (3-6 months), 12-month and extended (>12 months) durations of 
Time Interval 
(months) 
Primary end point 
 
Clopidogrel 
(%) 
Placebo 
(%) 
ARR 
(%) 
RRR 
(%) 
95% CIs 
NNT 
(per interval) 
NNT 
(per month) 
 
CURE trial 
0-1 
4.3 
5.5 
1.2 
22 
9 to 32% 
84 
84 
1-3 
1.8 
2.5 
0.8 
32 
13 to 46% 
120 
240 
3-6 
1.8 
1.8 
0.0 
4 
-27 to 27% 
1725 
5174 
6-9 
1.3 
1.4 
0.1 
6 
-34 to 34% 
1057 
3171 
9-12 
1.1 
1.3 
0.2 
14 
-32 to 44% 
533 
1600 
0-12 
10.3 
12.6 
2.4 
19 
 
42 
507 
 
CHARISMA trial 
0-28 
6.8 
7.3 
0.5 
7* 
-5 to 17% 
200 
5591 
0-28* 
6.9 
7.9 
1.0 
12 
0 to 23% 
100 
2800 
*Subgroup of patients with clinically evident atherosclerotic disease 
ARR – absolute risk reduction; RRR – relative risk reduction; CI – confidence intervals; NNT– number 
needed to treat 

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therapy [Navarese et al, 2015; Palmerini et al, 2015]. These analyses have shown 
that more prolonged durations of therapy reduce the risk of stent thrombosis and 
myocardial infarction but have no effect on cardiovascular death and increase the 
risk of major bleeding. Indeed, prolonged durations of therapy had either no or 
adverse effects on overall total mortality because of an increase in non-
cardiovascular death. However, switching from dual anti-platelet therapy to 
monotherapy (usually aspirin alone) is associated with a rebound prothrombotic 
effect especially with regard to an excess of stent thrombosis [Mauri et al, 2014; 
Bonaca et al, 2016; Bueno et al, 2016]. In the DAPT trial [Mauri et al, 2014], this 
phenomenon occurred irrespective of the timing of switching to monotherapy with 
rebound stent thrombosis and myocardial infarction seen whether dual anti-platelet 
therapy was stopped after 12 or 30 months. So, unless dual anti-platelet therapy is 
life-long, there will remain a small persistent short-term 3-month risk of rebound 
stent thrombosis and myocardial infarction following the transition from dual to 
monotherapy. 
 
1.2 
BLEEDING AND TOTAL MORTALITY 
Large registries and trials have shown that major bleeding is associated with an 
increase in mortality that could potentially negate the benefits of acute coronary 
syndrome treatment [Moscucci et al, 2003; Yusuf et al 2006; Stone et al, 2008; 
Budaj et al 2009]. Importantly, these bleeding risks are not confined to the initial 
hospitalization phase but are seen beyond hospitalisation [Yusuf et al, 2006; Rao 
et al, 2006; Stone et al, 2007]. 
 
The association between bleeding and mortality has been a consistent feature of 
acute coronary syndrome trials irrespective of the intervention being assessed. 
Moreover, improvements in outcome are seen with interventions that are 
associated with a lower bleeding risk. For example, in the OASIS-5 trial [Yusuf et 
al, 2006], fondaparinux had similar antithrombotic benefits to enoxaparin but was 
associated with lower rates of major bleeding and marked reductions in all-cause 
mortality. Similar benefits have also been reported for randomised controlled trials 
of arterial access sites in patients treated with an invasive strategy for either ST-
segment [Karrowni et al, 2013] or non-ST-segment [Valgimigli et al, 2015] 
myocardial infarction. Again, because radial artery access was associated with less 
bleeding, overall all-cause mortality was lower [Karrowni et al, 2013; Valgimigli et 
al, 2015]. There have been various mechanisms proposed for the link between 
bleeding and mortality that include rebound hypercoagulability, discontinuation of 
anti-thrombotic treatments, inflammation and ischaemia [Steg et al, 2011]. The 
European Society of Cardiology Working Group on Thrombosis has called for 
clinical trials to address bleeding in acute coronary syndrome including the 
exploration of the duration of dual anti-platelet therapy [Steg et al, 2011]. 
 
1.3 
REDUCING ATHEROTHROMBOTIC EVENTS 
In patients with acute coronary syndrome, the risk of a recurrent adverse cardiac 
event is related to the burden of coronary artery disease. Coronary intervention by 
either percutaneous coronary intervention or coronary artery bypass graft surgery 
effectively reduces this risk by relief of obstructive coronary disease. Coronary 
artery bypass graft surgery generally provides complete revascularization because 

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the bypass grafts are placed in distal locations ‘bypassing’ the more proximal 
disease. By contrast, percutaneous coronary intervention provides a focal 
treatment to individual lesions, and treatment may be incomplete because not all 
of the lesions may be treated by stents. Audit of the British Cardiovascular Society 
Intervention (BCIS) database indicates that in 2013 to 2014, 49% of all 
percutaneous coronary intervention procedures were associated with residual 
disease (≥1 stenosis >50% severity), fulfilling the criteria for incomplete 
revascularisation. Patients with acute coronary syndrome and incomplete 
revascularisation have a residual burden of coronary disease that is a substrate for 
recurrent plaque rupture, coronary thrombosis and future cardiac events. 
Prolonged dual antiplatelet therapy may mitigate this risk and prolonged therapy 
may benefit those patients with incomplete revascularisation following the index 
procedure to a greater extent than patients with complete revascularisation. 
 
1.4 
PILOT DATA: ONE-YEAR MORTALITY FOLLOWING MYOCARDIAL 
INFARCTION  
Clinical trial populations tend to be highly selected and hence do not reflect real 
world clinical practice. Using our national datasets, we have explored one-year 
mortality following acute coronary syndrome (Table 2). Perhaps as anticipated, all 
event rates are much higher in real world populations. Although cardiovascular 
death is 4-fold higher, the proportion of non-cardiovascular death is 8-fold higher 
and includes >3-fold higher rates of fatal bleeding. This reinforces the need to 
address this question in the population that will be treated in routine clinical 
practice. 
 

