Preventing Stroke, Premature Death and Cognitive Decline in a Broader Community of Patients With Atrial Fibrillation Using Healthcare Data for Pragmatic Research: A Randomised Controlled Trial
Phase: PHASE4
Conditions: Atrial Fibrillation
Sponsor: University of Birmingham

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OPEN ACCESS AFTER REC APPROVAL  
PROTOCOL TITLE 
Preventing stroke, premature death and cognitive decline in a broader community 
of patients with atrial fibrillation using healthcare data for pragmatic research:         
A randomised controlled trial  
 
 
SHORT STUDY TITLE / ACRONYM 
DaRe2THINK 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 4.1; 21 Jul 2022   
[This protocol has regard for the HRA guidance] 
 
SPONSOR 
University of Birmingham, UK 
 
 
FUNDER 
National Institute for Health Research (HTA 19/109 - NIHR130280) 
 
RESEARCH REFERENCE NUMBERS 
Sponsor Number: 
RG_20-141 
IRAS ID: 
290420 
REC Number: 
21/NE/0021 
Clinicaltrials.gov: 
NCT04700826 
ISRCTN: 
ISRCTN21157803 
EudraCT Number: 
2020-005774-10 
 
COMPLIANCE STATEMENT 
This protocol describes the DaRe2THINK trial only. The protocol should not be used as a guide for the 
treatment of patients not taking part in DaRe2THINK.  
The study will be conducted in compliance with the latest versions of the approved protocol, UK Policy 
Framework for Health and Social Care Research, Data Protection legislation, and the principals of 
Good Clinical Practice. 
Whilst every care has been taken during the drafting of this protocol, future amendments may be 
necessary which will require approvals prior to implementation. 
OPEN ACCESS AFTER REC APPROVAL  
 

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PROTOCOL DEVELOPMENT AND SIGN OFF 
Protocol Amendments 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version: 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
1 
17 Jun 2021 
2.0 
Substantial 
1. Clarification of exclusion criterion for women 
based on latest NICE guidance. 
2. Addition of exclusion criterion for patients 
already enrolled in a Clinical trial. 
3. Clarification of per protocol and per treatment 
analysis. 
4. Addition of imaging sub-study. 
5. Other minor/non-substantial corrections. 
2 
27 Jan 2022 
3.0 
Substantial 
1. Option for Primary Care investigators to send 
out text messages via NHS clinical systems to 
potentially eligible participants.  
2. Addition of mechanism for potential study 
participants to contact the central study team 
after invitation from Primary Care investigators. 
3. Addition of new links to NICE prescribing 
support for anticoagulation.  
4. Update to Key Study Contacts page. 
3 
06 Jun 2022 
4.0 
Substantial 
1. Revision of age inclusion criteria from 60-73 
to 55-73 years based on updates received from 
live national screening data. 
2. Reorganisation of selection criteria to 
separate the automated screening processes 
from elements requiring Primary Care input. 
3. Clarification that only patients with prior 
systemic thromboembolism should be excluded. 
4. Clarification of a 3-year time period for 
exclusion of patients with prior major bleeding 
that required hospitalisation.  
5. Updates made to Section 9.3 to reflect 
changes in data management within CPRD. 
6. Other minor/non-substantial corrections, 
including updates to the trial flowchart. 
4 
21 Jul 2022 
4.1 
Substantial 
[additions 
following MHRA 
review of v4.0] 
1. Additional exclusion criterion for women who 
are of childbearing potential (WOCBP). 
2. Addition and amendment of protocol text 
relating to WOCBP. 
3. WOCBP added to sub-study exclusion list 
and clarification of inclusion periods. 
 
 

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CHIEF INVESTIGATOR & STATISTICIAN SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted, and that the study 
will be conducted in compliance with the approved protocol and will adhere to the principles outlined in 
the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations 
(SI 2006/1928) and any subsequent amendments of the clinical trial regulations, GCP guidelines, the 
Sponsor’s (and any other relevant) Standard Operating Procedures, and other regulatory 
requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written 
consent of the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
Chief Investigator: 
Signature:  
............................................................................... 
Signature Date:  
12/10/2022 
Name (please print): 
Prof. Dipak Kotecha 
 
Protocol Version: 
4.1 
Protocol Date:  
21/07/2022 
 
 
Trial Statistician: 
Signature:  
............................................................................... 
Signature Date:  
13/10/2022 
Name (please print): 
Samir Mehta 
 
Protocol Version: 
4.1 
Protocol Date:  
21/07/2022 
 
Sponsor Statement  
Where the University of Birmingham takes on the sponsor role for protocol development oversight, the 
signing of the IRAS form by the Sponsor will serve as confirmation of the approval of this protocol. 
 
 
 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I have read and agree to the protocol, as detailed in this document.  I agree to adhere to the protocol 
as outlined and agree that any suggested changes to the protocol must be approved by the Trial 
Steering Committee prior to seeking approval from the Research Ethics Committee and Regulatory 
Authority. 
I am aware of my responsibilities as an Investigator under the guidelines of Good Clinical Practice 
(GCP), the Declaration of Helsinki, local regulations (as applicable) and the trial protocol and I agree 
to conduct the trial according to these guidelines and to appropriately direct and assist the staff under 
my control who will be involved in the trial. 
 
 
Site Principal Investigator: 
Signature:  
............................................................................... 
Signature Date:  
....../....../...... 
Name (please print): 
............................................................................... 
 
Protocol Version: 
………………… 
Protocol Date:  
....../....../...... 
Site Name and Postcode (please print): 
................................................................................................................................................. 
................................................................................................................................................. 
 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL TITLE 
1 
PROTOCOL DEVELOPMENT AND SIGN OFF 
2 
CHIEF INVESTIGATOR & STATISTICIAN SIGNATURE PAGE 
3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
4 
TABLE OF CONTENTS 
5 
KEY STUDY CONTACTS 
7 
STUDY SUMMARY 
9 
ABBREVIATIONS 
11 
PLAIN ENGLISH SUMMARY 
12 
SCIENTIFIC ABSTRACT 
13 
TRIAL FLOW CHART 
14 
1 
BACKGROUND, RATIONALE & AIMS 
15 
1.1 The burden of atrial fibrillation 
15 
1.2 The need for new trials 
15 
1.3 A joined-up approach across the NHS 
16 
1.4 The DaRe2 trial pipeline 
16 
1.5 Application to patients with AF and beyond 
17 
2 
DESIGN CONSIDERATIONS 
18 
2.1 Design summary 
18 
2.2 Assessment of risk for control patients 
18 
2.3 Assessment of risk for anticoagulated patients 
18 
2.4 Hypotheses for primary, key secondary & health economic outcomes 
19 
2.5 Hypotheses for other secondary outcomes 
19 
2.6 Overarching challenge and opportunity 
19 
3 
STUDY METHODS 
20 
3.1 Approach to study selection criteria 
20 
3.2 Participant inclusion criteria based on coding in the Primary Care record 
20 
3.3 Participant exclusion criteria based on coding in the Primary Care record 
20 
3.4 Participant exclusion criteria based on review by Primary Care staff 
20 
3.5 General Practice selection criteria 
21 
3.6 Participant identification and Screening 
21 
3.7 Consent to contact 
22 
3.8 Consent procedures for trial enrolment 
23 
3.9 Women of childbearing potential 
24 
3.10 Randomisation 
24 
3.11 Trial treatments 
25 
Table 1: Suggested dose of DOACs 
26 
3.12 Blinding 
27 
3.13 Internal pilot 
27 
3.14 Withdrawal 
29 
3.15 Change of Primary Care provider 
29 
3.16 Treatment duration and End of Trial 
29 
4 
OUTCOMES 
30 
4.1 Timing & assessment of outcomes 
30 
4.2 Primary outcome 
30 
4.3 Secondary outcomes 
30 
4.4 Cost-effectiveness outcomes 
30 
4.5 Process outcomes 
31 
4.6 Rationale for outcomes 
31 
5 
DATA MANAGEMENT 
32 
5.1 Baseline and follow-up data 
32 
5.2 Quality of CPRD data 
32 
Table 2: Quality assurance processes 
32 
Table 3: Drug codes used for the participant selection criteria 
33 
5.3 Validation of clinical events 
33 
Table 4: Data validation Study-Within-A-Trial 
34 
5.4 Patient-reported cognitive function 
35 
5.5 Patient-reported quality of life 
36 
5.6 Additional patient-reported events 
37 
5.7 Coordination of data processes 
37 

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6 
SAFETY REPORTING 
38 
6.1 Overview 
38 
6.2 Definitions 
38 
Table 5: Definitions of adverse events 
38 
6.3 Operational use within a pragmatic NHS-embedded trial 
39 
6.4 Reporting of SUSARs 
40 
6.5 Safety net to capture adverse events 
41 
6.6 Responsibilities of the Principal Investigator 
41 
6.7 Responsibilities of the Clinical Practice Research Datalink team 
42 
6.8 Responsibilities of the Chief Investigator/ Deputy Chief Investigator or delegate 
42 
6.9 Responsibilities of the Sponsor 
43 
6.10 Responsibilities of the oversight committees 
43 
7 
STATISTICAL CONSIDERATIONS 
44 
7.1 Sample size derivation 
44 
7.2 Primary outcome on composite clinical events 
44 
7.3 Key secondary outcome on cognitive function 
44 
7.4 Data analysis overview 
44 
7.5 Analysis of the primary outcome 
45 
7.6 Analysis of secondary outcomes 
45 
7.7 Planned Subgroup Analyses 
46 
7.8 Interim analyses and impact on sample size 
46 
7.9 Stopping Criteria 
46 
7.10 Health economic evaluation 
46 
7.11 Analysis of virtual control data 
47 
8 
ETHICAL, REGULATORY & GOVERNANCE ISSUES 
48 
8.1 Ethical framework 
48 
8.2 Ethical review 
48 
8.3 Protocol review 
48 
8.4 Public and Patient Involvement (PPI) 
49 
8.5 Regulatory compliance 
49 
9 
DATA SECURITY 
50 
9.1 Data security at the University of Birmingham (coordinating institution) 
50 
9.2 Data security at University Hospitals Birmingham (lead NHS institution) 
51 
9.3 Data security at CPRD 
51 
9.4 Data security for cognitive function 
51 
9.5 Data security for health economic analysis 
52 
9.6 Data protection and patient confidentiality 
52 
10 
OVERSIGHT & MONITORING 
53 
10.1 Trial Management Group 
53 
10.2 Trial Steering Committee 
53 
10.3 Data Monitoring Committee 
53 
10.4 Expert Advisory Group 
53 
10.5 Protocol deviations 
53 
10.6 Data access 
54 
10.7 Archiving 
54 
10.8 Trial monitoring 
54 
10.9 Clinician responsibility 
54 
11  
FINANCIAL CONSIDERATIONS 
55 
11.1 Trial funding 
55 
11.2 Payment to participants 
55 
11.3 Insurance 
55 
12 
DISSEMINATION POLICY 
56 
12.1 Study teams 
56 
12.2 Publications 
56 
12.3 Study participants 
56 
12.4 Community engagement 
56 
13 
DaRe2THINK sub-studies 
57 
13.1 Validation of clinical events 
57 
13.2 Neuro-vascular imaging 
57 
Table 6: DaRe2THINK-NV sub-study 
58 
14 
REFERENCES 
60 
15 
SCHEDULE OF ASSESSMENT 
63 

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KEY STUDY CONTACTS 
 
Chief 
Investigators 
Dipak Kotecha (Chief Investigator), Professor of Cardiology, Institute of Cardiovascular 
Sciences, University of Birmingham & Institute of Translational Medicine, University 
Hospitals Birmingham NHS Foundation Trust; Email: d.kotecha@bham.ac.uk  
David Shukla (Deputy Chief Investigator), General Practitioner & Lead for the West 
Midlands Primary Care CRN team, Institute of Applied Health Research, University of 
Birmingham; Email: david.shukla@nihr.ac.uk  
Trial 
Management 
Group * 
Susan Beatty, Clinical Operations Manager, Clinical Practice Research Datalink, MHRA; 
Email: Susan.Beatty@mhra.gov.uk 
Samir Mehta, Statistician, Birmingham Clinical Trials Unit; Email: s.mehta.1@bham.ac.uk   
Tim Williams, Head of Interventional Research, Clinical Practice Research Datalink, 
MHRA; Email: tim.williams@mhra.gov.uk  
Sophie Breeze, Clinical Study Development Manager, Clinical Practice Research Datalink, 
MHRA; Email: sophie.breeze@mhra.gov.uk  
Alastair Mobley, DaRe2THINK Senior Trial Coordinator; Email: alastair.mobley@nihr.ac.uk  
Xiaoxia Wang, DaRe2THINK Health Data Analyst; Email: xiaoxia.wang@uhb.nhs.uk   
Rebecca Ghosh, Senior Researcher, Clinical Practice Research Datalink, MHRA; Email: 
Rebecca.Ghosh@mhra.gov.uk  
Karen Lancaster, Primary Care Recruitment Lead, Clinical Practice Research Datalink; 
MHRA, Email: Karen.Lancaster@mhra.gov.uk 
Stuart Fordyce, Primary Care Recruitment Manager, Clinical Practice Research Datalink, 
MHRA; Email: Stuart.Fordyce@mhra.gov.uk 
Maximina Ventura, DaRe2THINK Project Research Officer; Email: 
Maximina.Ventura@uhb.nhs.uk 
Alice Young, DaRe2THINK Administrator; Email: alice.young@uhb.nhs.uk 
Data 
Coordination 
Team * 
Krish Nirantharakumar (Chair), UKRI Innovation Clinical Fellow & Honorary Consultant in 
Public Health Medicine, University of Birmingham; Email: k.nirantharan@bham.ac.uk 
[Health record coding] 
Naomi Allen, Professor in Epidemiology, University of Oxford & Chief Scientist, UK 
Biobank; Email: naomi.allen@ndph.ox.ac.uk [Cognitive function] 
Melanie Calvert, Professor of Outcomes Methodology & Director, Centre for Patient 
Reported Outcomes Research & Birmingham Health Partners Centre for Regulatory 
Science and Innovation; Email: m.calvert@bham.ac.uk [Patient-reported outcomes] 
Alastair Denniston, Director of INSIGHT - the Health Data Research Hub for Eye Health & 
Honorary Professor, University Hospitals Birmingham NHS Foundation Trust & University 
of Birmingham; Email: a.denniston@bham.ac.uk [Secondary care data integration] 
George Gkoutos, Professor of Bioinformatics, University of Birmingham & University 
Hospitals Birmingham NHS Foundation Trust; Email: g.gkoutos@bham.ac.uk [Outcome 
validation] 
Puja Myles, Head of Observational Research, Clinical Practice Research Datalink, MHRA; 
Email: puja.myles@mhra.gov.uk [Primary care data integration] 
Health 
Economics 
Team * 
Sahan Jayawardana, Health Economist, London School of Economics and Political 
Science; Email: s.a.jayawardana@lse.ac.uk  
 