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Table 2.  
Comparative Event Rates Following Acute Coronary Syndrome 
 
 
1.5 
ELECTRONIC HEALTH RECORDS FOR MAJOR CLINICAL TRIALS 
We have previously demonstrated our ability to undertake large clinical trials and 
to exploit electronic health records to describe the diagnosis, investigation, 
treatment and clinical outcomes of patients with coronary heart disease [Pell et al, 
2008; Mills et al, 2011; Mills et al, 2012; Shah et al, 2015a; SCOT-HEART, 2015; 
Shah et al, 2015b; Williams et al, 2016]. In particular, we have used electronic 
health records to describe the implementation of sensitive [Mills et al, 2011; Mills 
et al, 2012] and high-sensitivity [Shah et al, 2015a; Shah et al, 2015b] cardiac 
troponin I assays in patients presenting with suspected acute coronary syndrome. 
We were able to report utilisation of healthcare resources including invasive 
coronary angiography, changing patterns of clinical diagnosis, and alterations in 
therapeutic interventions. Furthermore, we were able to follow-up patients for 
recurrent hospitalisations and survival, and reported many major findings that have 
informed current clinical practice and international guidelines. This laid the 
foundation for the ongoing British Heart Foundation-funded multicentre High-
Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome 
(High-STEACS) trial (NCT1852123) of over 20,000 patients presenting with 
suspected acute coronary syndrome. 
 
We have recently reported the Scottish COmputed Tomography of the HEART 
(SCOT-HEART) trial that assessed the additive value of computed tomography 
coronary angiography (CTCA) in the rapid access chest pain clinic [SCOT-HEART, 
2015]. This was conducted in 12 hospitals across Scotland and defined the 
influence of CTCA on the diagnosis, investigation, treatment and outcome of over 
4,000 patients with suspected angina pectoris due to coronary heart disease. Using 
national electronic health record datasets, we described numerous clinical 
outcomes 
including 
rates 
of 
invasive 
coronary 
angiography, 
coronary 
revascularisation, recurrent myocardial infarction, and cardiac and all-cause death 
[SCOT-HEART, 2015]. In subsequent post-hoc analyses, we were also able to 
obtain community prescribing data and identify the timing and changes in 
preventative and anti-anginal therapy consequent on the recommendations of the 
treating clinician in the light of the CTCA findings [Williams et al, 2016]. This has 
proven extremely powerful and demonstrates the feasibility and uniqueness of our 
 
CURE 
(Clopidogrel) 
TRITON 
(Prasugrel) 
TRILOGY 
(Prasugrel) 
PLATO 
(Ticagrelor) 
Randomised 
Controlled 
Trial Average 
Scotland 
(Clopidogrel) 
2006-2010 
(one-year 
event rates) 
All-cause 
Mortality 
5.8% 
3.0% 
8.3% 
4.5% 
5.40% 
25.4% 
Cardiovascular 
Death 
5.1% 
2.1% 
6.6% 
4.0% 
4.45% 
17.8% 
Non-
cardiovascular 
Death 
0.7% 
0.9% 
1.7% 
0.5% 
0.95% 
7.6% 
Fatal Bleeding  
0.2% 
0.4% 
0.2% 
0.3% 
0.28% 
0.9% 

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proposed approach. 
 
The use of electronic health records, routinely collected data and pragmatic trials 
is increasingly being recognised as the most appropriate approach to address 
many of the outstanding questions we face today [Ford & Norrie, 2016]. 
 
1.6  
IMPORTANCE 
Determining the default strategy for the duration of dual anti-platelet therapy is 
important because there is considerable heterogeneity in clinical practice and there 
are both harms and benefits from the intervention. For the public and patients, it is 
unclear what is the best duration of treatment to maximize the benefit (prevention 
of myocardial infarction) and minimize the harm (major bleeding) as well as to 
establish the effect on overall mortality. Patients prefer not to take medication 
unless it is necessary and are particularly concerned about the risks and harms of 
treatments. Dual anti-platelet therapy causes excessive minor and major bleeding 
(up to 1 in 6 patients) that can be very problematic for patients and occasionally 
fatal. However, patients also want the reassurance that they will not suffer another 
heart attack, require further invasive procedures or develop additional potentially 
life threatening disease.  
 
For clinicians and health care providers, there remains much uncertainty regarding 
the length of therapy after acute coronary syndrome. Duration of therapy is seen 
as a major priority for future research by numerous national and international 
guideline committees as well as having financial implications in terms of drug costs 
and therapy management in primary care. Currently there is equipoise with 
significant variations in local and regional practice that are confusing for patients, 
primary care physicians and cardiologists. Indeed, the Scottish Intercollegiate 
Guideline Network has varied between 3 and 6 months in its recommendations, 
and the European and North American guidelines recommend up to 12 months but 
acknowledge that shorter durations may be appropriate. All would welcome having 
clear evidence and guidance [Steg et al, 2011; Sharma et al, 2016].  
 
There are considerable cost implications for duration of therapy, especially for the 
latest generation of P2Y12 receptor antagonists with prasugrel and ticagrelor 
costing £50-60 per month. Major pharmaceutical companies have to date not 
funded trials comparing shorter (<12 months) durations of dual anti-platelet 
therapy, and arguably it is not in their commercial interest to do so. In addition, 
many patients were excluded from the major trials because of potential bleeding 
concerns. There is therefore a major concern that the evidence to date has been 
extrapolated to a broader population with a higher risk of adverse outcomes from 
bleeding. This has the potential for unnecessary harm that could attenuate or nullify 
any benefit from reducing cardiovascular events. 
 
1.7 
SCIENTIFIC PRINCIPLES UNDERLYING THE PROPOSED RESEARCH 
We propose a novel approach to assess the strategy for the duration of dual anti-
platelet therapy in type 1 myocardial infarction using routinely collected electronic 
health records linked to an international randomised controlled trial [Ford & Norrie, 
2016]. We will compare the proportion of patients with different baseline 

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characteristics (in terms of bleeding and atherothrombotic risks) among those 
included and not included in the trial (those who are not approached or refuse to 
participate) and within countries, where possible.. This design (i) facilitates a large 
adequately powered trial, (ii) represents ‘real world’ clinical practice and includes 
all patients who, in the opinion of the treating physician, should be managed with 
dual anti-platelet therapy, (iii) will allow valid extrapolation of results to patients who 
would otherwise not participate in clinical trials and who arguably have the greatest 
potential to incur benefits and risks, (iv) makes for a highly efficient and cost-
effective method of research delivery, (v) ensures optimal comparability and 
avoidance of bias, and (vi) generates adequate statistical power to address these 
pressing clinical questions. 
 