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Elias Mossialos, Professor & and Director of LSE Health, London School of Economics 
and Political Science; Email: e.a.mossialos@lse.ac.uk  
Expert 
Advisory 
Group * 
Simon Ball (Chair), Executive Medical Director, University Hospitals Birmingham NHS 
Foundation Trust & Health Data Research UK Midlands; Email: simon.ball@uhb.nhs.uk  
Colin Baigent, Professor of Epidemiology & Deputy Director, Clinical Trial Service Unit, 
University of Oxford; Email: colin.baigent@ndph.ox.ac.uk  
Peter Brocklehurst, Director, Birmingham Clinical Trials Unit; Email: 
p.brocklehurst@bham.ac.uk  
Will Lester, Consultant Haematologist, University Hospitals Birmingham NHS Foundation 
Trust; Email: will.lester@uhb.nhs.uk  
Richard McManus, Professor of Primary Care & General Practitioner, University of Oxford; 
Email: richard.mcmanus@phc.ox.ac.uk  
Stefano Seri, Professor & Consultant in Clinical Neurophysiology, Birmingham Women’s 
and Children’s NHS Foundation Trust & Aston University; Email: s.seri@aston.ac.uk  
Janet Valentine,  ISCF Challenge Director, Innovate UK; Email: 
Janet.Valentine@iuk.ukri.org 
Trial Steering 
Committee * 
A John Camm (Chair), Professor of Clinical Cardiology, St. George’s University of London; 
Email: jcamm@sgul.ac.uk  
Sandra Haynes MBE, Patient and Public Involvement team lead  
Dame Julie Moore, Professor of Healthcare Systems, University of Warwick; Email: 
julie@damejuliemoore.uk  
Amy Rogers, General Practitioner & University of Dundee; Email: a.rogers@dundee.ac.uk  
Mary Stanbury, Patient & Public Involvement 
Paul McGreavy, Patient & Public Involvement 
Data 
Monitoring 
Committee  
Marcus Flather, Professor of Medicine and Clinical Trials, University of East Anglia; Email: 
m.flather@uea.ac.uk  
Suzy Walker, General Practitioner, Fortrose Medical Practice, Highland; Email: 
suzy.walker@nhs.scot 
Duolao Wang, Professor of Biostatistics, Liverpool School of Tropical Medicine; Email: 
duolao.wang@lstmed.ac.uk  
 
* The Chief Investigator and Deputy Chief Investigator will co-chair the Trial Management Group and contribute 
to other committees as required. 
 

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STUDY SUMMARY 
Title 
Preventing stroke, premature death and cognitive decline in a broader 
community of patients with atrial fibrillation using healthcare data for 
pragmatic research: A randomised controlled trial 
Acronym 
DaRe2THINK  
Trial Design  
Individual-patient, randomised, parallel-group, open-label, event-driven 
superiority trial  
Funder  
National Institute for Health Research (NIHR) Health Technology 
Assessment Programme 
Sponsor 
University of Birmingham, UK 
Trial Methods 
Data-enabled randomised trial embedded within NHS Primary Care using 
the Clinical Practice Research Datalink (CPRD) Interventional Research 
Services Platform, with automated screening, targeted patient enrolment 
and ‘no-visit’ follow-up through innovative technology-supported methods; 
Primary outcome assessment at five years from study start (or when 
primary outcome events reached) 
Trial Medications 
1:1 allocation to direct oral anticoagulants (DOAC) or no therapy; choice of 
DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local 
practice 
Primary Outcome 
Composite of cardiovascular mortality, ischaemic cerebrovascular events 
(stroke and transient ischaemic attacks), all thromboembolic events 
(including arterial and venous thromboembolism), myocardial infarction and 
vascular dementia  
Key secondary outcome 
Change in cognitive function status assessed through validated periodic 
objective testing with the UK Biobank cognitive function panel (primary 
parameter: fluid intelligence score) 
Health economic outcome 
Incremental cost per quality-adjusted life-year gained from the use of 
DOAC compared to no therapy from healthcare and societal perspectives 
Additional secondary outcomes 
• Individual components of the primary outcome 
• Cumulative event rates for components of the primary outcome 
• Composite of non-fatal stroke, non-fatal myocardial infarction and 
cardiovascular death 
• Any major bleeding or clinically-relevant non-major bleeding that 
requires hospitalisation 
• Minor bleeding that requires attention from primary care  
• Haemorrhagic stroke and other types of intracranial bleeding 
• All-cause general practice visits 
• All-cause hospital admissions and duration of stay 
• Heart failure hospitalisation and duration of stay 
• All-cause mortality 
• Patient-reported quality of life using the EQ-5D-5L index score 
• Patient-reported quality of life using the EQ-5D-5L visual analogue score 
Process outcomes 
 
• Number/proportion of potential participants located by CPRD and 
notified to the lead NIHR Clinical Research Network (CRN) 
• Number/proportion of primary care practices that have completed sign-
up processes 
• Number/proportion of patients eligible on automated screening that are 
successfully recruited 

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• Rate of patient recruitment 
• Patient-reported compliance to DOAC therapy in the DOAC arm 
• Repeat prescriptions obtained for DOAC therapy 
• Missing data rates for patient-reported outcomes 
Outcome derivation 
Extraction of coded electronic health records from primary care (CPRD) 
and secondary care (Hospital Episode Statistics); patient-reported cognitive 
function (yearly) and quality of life (6-monthly) obtained through digital 
methods 
Trial Duration 
Anticipated 2 years recruitment and further 3 years follow-up to achieve 
number of events; consent for further outcome assessment at 10-years and 
lifetime follow-up through electronic records 
Planned Trial Sites 
Up to 600 General Practices across England that are part of the CPRD 
network, facilitated by the NIHR CRN 
Total Number of Participants  
3,000 
Inclusion criteria based on coding 
in Primary Care 
1. Diagnosis of AF (previous, current or chronic) 
2. Age at enrolment ≥55 years to ≤73 years  
Exclusion criteria based on coding 
in Primary Care 
1. Prior documented stroke, transient ischaemic attack or systemic     
thromboembolism.  
2. Combination of multiple known risk factors for stroke where oral 
anticoagulation would ordinarily be started, including: Heart failure; 
Hypertension; Age 65 years or older; Diabetes mellitus; Previous 
myocardial infarction, peripheral artery disease or aortic plaque; and/or 
Female gender. 
3. Any prior history of intracranial bleeding.  
4. Prior major bleeding requiring hospitalisation in the last 3 years. 
5. Condition that poses a significant risk for bleeding (within 12 months) 
including gastrointestinal ulceration, brain/spinal/ophthalmic injury or 
surgery, arteriovenous malformations or vascular aneurysms, major 
intraspinal or intracerebral vascular abnormalities, hepatic disease 
associated with coagulopathy, known or suspected oesophageal varices, 
and cancers with high bleeding risk. 
6. Estimated glomerular filtration rate <30 mL/min/1.73m2 measured within 
the last 12 months. 
7. Patients receiving systemic treatment with azole-antimycotics within the 
last 3 months (ketoconazole, itraconazole, voriconazole and 
posaconazole). 
8. Documented diagnosis of dementia. 
9. Hypersensitivity or known intolerance to direct oral anticoagulants. 
Exclusion criteria based on review 
by Primary Care staff 
1. Currently receiving an anticoagulant. 
2. Any clinical indication for anticoagulation. 
3. Active clinically-significant bleeding. 
4. Life expectancy estimated <2 years. 
5. Participant unable or unwilling to provide informed consent for access 
and linkage of past and future electronic healthcare records. 
6. Currently participating in another clinical trial. 
7. Women of childbearing potential. 
 
 
 

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ABBREVIATIONS 
ABPI  
Association of the British Pharmaceutical Industry 
AE 
Adverse event 
AF  
Atrial fibrillation 
AR 
Adverse reaction 
BNF 
British National Formulary 
CCG 
Clinical Commissioning Group 
CHA2DS2-VASc  
Thromboembolic risk score (including heart failure, hypertension, age, diabetes, 
vascular disease and gender) 
CPRD 
Clinical Practice Research Datalink 
CRN  
Clinical Research Network 
CTA 
Clinical Trial Authorisation 
CTIMP  
Clinical Trial of Investigational Medicinal Product 
DIBD 
Developmental International Birth Date 
DMC 
Data Monitoring Committee 
DOACs 
Direct oral anticoagulants 
DSUR 
Development Safety Update Report 
EudraCT No. 
European Union Drug Regulating Authorities Clinical Trials Number 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HDR-UK 
Health Data Research - United Kingdom 
HES  
Hospital episode statistics  
ICER 
Incremental cost-effectiveness ratio 
IRSP 
Interventional Research Services Platform 
ISRCTN 
International Standard Randomised Controlled Trial Number 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
NICE  
National Institute for Health and Care Excellence 
ONS 
Office for National Statistics 
NIHR 
National Institute for Health Research 
PIS 
Participant Information Sheet 
PPI 
Public and Patient Involvement 
PRO 
Patient-reported outcome 
QALY 
Quality-adjusted life-year 
RCT 
Randomised controlled trial 
REC 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture case report system 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SAP 
Statistical analysis plan 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
SWAT 
Study-Within-A-Trial 
TMG  
Trial Management Group 
TSC 
Trial Steering Committee 
UHB 
University Hospitals Birmingham NHS Foundation Trust 
WOCBP 
Women of childbearing potential 

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PLAIN ENGLISH SUMMARY 
The National Health Service (NHS) is unlike any other in the world, caring for people throughout their 
lives both in the community and in hospitals.  At the heart of DaRe2THINK is that health data collected 
within these services can be used for the benefit of patients.  Clinical trials are an important way to 
understand how new treatments can be used in the NHS, but many trials struggle to find the right 
patients, or be relevant to their needs.  The DaRe2 approach (healthcare Data for pragmatic clinical 
Research in the NHS – primary 2 secondary) will test a new way of running trials based at General 
Practitioner (GP) surgeries using routine NHS information.  We will include patients that don’t normally 
take part in clinical trials and follow them up without the need to revisit their GP or attend hospital.  
This approach could improve the health and well-being of those treated by the NHS, whilst reducing 
the time needed from staff and patients to engage in important research. 
 
As an example of this new system, DaRe2THINK will target an issue of huge importance to patients, 
our NHS and the social care system.  Atrial fibrillation (AF) is a common heart rhythm condition that 
leads to a high chance of stroke, frequent hospital admissions and poor quality of life.  Patients also 
have a much higher risk of cognitive decline (trouble remembering, concentrating or making every-day 
decisions) and dementia.  This may be due to silent ‘micro-strokes’ that gradually damage the brain 
over time.  Blood thinning tablets (anticoagulants) greatly reduce the number of patients with AF that 
will suffer a stroke, but are usually only given to older patients or those with other health issues.  This 
may be too late to avoid dementia.  It also leaves those younger than 65 years, and some patients 
aged 65-75 without treatment that could prevent these devastating complications. 
 
A new class of blood thinning tablets are now widely used in the NHS which are more convenient for 
patients to take, and have a lower risk of bleeding than older treatments.  These drugs could provide 
an effective way to prevent strokes, brain damage and dementia in later life for a broader group of 
patients, but this needs to be tested in a clinical trial.  With the support of a Patient and Public 
Involvement Team and a national network of research nurses and GPs, the trial will include 3,000 
patients from up to 600 GP surgeries across England.  Each patient will either continue their current 
treatment or start an additional blood thinning tablet on a random basis.  Patients will be followed up 
automatically within the NHS to look at the difference in those who suffer from strokes, blood clots, 
heart attacks, other problems with the blood vessels and dementia.  Patients will self-report their 
memory, reaction times and quality of life using simple questionnaires through their mobile phone or 
the internet, again without needing to revisit their doctor. 
 
DaRe2THINK will answer important questions for a growing number of patients with AF.  The 
combination of information from the community as well as hospitals across the NHS will allow us to 
see whether these blood thinning tablets should be prescribed more widely.  DaRe2THINK will allow 
us to develop and improve this new clinical trial system so that future research in the NHS will 
continue to benefit those patients most in need. 
   
 
 

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SCIENTIFIC ABSTRACT 
Research question: Using an efficient, nationwide, primary care approach for an NHS-embedded 
randomised controlled trial (RCT), does direct oral anticoagulant (DOAC) therapy reduce premature 
death, stroke and other thromboembolic consequences of atrial fibrillation (AF) in younger patients, 
including prevention of cognitive decline and vascular dementia? 
Background: Current RCT methodology often leads to recruitment of highly selected participants with 
less diversity than the clinical population, and challenges with enrolment and retention of patients. 
New RCT approaches are needed that can realise the value of the world-leading data quality and 
infrastructure of the NHS.  AF is the most common heart rhythm abnormality, expected to double in 
prevalence in the next few decades, and leads to a considerable burden for patients and society at-
large.  In particular, the impact of stroke, cognitive decline and vascular dementia are all major public 
health concerns. 
Aims and objectives: DaRe2THINK will test the hypothesis that DOACs are effective and cost-
effective in patients with AF at low or intermediate risk of stroke by using an ambitious and innovative 
data-enabled approach through the Clinical Practice Research Datalink (CPRD) in Primary Care 
General Practices across England. 
Methods: Individual-patient, open-label, event-driven RCT with 1:1 allocation to DOAC or no 
additional therapy (usual care).  Automated screening of over 12 million patients, with targeted 
recruitment to practices with eligible patients, regular updates to General Practitioners, simple 
processes for centre inclusion and patient randomisation, and no additional visits after baseline for any 
patient.  The primary outcome is a comprehensive composite of any thromboembolic event, including 
cardiovascular mortality, ischaemic stroke, pulmonary or venous thromboembolism, myocardial 
infarction and vascular dementia, ascertained entirely using electronic healthcare records within both 
primary and secondary NHS care.  The key secondary outcome is the change in cognitive function, 
using technology solutions to provide ‘no-visit’ patient-reported follow-up, saving time for clinical staff 
and patients.  We will carefully assess and validate safety outcomes relating to major and minor 
bleeding, and a systematic health economic analysis will determine NHS and societal cost-
effectiveness.  A sub-study using cerebral and retinovascular imaging will be performed to understand 
the mechanistic effects of DOAC therapy. 
Timelines for delivery: Total duration 60 months, including 3-stage internal pilot (8 months), patient 
recruitment (24 months), and additional 36 months follow-up for primary and secondary outcomes.  A 
further outcome assessment at 10 years will specifically target development of vascular dementia. 
Anticipated impact and dissemination: DaRe2THINK will demonstrate the operational capabilities 
of using the NHS record for interventional research.  We will recruit a diverse, population-relevant 
cohort using automated nationwide screening, prioritisation of centres with recruitable patients, and 
remote technology-enhanced follow-up.  These innovations will allow us to answer a key question for 
21st century healthcare relating to an increasingly common condition with considerable burden on 
patient quality of life, the health of the nation and our economy.  Current and future impacts from AF 
and vascular dementia will be unsustainable unless we can expand prevention.  DaRe2THINK will 
develop close collaboration between the NIHR Clinical Research Network, CPRD, patient groups, 
academic institutions and the NHS to address this and future evidence-gaps in clinical practice. 

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TRIAL FLOW CHART
 
* please see the current protocol (section 3) for detailed inclusion and exclusion criteria. 