1.8  
RATIONALE FOR THE TRIAL 
Although several major trials have consistently demonstrated the benefits of dual 
anti-platelet therapy in patients with acute coronary syndrome, the optimal duration 
of therapy is unresolved, and the benefit of prolonged therapy may not outweigh 
the bleeding hazards. There are increasing calls for randomised controlled trials to 
assess duration of therapy following acute coronary syndrome [Steg et al, 2011; 
Sharma et al, 2016]. Current European Society of Cardiology guidelines [Roffi et 
al, 2015] recommend 12 months of dual antiplatelet therapy despite this lack of 
clear definitive evidence and the real concern that major bleeding exceeds the 
modest benefits of reducing atherothrombotic events beyond 3 months.  
 
We will test the hypothesis that compared to 12 months, 3 months of dual anti-
platelet therapy is safer for patients with type 1 myocardial infarction.  
 
 

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2. 
STUDY OBJECTIVES 
 
Our principal question is: should the default strategy for the duration of dual anti-
platelet therapy be 3 or 12 months after type 1 myocardial infarction? Given the 
opposing long-term harms and short-term benefits of dual antiplatelet therapy from 
recent meta-analyses, we propose to focus on the primary end-point of all-cause 
mortality. All-cause mortality is felt to be the only single outcome which could 
reliably capture the trade off in benefit from avoiding recurrent cardiovascular 
events in the acute term (part of which benefit should lead to fewer deaths) and the 
harms from bleeding over the longer term (part of which will lead to more deaths). 
All-cause mortality is also a simple outcome to measure and is highly complete and 
accurate in routine datasets, and any difference or similarity seen in all-cause 
mortality should be convincing as to which is overall the better duration of therapy 
for both patients and clinicians.  
 
Of course, secondary outcomes such as cardiovascular death, myocardial 
infarction, non-cardiovascular death and major bleeding will also be of major 
interest. We may also be able to identify subgroups of patients who experience 
substantially greater benefits or on the other hand have much greater hazards, 
which will allow a more nuanced recommendation for a treatment policy than simply 
one size fits all.    
 
2.1 
STUDY ENDPOINTS 
 
Table 3. 
Study Endpoints 
*Other endpoints will be collected where possible, but this will be country specific. 
 
Safety 
Efficacy 
Primary 
Endpoint 
All-cause mortality  
All-cause mortality 
 
 
 
Secondary 
Endpoints 
Non-cardiovascular death 
(including fatal bleeding) and 
major non-fatal bleeding 
Cardiovascular death or non-
fatal myocardial infarction 
 
Non-cardiovascular death  
(including fatal bleeding) 
Cardiovascular mortality  
(cardiac and non-cardiac) 
 
Major fatal and non-fatal 
bleeding  
Myocardial infarction (fatal and 
non-fatal) 
 
Hospitalisation for bleeding 
Stent thrombosis 
 
Intracranial haemorrhage 
Coronary revascularisation 
 
Gastrointestinal bleeding 
Thrombotic stroke 
 
 
 
Other 
endpoints* 
Blood Transfusion 
 
 
Haemoglobin  
 
 
Iron Therapy 
 

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3 
STUDY DESIGN 
This will be a prospective multicentre international open-label randomised 
controlled trial assessing the duration of dual antiplatelet therapy in patients with 
type 1 myocardial infarction.  
4. 
STUDY POPULATION 
 
4.1 
NUMBER OF PARTICIPANTS 
We plan to recruit 18,318 patients with type 1 myocardial infarction from both UK 
hospitals and international hospitals. The international sites will use a separate 
country-specific protocol.  
 
Recruitment in the UK was halted after 4,576 patients because the funder felt the 
trial was no longer deliverable due to the current challenging environment. The 
statistical analysis will include the 4,576 patients recruited in the UK and as many 
international patients who have completed follow-up at the time of analysis.  
 
4.2 
INCLUSION CRITERIA 
For inclusion in the study, participants will fulfil the following criteria: 
 
 Aged ≥18 years 
 Clinical diagnosis of type 1 myocardial infarction within 12 weeks  
 In the opinion of the attending clinician requires dual anti-platelet therapy 
with aspirin and a P2Y12 receptor antagonist.  
 Resident in the country of recruitment with their unique health identifier  
 The attending clinician has equipoise regarding the duration of therapy 
 Provision of informed consent 
 
4.3  
EXCLUSION CRITERIA 
Participants will not enter the study if any of the following exclusion criteria are 
fulfilled: 
 
 Clear indication for specific duration of dual anti-platelet therapy  
 Type 2 myocardial infarction 
 Contraindication to aspirin or P2Y12 receptor antagonist. 
 Non-resident in the country of recruitment 
 Previous recruitment into the trial 
 Inability or unwilling to give informed consent 
 
4.4 
CO-ENROLMENT 
Given the simplicity of the intervention, the minimal burden on the trial participant 
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other studies will be permitted for the majority of patients except where this would 
undermine the primary end-points of the trials. Co-enrolment in observational 
studies will be permitted. Co-enrolment in interventional trials will require 
agreement between the Chief Investigators and Trial Steering Committees of the 
respective trials as well as the trials Sponsors and will be performed in accordance 
with the ACCORD guidelines for co-enrolment GL001. 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
Patients will be identified and recruited from the cardiology and general medical 
hospital wards. All patients will be approached for study recruitment by their usual 
care team including appropriately trained members of the research team to whom 
this task has been delegated (this is not restricted to clinicians). Patients will be 
provided with a Patient Information Sheet and given an opportunity to ask questions 
about participation in the trial. 
 
5.2 
CONSENTING PARTICIPANTS 
After an appropriate period of time, patients willing to participate in the study will be 
asked to provide written informed consent by the patient’s usual care team or 
appropriately trained members of the research team to whom this task has been 
delegated (this is not restricted to clinicians). Written informed consent will be 
obtained before any study related procedures are performed. 
 
5.3 
SCREENING FOR ELIGIBILITY 
The patient’s usual care team or appropriately trained members of the research 
team to whom this task has been delegated (this is not restricted to clinicians) will 
identify potential participants and confirm and document eligibility. This will be 
based on routinely collected clinical data and review of clinical records. 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
Ineligible and non-recruited patients will receive standard medical care. 
Characteristics and profile of these patients will be determined from routinely 
collected electronic health record data so a screening log will not be required.  
 