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1 
BACKGROUND, RATIONALE & AIMS 
1.1 The burden of atrial fibrillation 
Atrial fibrillation (AF) is one of the most pressing concerns in the National Health Service (NHS) due to 
high cost, poor patient quality of life, and excess morbidity and mortality.  Using primary care data 
from the Clinical Practice Research Datalink (CPRD), the predicted prevalence of AF in the UK will 
increase from 700,000 patients in 2010, to between 1.3 and 1.8 million patients by 2060.[1]   
This burden will largely fall on general practice, but also have major implications on secondary care; 
one in four patients admitted with a stroke have AF [2], half of AF patients develop heart failure that 
responds poorly to treatment [3,4], and the rate of death and hospital admissions (regardless of 
cause) are doubled at all ages.  Strokes secondary to AF lead to greater neurological damage, and 
the common occurrence of undetected and clinically-silent ‘micro-strokes’ in AF patients has 
intensified attention on early diagnosis.[5]  Even at an average age of 64 years, 30% of patients with 
AF have evidence of cognitive impairment [6], with dementia risk higher in those with AF regardless of 
previously diagnosed strokes.[7] 
Oral anticoagulation substantially reduces morbidity in AF patients [8], and the direct oral 
anticoagulants (DOACs) now used routinely in the NHS have distinct advantages compared to 
conventional warfarin therapy.[9]  However, choosing which patients with AF should receive 
anticoagulants is difficult as clinical risk scores only have a modest ability to predict stroke.  Risk 
scores such as CHA2DS2-VASc used in the NICE guidelines [10] have revolutionised our approach to 
stroke prevention, but typically prioritise treatment of older patients or those with multiple risk factors.  
In contrast, patients aged less than 65 years, and some of those aged 65-75, do not routinely receive 
anticoagulation due to a lack of trial data.  Although their annual risk of events is relatively low, when 
strokes and cardiovascular events occur in this younger population they can have a profound effect on 
patients and their families, with long-term social and NHS impact.  Further, although warfarin does not 
reduce the rate of cognitive decline compared to aspirin in older patients [11], observational data is 
suggestive that in younger AF patients at low or intermediate risk of stroke, anticoagulants could 
potentially reduce the risk of dementia.[12]  Preventing cognitive decline and dementia is a national 
priority due to the high burden and cost of these conditions (£26 billion per year in the UK in 2014), 
and the prediction that dementia will affect over 2 million British people by 2050.[13]  Interrupting the 
process of strokes and micro-strokes due to AF could have important advantages for the patient, the 
NHS and society as a whole. 
 
1.2 The need for new trials  
The increase in UK prevalence of AF in recent years [14] is predicted to rise even further.[1]  The 
financial cost of AF is high and increasing [15]; this will be unsustainable for the NHS unless we 
develop better approaches to tackle the high rate of hospitalisation (a key driver of NHS cost), and the 
adverse impact on cognitive function (societal cost).  Patients with AF at low risk of stroke treated with 
anticoagulants in the nationwide Swedish registry had a significantly lower risk of dementia (38% 
reduction, 95% CI 19-52%).[12]  Similar findings have been seen in other cohort studies [16], with 
DOACs associated with half the rate of new-onset dementia compared to warfarin.[17]  However, we 
must take care not to over-extrapolate observational data, as treatment biases can play a major 
role.[18]  A robust, randomised controlled trial (RCT) is the only way to demonstrate the effect of 

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DOACs and thereby provide guidance to the National Institute for Health and Care Excellence and 
clinicians.   
A conventionally run RCT would have major challenges in screening sufficient numbers of patients for 
such a trial.  Current RCT methodology often leads to costly recruitment of highly selected participants 
with less diversity than the clinical population.  Most RCTs are based in secondary care and suffer 
from challenges in enrolment and retention of patients.  The current coronavirus pandemic has further 
curtailed clinical research.  Additionally, in patients at lower risk of stroke, the benefit of oral 
anticoagulation must be balanced against the risk of bleeding.[5]  In particular, minor bleeding is 
common [19] and could have an impact on quality of life that mitigates other advantages.  Accurate 
identification of these events is only possible through integration of both community and hospital-level 
data, as many patients will not come to the attention of hospital clinicians.  Hence a new approach is 
needed that will allow for efficiencies in screening, recruitment and outcome assessment, whilst also 
reducing cost and achieving generalizable results. 
 
1.3 A joined-up approach across the NHS 
With the majority of patient contacts in the NHS occurring within Primary Care, General Practice 
provides the ideal setting for undertaking larger-scale research, recruiting from diverse populations not 
normally accessible for hospital-based research studies.  300 million consultations per year occur 
within General Practice, compared to 24 million Emergency Department visits.[20]  The NIHR Clinical 
Research Network (CRN) works with 38% of ‘research active’ General Practices across England, and 
with an increasing shift from acute to community (‘place-based’) care, a major opportunity exists for 
primary care research to add value to the NHS and benefit patients.[21]   
CPRD is a government agency and part of the Medicines and Healthcare products Regulatory Agency 
(MHRA).  CPRD staff have been working hard over the last decade to create a research environment 
in Primary Care that is secure, robust and unique across the world.  Electronic health records from the 
major software providers in the UK are available within the CPRD system, and data are updated on a 
daily basis.  Over 1,800 General Practices are currently part of the CPRD network which continues to 
grow, resulting in a catchment population of over 15 million patients across the UK, and over 12 million 
in England.  CPRD is representative of the diverse UK population and therefore provides a unique 
opportunity for real-world RCTs that can improve medical care for actual NHS patients.  CPRD has a 
similar spread across deciles of age and gender compared to data from the Office for National 
Statistics [22], and a comparable ethnicity profile compared to the UK Census (e.g. 12.7% total non-
white in the Census, versus 13.2% for age-standardised CPRD).[23] 
By linking CPRD data with that from NHS Digital, which includes Hospital Episode Statistics (HES) 
from all secondary care utilisation within the NHS, we can obtain a near totality of clinical event data 
for patients who provide consent.  This joined-up approach is key to addressing important gaps in 
evidence for common and high-morbidity conditions such as AF. 
 
1.4 The DaRe2 trial pipeline 
A broad spectrum of current and foreseeable challenges to the NHS could be tackled by better linkage 
of routine clinical data from secondary to primary care (and vice-versa), providing a robust basis for 
new evidence generation.  The DaRe2 approach (healthcare Data for pragmatic clinical Research in 
the NHS – primary 2 secondary) was designed to operationalise efficient, nationwide, primary care 

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approaches for NHS-embedded RCTs, providing automated screening, targeted patient enrolment 
and ‘no-visit’ follow-up through innovations in big data and technology solutions: 
1. A National platform utilising CPRD with the capacity to run clinician-designed RCTs in primary 
care, demonstrating the capability of research for patient benefit within the NHS. 
2. Automated screening of inclusion and exclusion criteria across more than 12 million primary care 
patients within 1 in 5 of GP surgeries in the NHS, providing rapid and cost-efficient screening of a 
diverse and representative proportion of the UK population. 
3. Targeted enrolment at GP surgeries identified as having potentially eligible patients, reducing the 
time taken for recruitment and avoiding screening failures. 
4. Updates to participating GPs on a weekly basis highlighting potentially eligible patients, simplifying 
the process of patient identification and recruitment. 
5. Established and straightforward enrolment of patients at the GP surgery with built-in 
randomisation, allowing for immediate entry to an RCT, and then drug prescription via clinical 
systems. 
6. No-visit follow-up and minimal loss to follow-up, utilising all the capabilities of NHS records for 
capture of endpoints: (a) without the patient needing to attend a research facility or to schedule 
periodic visits; (b) with no need for NHS staff to complete arduous case report forms; and (c) no 
requirement for costly and complex trials unit management or a contract research organisation.  
The coronavirus pandemic has clearly demonstrated the need for new approaches that can avoid 
the need for patient visits, whilst still providing robust data suitable for regulatory and guideline 
recommendations. 
7. Innovations in technology for e-consent and patient-reported outcomes, with secure data 
acquisition through web-based approaches via the patient’s own smartphone, tablet or computer. 
8. Sample size and power calculations based on real-world outcomes in UK patients matching 
inclusion and exclusion criteria, ensuring that NHS resources are not wasted on ineffective trials.  
9. ‘Virtual’ controls, with full data on outcomes in patients meeting enrolment criteria nationally but not 
consented to enter the trial, a key innovation to explore variation in clinical events and for external 
validation of results. 
10. An approach that showcases the potential for world-leading NHS-based research and the 
underpinning methodology, whilst mitigating risk through the experience of CPRD and the NIHR 
Primary Care CRN. 
 
1.5 Application to patients with AF and beyond 
DaRe2THINK will be the first exemplar of this system, and is appropriately focused on the intersection 
of key national priorities for healthcare; atrial fibrillation (a heart rhythm condition that will double in 
prevalence in the next few decades) and the impact this condition has on stroke, thromboembolic 
events, cognitive impairment and vascular dementia. These are all major burdens on our patients, as 
well as health and social care services.  DaRe2THINK will test the hypothesis that direct oral 
anticoagulants (DOACs), now commonly used in the NHS for older patients with AF, are effective and 
cost-effective at reducing major adverse clinical events in younger patients at low or intermediate risk 
of stroke, and can reduce the high rate of cognitive decline.  The health technology innovations noted 
above will allow us to answer this important clinical question, as well as demonstrate the capacity and 
potential of this system for future, large-scale NHS-embedded clinical trials for patient benefit.  

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2 
DESIGN CONSIDERATIONS 
2.1 Design summary 
DaRe2THINK has been designed with an active Patient and Public Involvement (PPI) team and is an 
individual-patient, randomised, parallel-group, open-label, event-driven superiority trial with 1:1 
allocation to either DOAC or no added therapy.  A staged internal pilot programme is incorporated into 
the design of this Clinical Trial of an Investigational Medicinal Product (CTIMP).  Sub-studies are listed 
in section 13. 
DaRe2THINK will also test a health technology platform for research for patient benefit based in 
Primary Care in the NHS, including patient screening entirely through the CPRD Interventional 
Research Services Platform (IRSP), and follow-up through linked NHS outcomes and integrated 
technology solutions.  For feasibility reasons, DaRe2THINK will focus on England only, where the 15 
local CRNs can provide their expert assistance in promotion, setting-up and then enrolling General 
Practices and patients.   
 
2.2 Assessment of risk for control patients 
AF is associated with considerable morbidity, including 10-40% of patients hospitalised every year and 
20-30% of strokes due to AF [2], heart failure in 30-50% of patients [24], and substantial impairment of 
quality life and psychosocial impact on patients and their families.[25]  These risks are not confined to 
older patients.  Using the UK primary care THIN dataset (2005-2018), we compared clinical outcomes 
in 16,574 AF patients with CHA2DS2-VASc <2 and not taking anticoagulants against 18,895 patients 
without AF.  Rates of major adverse outcomes were still double in these younger patients, despite 
their apparently ‘low or intermediate’ risk status: adjusted incidence rate ratio 1.94 for mortality (95% 
CI 1.80-2.10), 3.09 for stroke (2.66-3.61), 1.81 for other thromboembolic events (1.52-2.15) and 2.03 
for ischaemic heart disease (1.81-2.27).  Patients with AF had higher incidence of vascular dementia 
(1.82; 1.07-3.06), with no increase in Alzheimer’s Disease (0.99; 0.68-1.42), as would be expected 
from the assumed pathophysiology that AF leads to multiple silent micro-strokes causing ‘vascular’ 
cognitive decline.    
Patients with AF under the age of 60 have much lower incidence rates for the composite of ischaemic 
cerebrovascular and all thromboembolic events, even for those with other risk factors, providing a 
useful distinction between the balance of benefit and potential risk from anticoagulation.  For example, 
the incidence rate for the composite outcome was 16.6 per 1000 patient years for AF patients aged 
60-73 (regardless of comorbidity), compared to 8.0 for patients aged 50-60 with heart failure and a 
prescription for diuretics, 14.5 for those aged 50-60 with diabetes and at least one antidiabetic 
therapy, and 14.3 for those aged 50-60 with hypertension treated with two or more drugs.  
 
2.3 Assessment of risk for anticoagulated patients 
Although anticoagulants dramatically reduce thromboembolic events in patients with AF [26], the risk 
of bleeding is a concern, particularly when the event rates for stroke and thromboembolism are low.  
The bleeding risk with DOACs is lower than vitamin K antagonists, both for major and minor bleeding, 
and in particular is halved for intracranial haemorrhage.[27]  In the Apixaban for Reduction in Stroke 
and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, the rate of non-major 
bleeding was 10.1% for apixaban versus 14.2% for warfarin, and 3.1% versus 4.5% for major bleeding 

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respectively.[19]  DOACs have demonstrated equivalent or better efficacy for prevention of stroke and 
other adverse events compared to warfarin in both trials and real-world data.[8,9,28]  It is also 
important to note that risk factors for thromboembolism are also risk factors for bleeding.[29]  Based 
on this literature, it is clear that DOACs are the preferred therapy to test the balance of 
thromboembolic prevention and bleeding risk with anticoagulants in the patient group with low or 
intermediate risk of stroke. 
 
2.4 Hypotheses for primary, key secondary & health economic outcomes 
Compared to standard of care (no anticoagulant therapy), DOACs in patients with AF and a low or 
intermediate expected risk of stroke will:  
1. Reduce the composite of cardiovascular mortality, ischaemic stroke, thromboembolic events, 
myocardial infarction and vascular dementia compared to no treatment, ascertained using 
electronic health record data from primary and secondary NHS care. 
2. Prevent cognitive decline, determined by yearly technology-supported cognitive testing 
completed remotely by participants. 
3. Be cost-effective from a healthcare and societal perspective at a willingness to pay threshold of 
£20,000 - £30,000 per quality-adjusted life-year. 
 
2.5 Hypotheses for other secondary outcomes 
Compared to standard of care (no anticoagulant therapy), DOACs in patients with AF and a low or 
intermediate expected risk of stroke will:  
1. Reduce individual components of the primary outcome and their cumulative event rates, in 
addition to the conventional composite of non-fatal stroke, non-fatal myocardial infarction and 
cardiovascular death, as well as all-cause mortality. 
2. Have an acceptable safety profile in terms of major bleeding, clinically-relevant non-major 
bleeding and minor bleeding that requires clinical attention. 
3. Reduce healthcare utilisation, including General Practice visits, hospital admissions (all-cause 
and heart failure-specific) and the duration of hospital stay. 
4. Improve patient-reported quality of life using the EQ-5D-5L questionnaire. 
 
2.6 Overarching challenge and opportunity 
RCTs are the foundation of evidence-based practice but involve escalating cost and usually target a 
selected group of patients.  The advantages of a trial based at the community level of healthcare 
include:  
1. Results that are more generalizable to the true population. 
2. Utilisation and repurposing of data already collected as part of standard NHS care. 
3. Operational, logistical and efficiency benefits leading to the ability to test interventions or NHS 
pathways at a scale not previously possible.    
 

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3 
STUDY METHODS 
3.1 Approach to study selection criteria 
DaRe2THINK will operate using a system of automated patient pre-screening using coded Primary 
Care health records across the >13 million patients registered in CPRD GP surgeries across England.  
The trial adopts a pragmatic approach to the screening criteria, aiming to display to Investigators only 
those patients who are likely to fulfil enrolment criteria.  Investigators who are medical practitioners are 
still required to approve specific exclusion criteria based on review of the medical record (see section 
3.4 for further details, and section 5 for information about data processing and coding).  Automated 
pre-screening exclusion criteria for medical conditions are based on secure definitions (presence of 
coding for that condition plus recent prescription of relevant medical therapy) to avoid exclusion where 
an unsubstantiated or transient code is present in the medical record. 
 