5.5 
RANDOMISATION 
5.5.1 Randomisation Procedures 
 
A web-based computer-generated randomisation process will be used to ensure 
allocation concealment and reduce bias. The randomisation system will be 
provided by ECTU and patients will be randomised using their unique health 
identifier to prevent inadvertent duplicate randomisation. International sites will use 
their own randomisation system which will be described in their country specific 
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each of the following groups of patients: (i) conservative non-invasive strategy 
(invasive coronary angiography is not planned), (ii) invasive coronary angiography 
is planned but has not yet occurred, (iii) an invasive coronary angiogram has been 
performed and the patient has been referred or undergone CABG surgery, (iv) an 
invasive coronary angiogram has been performed and the patient has had at least 
one drug eluting stent implanted, (v) an invasive coronary angiogram has been 
performed and the patient has had only bare metal stents implanted  (this group 
will also include patients who have had balloon angioplasty only performed without 
stent implantation), (vi) an invasive coronary angiogram has been performed and 
the patient is to receive medical management only.  
 
Block size will be randomly determined, and each block will contain both treatments 
in a 1:1 ratio. 
 
5.5.2 Treatment Allocation 
Patients will be randomised 1:1 to 3 or 12 months of dual anti-platelet therapy. Dual 
anti-platelet therapy will consist of aspirin plus a P2Y12 receptor antagonist 
(clopidogrel, ticagrelor or prasugrel) chosen by the attending clinician. The 
participant will be provided with a study card detailing the duration of therapy that 
they have been randomised to. 
 
5.5.3 Methods to Ensure Blinding 
This is an open-label trial and there will be no masking of treatment allocation or 
need for unblinding. 
 
5.5.4 Discontinuation of the Investigational Medicinal Product 
Changes to the duration of therapy will be discouraged but can be changed at the 
discretion of the attending clinician. Given that discontinuation of dual anti-platelet 
therapy can be inconsistent [Bueno et al, 2016], the patient’s General Practitioner 
and Consultant Cardiologist will be contacted with a prompt to discontinue the dual 
antiplatelet therapy before the randomised duration of therapy ends. 
 
5.6 
WITHDRAWAL OF STUDY PARTICIPANTS 
Participants are free to withdraw from the study at any point or a participant may 
be withdrawn by the attending clinician. If a participant wishes to withdraw they will 
need to contact their local research team who will document the nature and primary 
reason for withdrawal, if possible. The contact details for the local site will be 
provided on a study card. Unless the participant specifically withdraws consent any 
data collected up to the point of withdrawal will be retained and analysed and data 
will continue to be collected remotely from the participant’s medical notes and via 
data linkage. 
 
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6 
INVESTIGATIONAL MEDICINAL PRODUCTS 
 
6.1. 
STUDY DRUGS 
There are four IMPs being used in the study: aspirin (75 mg tablet), clopidogrel (75 
mg tablet), ticagrelor (90 mg tablet) and prasugrel (10 mg tablet or 5 mg tablet if 
participant is over 75 years or weight <60 kg).  
 
All IMPs have marketing authorisations for the condition (acute coronary syndrome) 
under investigation here. As several brands of both clopidogrel and aspirin are 
marketed in the UK, the IMPs are defined by the active substance only.  All 
authorised brands may be used and pharmacies may provide the brand of drug 
which is available to them. 
 
All drugs will be stored, used and prescribed by an authorised healthcare 
professional according to local clinical practice guidelines.  
 
The Summary of Product Characteristics (SPCs) for all 4 IMPs are provided in a 
separate document which has been signed and verified by the CI and the Sponsor. 
 
6.2. 
PARTICIPANT COMPLIANCE 
 
Compliance with the randomised duration of therapy will be assessed using routine 
collected prescribing data, where possible, for the purposes of the study outcomes. 
Non-compliance will not be recorded or reported to the Sponsor.  
6.3. 
OTHER MEDICATIONS 
 
6.3.1 Prohibited Medications 
 
There are no prohibited medications in this study. Patients will be treated as per 
standard care. 
 

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7 
STUDY ASSESSMENTS 
7.1 
DATA COLLECTION AND OUTCOME ASSESSMENTS  
Baseline patient characteristics, past medical history and medication use will be 
obtained from the randomisation database and data linkage from the participant’s 
electronic health records. 
 
Outcome measures for patients recruited in Scotland will be obtained through the 
Farr Institute in collaboration with the electronic Data Research and Innovation 
Service (eDRIS) and the General Register Office as we have successfully achieved 
with the SCOT-HEART [SCOT-HEART, 2015; Williams et al, 2016] and 
HighSTEACS [Shah et al, 2015a; Shah et al, 2015b] trials (Tables 2 and 3). We 
will capture all hospital admission events and will have access to clinical records 
and imaging as required through NHS Safe Havens. Outcome measures for 
patients recruited in England will be obtained through NHS Digital. We will record 
the following safety endpoints: all-cause death, non-cardiovascular death, fatal 
bleeding, major bleeding (including gastrointestinal and intracranial haemorrhage), 
hospitalization for bleeding (all ICD-10 coded), as well as blood transfusions, where 
possible). The bleeding data will be used to classify bleeding events using the 
standardized bleeding definition for cardiovascular clinical trials as defined by the 
Bleeding Academic Research Consortium (BARC) [Mehran et al, 2011]. We will 
record the following efficacy endpoints: all-cause death, cardiovascular (cardiac 
and non-cardiac) death, myocardial infarction (non-fatal and fatal) [Thygesen et al, 
2012], stroke (non-fatal and fatal; thrombotic and haemorrhagic), coronary 
revascularisation (percutaneous coronary intervention and coronary artery bypass 
graft surgery), and stent thrombosis.  
 
7.2 
COMPLIANCE 
 
Compliance with the duration of therapy will be undertaken by record linkage with 
community-dispensed prescriptions and/or national registries, where possible.  
8. 
DATA COLLECTION 
Study data will be entered into an eCRF developed by Edinburgh Clinical Trials 
Unit. A source data plan will be created to indicate where the study data are 
originally documented. The study data obtained from electronic health records will 
either be entered directly into the eCRF or held in a trusted research environment. 
International sites will use their own data collection system to record the study data 
and the electronic health record data. 
 
8.1 DATA MANAGEMENT 
8.1.1 Personal Data 
The following personal data will be collected as part of the research: 
 

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Participant’s name, address, date of birth, GP contact details, health information 
and unique health identifier (Community Health Index (CHI) number or National 
Health Service (NHS) number will be collected. Personal data will be stored 
securely in the eCRF and by the research team at each site for a minimum of 5 
years after the study has finished. The location and duration of storage of personal 
data at the international sites will be documented in their country specific protocol. 
 
8.1.2 Transfer of Data 
Data collected or generated by the study may be transferred to external individuals 
or organisations outside of the Sponsoring organisation(s).  It may be provided to 
researchers running other research studies outwith NHS Lothian/University of 
Edinburgh. Following publication of the primary paper, a de-identified individual 
participant data set will be submitted to a data archive for sharing purposes.  
Participant information will only be used by organisations and researchers to 
conduct research in accordance with the UK Policy Framework for Health and 
Social Care Research. Where this information includes identifiable information, it 
will be held securely with strict arrangements about who can access the 
information. 
 
In order to perform data linkage, participant’s personal details including their unique 
health number will be transferred to central health care and government data 
services bodies. 
 
8.1.3 Data Processor 
The data processor is the Edinburgh Clinical Trials Unit, Usher Institute, University 
of Edinburgh. 
 
8.1.4 Data Controller 
The data controller is the University of Edinburgh and NHS Lothian who are the co-
sponsors of this study. 
9. 
STATISTICS AND DATA ANALYSIS 
 
9.1 
PROPOSED SAMPLE SIZE  
We plan to recruit 18,318 patients over 3 years across all participating countries. 
Of these, based on contemporary practice data for Scotland just under 7.5% will 
be treated with either coronary artery bypass graft surgery or percutaneous 
coronary intervention with a bare metal stent, giving a minimum sample size 
(excluding this 7.5%) for the main analysis of 16,944. If there is no substantial 
heterogeneity in outcome between these two groups, then they can be included in 
the analysis and further increase the power.  
 
Recruitment in the UK was halted after 4,576 patients because the funder felt the 
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statistical analysis will include the 4,576 patients recruited in the UK and as many 
international patients who have completed follow-up at the time of analysis.  
9.2  
SAMPLE SIZE CALCULATION 
No clinical trials have been published comparing duration of therapy for unselected 
patients with type 1 myocardial infarction. However, most patients with type 1 
myocardial infarction now undergo early percutaneous coronary intervention. From 
meta-analysis of stent trials comparing ≤6 months with 12 months of dual 
antiplatelet therapy [Palmerini et al, 2015] (among whom a large proportion of 
patients had acute coronary syndrome), the point estimates of the hazard ratios for 
all-cause mortality, non-cardiac mortality and bleeding were 0.87, 0.83 and 0.58 
respectively. Over a 5-year period (2006-2010) in Scotland 25.4% of patients died 
within one year of acute coronary syndrome of whom 7.6% died from a non-
cardiovascular cause, and 0.92% had a fatal bleed. 
 
The study has been powered to assess the primary endpoint of all-cause mortality 
across the combined medical therapy and percutaneous coronary intervention with 
drug-eluting stent arms (92.5% of the study population). Assuming a more 
conservative relative risk reduction of 10% (risk ratio 0.9), and that patients who 
consent to participate in the study have a one-third lower overall risk of mortality 
than unselected patients, shorter durations of therapy would lead to an absolute 
difference of 1.69% (0.1 x 0.254 x 0.667) from the 12-month duration of treatment 
rate of 16.9%. A sample size of 8,472 patients per group (16,944 overall) would 
provide 85% power to detect this difference at two-sided P<0.05 (Stata 15.1 
procedure ‘power two-prop’ without continuity correction). Given that this is an 
outcome ascertained by record linkage for geographically highly stable 
populations, we anticipate close to zero loss to follow up. To achieve the 16,944 
across combined medical therapy and percutaneous coronary intervention with 
drug-eluting stent arms (92.5% of the study population) we need to randomise 
16,944/0.925 = 18,318 participants. In addition, the study will have slightly 
increased power by using not just the occurrence of the event but also incorporating 
the time-to-event using log-rank statistics (and Cox proportional hazards models to 
adjust for baseline covariates). 
 
An initial check of the data linkage procedures will be performed at approximately 
10% of recruitment. The independent Trial Steering Committee will monitor all the 
assumptions behind the sample size calculations in aggregated data as the trial 
progresses. The full sample size of 16,944 would also allow us to detect an 
absolute risk reduction of 1% (from 6% to 5%) in non-cardiovascular mortality with 
81% power and an absolute risk reduction of 0.3% (from 0.6% to 0.3%) in bleeding 
death, with 83% power and two-sided P<0.05, with event rates being one-third 
lower in consented than in unselected patients. We do not expect to have power to 
estimate the treatment effect in coronary artery bypass graft surgery or 
percutaneous coronary intervention with bare metal stent groups.  
  
9.3 
PROPOSED ANALYSES 
 
For the primary outcome (all-cause mortality) we will compare time-to-event in a 
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participants, and adjusting for cardiac history (stratification factor in randomisation). 
For secondary outcomes of non-cardiovascular mortality and bleeding death, we 
will similarly estimate cause-specific hazard ratios, censoring for competing causes 
of death. All analyses will be by intention-to-treat.  
 
It is highly likely that baseline characteristics will have a major influence on the 
overall clinical benefits and risks [Steg et al, 2011]. We will explore efficacy and 
safety outcomes in the 4 pre-specified and stratified cohorts nested within the trial: 
(i) medically managed, (ii) percutaneous coronary intervention with bare metal 
stent, (iii) percutaneous coronary intervention with drug-eluting stent, and (iv) 
coronary artery bypass graft surgery.  
 
In a sensitivity analysis, we will consider a two-stage individual participant data 
(IPD) meta-analysis where the IPD from each country are analysed separately then 
combined by an appropriate fixed-effect or random effects meta-analysis model 
[Burke et al, 2017].  
 
The statistical methods will be documented in full in a detailed statistical analysis 
plan. The methods used will take into account the early stopping of the trial, and 
the limited numbers of events that will be available for analysis. A composite 
outcome of non-fatal bleeding and all-cause mortality will be explored. 
10. 
PHARMACOVIGILANCE 
 
Full details of contraindications and side effects that have been reported following 
administration of the IMPs can be found in the relevant Summary of Product 
Characteristics (SPC). The safety reporting processes and regulatory requirements 
for the international sites will be detailed in their country specific protocol. 
 
10.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial 
participant which does not necessarily have a causal relationship with an 
investigational medicinal product (IMP). 
 
An adverse reaction (AR) is any untoward and unintended response to an IMP 
which is related to any dose administered to that participant.  
 