3.2 Participant inclusion criteria based on coding in the Primary Care record 
 
1. Diagnosis of AF (previous, current or chronic). 
2. Age 55 to 73 years, with a six-month window to account for the use of pseudonymised patient 
records.a  
 
3.3 Participant exclusion criteria based on coding in the Primary Care record 
1. Prior documented stroke, transient ischaemic attack or systemic thromboembolism.  
2. Combination of multiple known risk factors for stroke where oral anticoagulation would ordinarily 
be started, including b: Heart failure; Hypertension; Age 65 years or older; Diabetes mellitus; 
Previous myocardial infarction, peripheral artery disease or aortic plaque; and/or Female gender. 
3. Any prior history of intracranial bleeding.  
4. Prior major bleeding requiring hospitalisation in the last 3 years. 
5. Condition that poses a significant risk for bleeding (within 12 months) including gastrointestinal 
ulceration, brain/spinal/ophthalmic injury or surgery, arteriovenous malformations or vascular 
aneurysms, major intraspinal or intracerebral vascular abnormalities, hepatic disease associated 
with coagulopathy, known or suspected oesophageal varices, and cancers with high bleeding risk. 
6. Estimated glomerular filtration rate <30 mL/min/1.73m2 measured within the last 12 months. 
7. Patients receiving systemic treatment with azole-antimycotics within the last 3 months 
(ketoconazole, itraconazole, voriconazole and posaconazole). 
8. Documented diagnosis of dementia. 
9. Hypersensitivity or known intolerance to direct oral anticoagulants. 
 
3.4 Participant exclusion criteria based on review by Primary Care staff  
1. Currently receiving an anticoagulant.c 
2. Any clinical indication for anticoagulation. 

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3. Active clinically-significant bleeding. 
4. Life expectancy estimated <2 years. 
5. Participant unable or unwilling to provide informed consent for access and linkage of past and 
future electronic healthcare records. 
6. Currently participating in another clinical trial. 
7. Women of childbearing potential.d 
 
a Screening for age is based on pseudonymised medical records, hence only year of participants birth 
is available.  Patients turning 55 within the next six months, or patients that turned 74 in the preceding 
six months may be included and will be considered eligible for enrolment. 
b For the automated pre-screening via CPRD IRSP, patients with a CHA2DS2-VASc score of 2 or more 
in men and 3 or more in women will automatically be excluded. Relevant criteria will be confirmed by 
the concurrent use of medical therapy: Heart failure (confirmed by use of loop diuretic therapy within 
the last 3 months); Hypertension (confirmed by use of anti-hypertensive therapy within the last 3 
months); and Diabetes mellitus (confirmed by use of oral antidiabetic therapy or insulin within the last 
3 months). Note that in the absence of other stroke risk factors, female gender is not independently 
associated with a higher risk of stroke or systemic thromboembolism.[30] 
c Patients with a prescription for an anticoagulant in the previous 6 months will be excluded 
automatically based on coding in the Primary Care record, but site staff are required to confirm 
potential participants are not taking anticoagulants to cover cases of extended duration prescriptions 
or therapy received from other sources (e.g. after hospital discharge). 
d Defined as fertile, following menarche and until becoming post-menopausal, unless permanently 
sterile.  For further information, see section 3.9. 
 
3.5 General Practice selection criteria 
This trial will recruit participants from GP practices in England that contribute to CPRD; as of 
September 2020, 1,337 practices in England (15%) are part of CPRD.  Centres that use the Egton 
Medical Information Systems (EMIS) web software platform will be included first, with practices using 
TPP SystmOne and InPS Vision software used to supplement recruitment if required.  Practices that 
are participating in any anticoagulant intervention studies where there is potential to confound or 
modify the effects in DaRe2THINK will be excluded. 
 
3.6 Participant identification and Screening 
The selection criteria will be applied within the CPRD IRSP at study start, based on the predefined 
code list.  A pseudonymised patient list is generated specific to each Primary Care practice.  Following 
the site approval process, site staff or an appropriately-delegated person at each practice will access 
the list, re-identify the patients and respond to a specified set of screening questions.  Recruitment will 
be focused on practices with multiple potential participants for cost efficiency, targeting up to 600 GP 
surgeries across England.  A further update will be performed for patients meeting the trial selection 
criteria at each participating practice on a weekly basis.  The IRSP maintains confidentiality of all 

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patient data according to CPRD internal governance and in line with the Data Protection Act 2018 (see 
section 9: Data Security). 
GPs, practice nurses and other research staff in Primary Care (e.g. Research Nurses and CRN 
Research Facilitators) will review records of potential participants on the IRSP.  For patients that meet 
the selection criteria, the Primary Care team will send out an invitation letter and/or text message 
informing them about the study, and providing access to the Participant Information Sheet.  This 
includes a link to the website with an information video for potential participants developed by the PPI 
team and the items on the informed consent form (ICF).  This will allow potential participants the 
opportunity to consider whether they would like to participate in the study.   
Study invitation letters will be generated by Investigators using a protocol embedded in the EMIS 
software that is activated at the practice.  When an invitation letter is generated, a NIHR code for 
“Invitation to participate in research study” will be inserted into the patient’s medical record.  The letter 
includes a weblink and Quick Response (QR) code for potential participants to complete the ‘consent 
to contact’ electronic form (see section 3.7).  A reminder alert to follow-up with the patient will appear 
on the patient record seven days after this letter is generated.  Text messages will be sent via the 
practice’s own text messaging system, normally used to inform patients about their NHS appointment.  
The text message will inform the patient about their eligibility for the study, and provide the weblink to 
the ‘consent to contact’ electronic form.  Telephone calls will also be made to potential participants, in 
particular to ensure that Black, Asian, and minority ethnic persons are not unduly disadvantaged from 
participating in the trial.  The process of weekly updates of potential participants will continue 
throughout the recruitment period to enrol incident AF patients and those that newly meet the inclusion 
criteria.  As part of the ongoing GP engagement plan, participating practices will be contacted 
regularly to notify them of patients suitable for screening at their practice.   
If a patient attends with newly-diagnosed AF, an investigator or delegate should update the patient’s 
medical record as normal, which will then be captured by CPRD.  Once the patient is listed on the 
weekly IRSP update, the site can send a study invitation letter/text message to the patient.  Screening 
must take place on IRSP before the patient can be given access to the ICF on REDCap.  Investigators 
may contact CPRD if they believe a patient is eligible but does not appear on their patient list in IRSP.  
CPRD will investigate any instances where this is reported, and can alert the Investigator if the patient 
does not meet the stipulated selection criteria.    
 
3.7 Consent to contact 
Eligible participants who have been successfully screened and invited by their Primary Care team will 
be directed to a Research Electronic Data Capture case report system (REDCap) electronic form to 
consent to communication by the central study team.  After reviewing the PPI information video, 
potential participants will be asked to complete the ‘consent to contact’ form by entering their name, 
Primary Care practice name, telephone number, email address and best timeslot for contact.  Central 
study staff will then telephone the potential participant, go through any questions arising from the 
Participant Information Sheet, and activate the REDCap e-consent process as documented in section 
3.8.   
 
 

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3.8 Consent procedures for trial enrolment  
Informed consent must be obtained prior to the participant undergoing procedures that are specifically 
for the purposes of the trial and are out-with standard routine care at the participating site.  The Site 
Principal Investigator (PI; usually the lead GP for the study at that centre) retains overall responsibility 
for the conduct of research at their site; this includes the taking of informed consent of participants at 
their site.  They must ensure that any person delegated responsibility to participate in the informed 
consent process (such as Practice Nurses or CRN Research Nurses) are duly authorised, trained and 
competent to participate according to the ethically approved protocol, principles of Good Clinical 
Practice (GCP) and the Declaration of Helsinki.  The consent process includes explicit consent for the 
transfer of identifiable information on the consent form itself.   
The consent process should include: 
• 
A two-way discussion between the potential participant and an individual knowledgeable about the 
research, the nature and objectives of the trial and possible risks associated with their 
participation. 
• 
The discussion of written material, namely the Participant Information Sheet and consent 
documentation approved by the Research Ethics Committee (REC), supplemented by verbal 
explanations from practice nurses, research nurses or GPs. 
• 
The opportunity for potential participants to ask questions. 
• 
An assessment of capacity; for consent to be ethical and valid in law, participants must be capable 
of giving consent for themselves. A capable person will understand: (1) the purpose and nature of 
the research; (2) what the research involves; (3) its benefits and risks; (4) alternatives to taking 
part; and be able to: (5) retain the information long enough to make an effective decision; (6) make 
a free choice; (7) make this particular decision at the time it needs to be made (though their 
capacity may fluctuate, and they may be capable of making some decisions but not others 
depending on their complexity); and (8) make the decision free of coercion. 
In the case of any patients that lack capacity for consent, they will not be accepted into the study, even 
for those who have a legally-designated representative.  Where a participant is able to consent but 
later becomes incapacitated, the original consent given endures the loss of capacity.  The right of a 
participant to refuse participation without giving reasons must be respected.   
 