A serious adverse event (SAE) or serious adverse reaction (SAR) is defined as any 
AE or AR that at any dose: 
 
 results in death of the clinical trial participant; 
 is life threatening*; 
 requires 
in-patient 
hospitalisation^ 
or 
prolongation 
of 
existing 
hospitalisation; 
 results in persistent or significant disability or incapacity; 
 consists of a congenital anomaly or birth defect; 
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*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. 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is 
classified as serious and is suspected to be caused by the IMP, that it is not 
consistent with the information about the IMP in the Summary of Product 
Characteristics (SPC). 
 
10.2 RECORDING AND REPORTING AEs, ARs, SAEs AND SARs  
Clinical observations, measurements and other data that have the potential to 
comprise Adverse Events will only be apparent to the investigators at the time of 
participant consent, or at times during subsequent participation when the 
investigators become aware of such observations, measurements or other data as 
part of their standard care activities. 
As the IMPs being used in the study all have marketing authorisations and well 
known safety profiles, clinical observations, measurements and other data that 
comprise Adverse Events and are identified by the sites as such, will be recorded 
in the participant’s health records but will not be recorded in an Adverse Event log, 
nor reported elsewhere. Clinical observations, measurements and other data that 
comprise Adverse Events will, however, be assessed for seriousness, causality, 
expectedness and severity as described below.  
The study outcomes listed in Table 3, which will be collected through routinely 
collected data from electronic health records, will not be recorded as SAEs and will 
therefore not be reported to the Sponsor. The study outcome data from the 
electronic health records will, however, be sent to the DMC and TSC at pre-
specified intervals throughout the trial. Due to recruitment being halted by the 
funder, the first pre-specified interval which will occur at approximately 25% mature 
data on the primary outcome, will coincide with final reporting. 
 
10.2.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 
10.1 for AEs identified at sites. All AEs identified by the site and assessed as 
Serious will not be recorded as SAEs, nor reported to the Sponsor, but the details 
of the events will be retained in the participants’ health records. 
 
10.2.2 Assessment of Causality 
The Investigator will make an assessment of whether an SAE is likely to be related 
to the IMP according to the definitions below.   
 
Unrelated: where an event is not considered to be related to the IMP. 

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Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the SAE has 
a causal relationship to the study drug. The assessment of causality will be made 
against the Reference Safety Information found in the Summary of Product 
Characteristics. 
 
All SAEs identified by sites and assessed as possibly Related to the IMP will not 
be recorded as SARs, nor reported to the Sponsor, but the details of the events will 
be retained in the participant’s health records.  
10.2.3 Assessment of Expectedness 
The evaluation of expectedness of SARs identified by sites will be made based on 
knowledge of the reaction and the relevant product information documented in the 
SPC 
 
The event may be classed as either: 
 
Expected: the SAR is consistent with the toxicity of the IMP listed in the SPC. 
 
Unexpected: the SAR is not consistent with the toxicity in the SPC. 
 
Only SARs which are identified by the sites, or by the Principal Investigator after 
the closure of sites, and considered unexpected (i.e. SUSARs) by the Principal 
Investigator (or another suitably qualified physician in the research team who has 
been delegated this role) will be recorded and reported to the Sponsor and Chief 
Investigator (CI) – see section 10.3. The Chief Investigator may not downgrade an 
event that has been assessed by an Investigator as a SUSAR. 
Fatal and life threatening SARs should usually be considered unexpected.  A fatal 
or life-threatening SAR can only be expected for an IMP when that specific SAR is 
explicitly listed as ‘fatal’ or ‘life threatening’ in the list of ARs (section 4.8 of the 
SPC) for that that IMP. An unexpected SAR comprises a SUSAR and should be 
recorded and reported as such. 
 
10.2.4 Assessment of Severity 
The Investigator will make an assessment of severity 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 

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action criteria.  For example, a headache may be severe but not serious, while a 
minor stroke is serious but may not be severe. 
 
10.3 REPORTING OF SUSARs 
 
Once an Investigator becomes aware that a SUSAR 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 SUSAR, they should not wait for this additional 
information before notifying ACCORD.  The SUSAR report form can be updated 
when the additional information is received. 
 
The SUSAR will be recorded on a SAE form and the report will provide an 
assessment of causality and expectedness at the time of the initial report to 
ACCORD according to Sections 10.2.2, Assessment of Causality and 10.2.3, 
Assessment of Expectedness. 
 
The SAE form will be transmitted via email to safety@accord.scot. Only forms in a 
pdf format will be accepted by ACCORD via email. Forms may also be sent by fax 
to ACCORD on +44 (0)131 242 9447 or may be submitted by hand to the office. 
Where missing information has not been sent to ACCORD after an initial report, 
ACCORD will contact the Investigator and request the missing information. The 
Investigator must respond to these requests in a timely manner.  
 
All reports sent to ACCORD and any follow up information will be retained by the 
Investigator in the Investigator Site File (ISF). 
 
10.4 REGULATORY REPORTING REQUIREMENTS 
ACCORD is responsible for pharmacovigilance reporting on behalf of the co-
sponsors (The University of Edinburgh and NHS Lothian). 
ACCORD has a legal responsibility to notify the regulatory competent authority and 
relevant ethics committee (Research Ethics Committee (REC) that approved the 
trial). Fatal or life threatening SUSARs will be reported no later than 7 calendar 
days and all other SUSARs will be reported no later than 15 calendar days after 
ACCORD is first aware of the reaction.  
ACCORD (or delegate) will inform Investigators at participating sites of all SUSARs 
and any other arising safety information. 
ACCORD will be responsible for providing safety line listings and assistance; 
however, it is the responsibility of the Investigator to prepare the Development 
Safety Update Report. This annual report will list all SUSARs reported during that 
time period. The responsibility of submitting the Development Safety Update 
Report to the regulatory authority and RECs, lies with ACCORD.  
 

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10.5  FOLLOW UP PROCEDURES 
After recording and reporting a SUSAR, the Investigator should make every effort 
to follow the event until a final outcome can be recorded or reported as necessary. 
Follow up information on a SUSAR will be reported to the ACCORD office. 
10.6  PREGNANCY 
Few patients will be of child-bearing potential in the trial. Such patients are advised 
against pregnancy following acute coronary syndrome because of the effect on the 
heart and the potential teratogenicity of the drugs prescribed. Pregnancy is not 
considered an AE or SAE. The IMPs being used in this study all have marketing 
authorisations and well known safety profiles so pregnancy information will not be 
recorded for any female participants or female partners of a male participant.  
11 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
 
11.1 TRIAL MANAGEMENT GROUP 
The trial will be managed and run by the Edinburgh Clinical Trials Unit which has 
full registration with the United Kingdom Clinical Research Collaboration. The study 
will be managed by a dedicated trial manager with support from a data 
programmer. The Clinical Trials Unit will also oversee the statistical and analytic 
aspects of the trial conduct. 
11.2 TRIAL STEERING COMMITTEE.  
The Trial Steering Committee (TSC) will be composed of external independent 
clinical trialists. They will oversee and support the strategic delivery of the trial by 
working with the applicants and Trial Management Group to deliver the goals of 
this innovative and challenging study. The terms of reference of the Trial Steering 
Committee, and the names and contact details are detailed in the TSC charter. 
 
11.3 DATA MONITORING COMMITTEE.  
The Data Monitoring Committee (DMC) will be composed of external independent 
experts. They will review emerging trial data to ensure the safety of patients and 
the integrity of the trial data as it emerges during study conduct. Interim analyses 
of the follow-up data will be supplied at approximately 25%, 50%, 75% and 100% 
mature data on the primary outcome (all-cause mortality) to ensure there is no 
overwhelming evidence of safety or efficacy that would require early termination of 
the trial. Appropriate criteria cannot be specified precisely, but the DMC will work 
on the principle that a difference of at least 3 standard errors in an interim analysis 
of a major outcome event (e.g. the primary outcome) may be needed to justify 
halting, or modifying, a study before the planned completed recruitment or trial 
follow-up. The terms of reference of the Data Monitoring Committee and the names 
and contact details are detailed in the DMC charter. 
 
Due to recruitment being halted by the funder the first interim analysis at 
approximately 25% mature data on the primary outcome will coincide with final 
reporting. 

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11.4 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring 
and audits on behalf of the sponsor, REC review, and regulatory inspection(s).  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. In the event of regulatory inspection, the Investigator agrees to 
allow inspectors direct access to all study records and source documentation. 
 
11.5 RISK ASSESSMENT 
A study specific risk assessment will be performed by representatives of the co-
sponsors, ACCORD monitors and the QA group, in accordance with ACCORD 
governance and sponsorship SOPs. Input will be sought from the Chief Investigator 
or designee. The outcomes of the risk assessment will form the basis of the 
monitoring plans and audit plans. The risk assessment outcomes will also indicate 
which risk adaptions could be incorporated into the trial design. 
11.6 BENEFIT and RISK BALANCE 
The potential risks and hazards of dual anti-platelet therapy relate to the opposing 
benefits and risks of therapy. There is no doubt that dual anti-platelet therapy is 
associated with a reduction in atherothrombotic events with reductions in 
myocardial infarction and potentially cardiovascular death. However, this benefit 
comes at a cost of increasing bleeding complications that include major 
gastrointestinal 
and 
intracranial 
haemorrhage 
that 
can 
be 
fatal. 
The 
atherothrombotic risk is time varying (greatest in the first three months) whilst the 
bleeding risk is continuous. Thus, 3 months therapy may be too brief and an excess 
of atherothrombotic events will not be counterbalanced by reductions in bleeding 
complications. Conversely, 12 months therapy may lead to an excess of major 
bleeding complications with minimal reductions in atherothrombotic events. This 
risk-to-benefit balance is at the centre of the trial question. 
 
The trial manager will liaise closely with all centres and encourage adherence to 
randomisation and the provision of promotional materials. There may be loss of 
equipoise during study conduct. We think this is unlikely since this question has 
remained unresolved for over 10 years with little new evidence anticipated to 
influence equipoise over the time course of the trial conduct. We will encourage all 
clinicians to contact the research team and discuss any potential issues as the trial 
progresses. We will be able to monitor trial prescription data throughout study 
conduct.  
 
11.7 STUDY MONITORING AND AUDIT 
ACCORD clinical trial monitors, or designees, will perform monitoring activities in 
accordance with the study monitoring plan. This will involve on-site visits and 
remote monitoring activities as necessary. ACCORD QA personnel, or designees, 
will perform study audits in accordance with the study audit plan. This will involve 
investigator site audits, study management audits and facility (including third 
parties) audits as necessary.  

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12 
GOOD CLINICAL PRACTICE 
 
12.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International 
Conference on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH 
GCP). 
Before the study can commence, all required approvals will be obtained and any 
conditions of approvals will be met.  
 
12.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained 
from the appropriate Regulatory Authority. The protocol and study conduct will 
comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, as 
amended. The study will be risk adapted as this trial is assessing only the duration 
of therapy in IMPs that already have a marketing authorisation and approval for 
use in patients with acute coronary syndrome.  
12.3 INVESTIGATOR RESPONSIBILITIES 
The Investigator 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 ICH GCP, the following areas listed in this section are also the 
responsibility of the Investigator.  Responsibilities may be delegated to an 
appropriate member of study site staff.  Delegated tasks must be documented on 
a Delegation Log and signed by all those named on the list prior to undertaking 
applicable study-related procedures. 
 
12.3.1 Informed Consent 
 
The Investigator is responsible for ensuring informed consent is obtained before 
any study specific procedures are carried out. The decision of a participant to 
participate in clinical research is voluntary and should be based on a clear 
understanding of what is involved. 
 
Participants must receive adequate oral and written information – appropriate 
Participant Information and Informed Consent Forms will be provided. The oral 
explanation to the participant will be performed by the Investigator or qualified 
delegated person and must cover all the elements specified in the Participant 
Information Sheet and Consent Form. 
 
The participant must be given every opportunity to clarify any points they do not 
understand and, if necessary, ask for more information. The participant must be 
given sufficient time to consider the information provided.  It should be emphasised 
that the participant may withdraw their consent to participate at any time without 
loss of benefits to which they otherwise would be entitled. 
 

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The participant will be informed and agree to their medical records being inspected 
by regulatory authorities and 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 will be signed in the Investigator Site File (ISF). The participant will 
receive a copy of the signed consent form and a copy will be filed in the participant’s 
medical notes. A copy of the consent form may also be transferred to the Edinburgh 
Clinical Trials Unit for monitoring. Monitoring of consent forms at international sites 
will be detailed in the country specific protocol. 
12.3.2 Study Site Staff 
The Investigator must be familiar with the IMP, 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 IMP, protocol and their trial 
related duties. 
12.3.3  Data Recording 
The Principal Investigator is responsible for the quality of the data recorded at 
each Investigator Site. 
12.3.4 Investigator Documentation  
Prior to beginning the study, each Investigator will be asked to provide particular 
essential documents to the ACCORD 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. 
 
ACCORD will ensure all other documents required by ICH GCP are 
retained in a Trial Master File (TMF) or Sponsor File, where required.  The 
Principal Investigator will ensure that the required documentation is 
available in local Investigator Site files ISFs. Under certain circumstances 
the TMF responsibilities may be delegated to the research team by 
ACCORD. 
 
12.3.5  GCP Training 
The CI and Principal Investigators must hold evidence of appropriate GCP training. 
Targeted GCP training will be provided for all other members of the research team 
to whom study related responsibilities have been delegated.  
 
12.3.6  Confidentiality 
All laboratory specimens, 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 
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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. 
 
12.3.7  Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the appropriate data protection legislation (including the General 
Data Protection Regulation and Data Protection Act) 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 individuals 
from the research team treating the participants, representatives of the sponsor(s) 
and representatives of regulatory authorities. 
 
Computers used to collate the data will have limited access measures via 
usernames and passwords. 
 
Published results will not contain any personal data that could allow identification 
of individual participants. 
13. 
STUDY CONDUCT RESPONSIBILITIES 
 
13.1 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.   
Proposed amendments will be submitted to the Sponsor for classification and 
authorisation. Amendments to the protocol must be submitted in writing to the 
appropriate REC, Regulatory Authority and local R&D for approval prior to 
implementation. The amendment submission process for international sites will be 
detailed in the country specific protocol.  
13.2 PROTOCOL NON-COMPLIANCE 
13.2.1 Definitions 
Deviation - Any change, divergence, or departure from the study design, 
procedures defined in the protocol or GCP that does not significantly affect a 
subject’s rights, safety, or well-being, or study outcomes. 
Violation - A deviation that may potentially significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being 
13.2.2 Protocol Waivers 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the 
sponsors and therefore will not be implemented, except where necessary to 

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eliminate an immediate hazard to study participants. If this necessitates a 
subsequent protocol amendment, this should be submitted to the REC, Regulatory 
Authority and local R&D for review and approval if appropriate. 
 
13.2.3 Management of Deviations and Violations 
Protocol deviations will be recorded in a protocol deviation log and logs will be 
submitted to the sponsors every 3 months. Each protocol violation will be reported 
to the sponsor within 3 days of becoming aware of the violation.Deviation logs / 
violation forms will be transmitted via email to QA@accord.scot. Only forms in a 
pdf format will be accepted by ACCORD via email. Forms may also be sent by fax 
to ACCORD on +44 (0)131 242 9447 or may be submitted by hand to the office. 
Where missing information has not been sent to ACCORD after an initial report, 
ACCORD will contact the Investigator and request the missing information. The 
Investigator must respond to these requests in a timely manner.  
Non-compliance with the randomised allocation will not be recorded as a protocol 
deviation and/or violation. 
 
13.3 URGENT SAFETY MEASURES 
The Investigator may implement a deviation from or change to the protocol to 
eliminate an immediate hazard to trial participants without prior approval from the 
REC and the MHRA. This is defined as an urgent safety measure and the 
investigator must contact the Clinical Trial Unit at the MHRA and discuss the issue 
with a medical assessor immediately (+44 (0) 20 3080 6456).  
The Investigator will then notify the MHRA (clintrialhelpline@mhra.gsi.gov.uk), the 
REC and ACCORD, in writing of the measures taken and the reason for the 
measures within 3 days by submitting a substantial amendment. 
 
13.4 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal 
Investigator or delegates, the co-sponsors  (QA@accord.scot) must be notified 
within 24 hours.  It is the responsibility of the co-sponsors to assess the impact of 
the breach on the scientific value of the trial, to determine whether the incident 
constitutes a serious breach and report to regulatory authorities and research 
ethics committees as necessary.  
 
13.5 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 5 years from the protocol-
defined end of study point.  Patient identifiable information will be kept beyond 5 
years to facilitate longer term follow up if necessary (this will be made explicit on 

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consent forms and patient information sheets).  When the minimum retention period 
has elapsed, study documentation will not be destroyed without permission from 
the sponsor. 
 
13.6 END OF STUDY 
It is anticipated that the study will last 4-5 years: three years for recruitment and 15 
months of follow-up. The end of study is defined as 15 months after the last 
participant’s last visit. However, longer term follow-up using record linkage may be 
performed at 5 and 10 years. The Investigators, trial management group 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, 
Regulatory Authority, R&D offices and co-sponsors 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. End of study notification will be reported to the co-
sponsors via email to resgov@accord.scot.  In accordance with ACCORD SOP 
CR011, a Clinical Study Report (CSR) will be provided to the Sponsor 
(QA@accord.scot) and REC within 1 year of the end of the study. Upon completion 
of the study, the Chief Investigator will upload clinical trial results onto the EudraCT 
database on behalf of the Sponsor.  
 
13.7 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 their 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 will have the benefit of NHS Indemnity. 
 
The manufacturer of the IMP has accepted limited liability related to the 
manufacturing and original packaging of the study drug and to the losses, 
damages, claims or liabilities incurred by study participants based on known or 
unknown Adverse Events which arise out of the manufacturing and original 
packaging of the study drug. 
 
 

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14. 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
 
14.1 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 clinical 
study report will be prepared in accordance with ICH guidelines.  
 
14.2 PUBLICATION 
 
The Clinical Study Report (CSR) will be submitted to the Sponsor and REC within 
1 year of the end of the study. Where acceptable, a published journal article may 
be submitted as the CSR. The Chief Investigator will provide the CSR to ACCORD, 
for review, prior to finalization. The clinical study report may be used for publication 
and presentation at scientific meetings. Investigators have the right to publish orally 
or in writing the results of the study. The results of the study, together with other 
mandated information, will be uploaded to the European clinical trials database 
within 1 year of the end of the study. 
 
14.3 DATA SHARING 
 
Following publication of the primary paper, a de-identified individual participant 
data set will be submitted to a data archive for sharing purposes.  Access to the 
de-identified dataset will be under a controlled access model in line with ECTU 
policies at that time. 
 
14.4  PEER REVIEW 
The study protocol has undergone independent review by an Edinburgh Clinical 
Trials Unit statistician and by the British Heart Foundation.  The protocol has been 
amended in accordance with their recommendations. 

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