Documentation of informed consent will take the form of: 
(1) An online portal using REDCap which can be accessed by the potential participant through any 
internet connected device to complete remote e-consent.  The latter is designed to avoid unnecessary 
physical contact, and where consultations are performed through telephone or video methods, which 
are now routine in Primary Care due to the coronavirus pandemic.  The latest version of the REC-
approved ICF should be used.  Electronic consent processes will follow the Sponsor’s SOPs and 
guidelines on remote consent (BCTU-GDL11), which are compliant with the HRA and MHRA Joint 
Statement on Seeking Consent by Electronic Methods (version 1.2; published 2018).  An e-signature 
is captured by the participant using their finger, stylus or mouse (depending on their setup and type of 
device they are using); see section 9.2 for details on database security for e-consent.  The Investigator 
or delegate(s) will then sign and date their portion of the e-ICF, and provide the NHS number for future 
linkage of healthcare records for the validation programme (see section 5.3).  Regardless of whether 

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the participant uses the consent to contact approach, or is directly enrolled by their Primary Care 
team, countersignature of the consent process must be performed by the Investigator or delegate and 
cannot be completed by any central study staff. 
(2) For potential participants that attend in person or contact their Primary Care team, the Investigator 
or delegate is required to log into the REDCap system with their practice ID and password to initiate 
the consent procedure.  The participant will be asked to complete the ICF on their internet connected 
device or a computer at the site.  The Investigator or delegate(s) will then sign and date the ICF and 
complete recruitment processes as above.  A written ICF will also be available at sites that can be 
completed physically if required; however, this still requires the Investigator to initiate and complete 
the consent process on REDCap using their practice ID and password.  Written ICFs are required to 
be uploaded to the REDCap system on completion.  
Regardless of the method of completion, consent will be documented in the electronic patient record, 
and the Trial Master File, with a copy provided to the participant (physical copy or email depending on 
the route of consent).  Any original written ICFs should remain in the Investigator Site File.  In the case 
of e-consent, copies of the digitally-signed form will be automatically sent as a PDF file to the patient 
and available for review by authorised REDCap users, including the Primary Care research team, Trial 
Coordinator, CI and sponsor.  After consent processes have been completed on REDCap, the 
Investigator is required to confirm consent in the CPRD IRSP in order to complete participant 
enrolment.  CPRD IRSP generates a study specific identifier translating into a practice and patient 
identifier to avoid any collection of identifiable personal data. 
 
3.9 Women of childbearing potential 
Participants considered as women of childbearing potential (WOCBP) are not eligible to take part in 
the trial, as pregnancy and breastfeeding are contraindications for treatment with specific DOACs.  As 
per the Heads of Medicines Agencies Clinical Trials Facilitation and Coordination Group (2020), the 
definition of WOCBP that Investigators should use is as follows: 
“Fertile, following menarche and until becoming post-menopausal, unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.” 
 
3.10 Randomisation 
Method: A simple randomisation will allocate the participants 1:1 to either DOAC therapy (intervention 
group) or to continue without oral anticoagulation (control; standard of care).   
Implementation: The CPRD IRSP includes a module for randomisation once informed consent and 
selection criteria have been confirmed.  The patient is assigned a unique randomisation number which 
is automatically generated by the IRSP.  Where the participant is allocated to the DOAC arm, the 
resulting prescription will be logged both on the IRSP and the electronic health record as per usual 
clinical practice.  

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Statistical software: The randomisation sequence will be generated using Stata version 15.1 
(StataCorp LP, Texas).  
Concealment of allocation: The Investigator is blinded to the allocation sequence, however, as an 
open label trial, both the Investigator and participant will be aware of the allocation post randomisation.  
Out-of-hours access to randomisation codes: There is no requirement to access randomisation codes 
out of hours or in an emergency situation in this trial. 
Procedures for handling incorrectly enrolled or randomised patients: Patients who fail to meet the 
eligibility criteria should not, under any circumstances, be enrolled.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be randomised and must be 
withdrawn from the trial.  Where a patient does not meet all the eligibility criteria but is randomised in 
error, the Investigator should inform the Sponsor (or delegate) via the Trial Coordinator immediately, 
and a discussion should occur between the Sponsor (or delegate) and the Investigator regarding 
whether to continue or discontinue the patient from treatment.  The Sponsor (or delegate) must ensure 
all decisions are appropriately documented. 
Procedure where a patient withdraws from the trial: If a patient withdraws from participation in the 
study, then their randomisation code cannot be reused.  No additional patients will be recruited to the 
trial to replace those patients withdrawn or lost to follow up. 
 
3.11 Trial treatments 
All participants will be provided with website links to further information on AF and anticoagulation 
therapy created and made freely available by the British Heart Foundation. 
If allocated to the control group no further action is required by the Investigator other than that required 
as standard of care.   
If allocated to the intervention group, the Investigator selects a particular DOAC in line with clinical 
requirements for that patient and regional prescription guidelines by the Clinical Commissioning Group 
(CCG) for each participating General Practice, taking into account any relevant contraindications from 
the Summary of Product Characteristics (SmPC).  
Potential trial treatments (apixaban, dabigatran, edoxaban and rivaroxaban) are approved for use in 
the NHS.  For the purposes of this trial, the Reference Safety Information (RSI) for apixaban will be 
used, available at www.medicines.org.uk/emc/product/2878/smpc.  See section 6 for details on safety 
data.  Prior to Investigators prescribing therapy, a list of specific contradictions and interactions will be 
presented on the CPRD IRSP to assist in the choice of DOAC.  Clinical responsibility and eligibility for 
the chosen DOAC will remain with the Investigator and will not be monitored, as there may be clinical 
reasons outside of the trial for this choice. This also includes consideration for any national or local 
guidelines in existence, that might include safety baseline blood tests, and any ongoing monitoring 
requirements.  The NICE Clinical Knowledge Summaries detail prescribing information on DOACs 
including initiation and monitoring (available at https://cks.nice.org.uk/topics/anticoagulation-
oral/management/). 
Dose reduction should only be used in specific patients as clinically required (see Table 1), with all 
other patients receiving the usual daily dose as demonstrated in RCTs.  Drug prescription will occur 
via the clinical electronic medical record system and dispensed alongside the patient’s usual 
medication by their community pharmacist.  When the DOAC drug is added to the medical record, 

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Investigators are required to add the following note in the ‘pharmacy text’ section: “This patient is part 
of the DaRe2THINK trial and is being prescribed an anticoagulant as part of an NHS drug trial – see 
www.birmingham.ac.uk/dare2think”.  This text should also be added as a ‘major alert’ and selected to 
display whenever the record is swapped to or entered.  This will allow other organisations (such as 
out-of-hours providers) to view the record. 
 
Table 1: Suggested dose of DOACs  
DOAC 
Usual dose* 
Reasons for dose reduction 
Reduced dose 
Apixaban 
5mg twice daily 
Two out of three indications: weight <60kg, 
age >80 years, serum creatinine >133mmol/L 
(or estimated creatinine clearance 
<30mL/min) 
2.5mg twice daily 
Dabigatran 
150mg twice daily 
Patients receiving regular oral verapamil 
(Consider dose reduction on an individual 
basis if estimated creatinine clearance 30-
50mL/min, in patients with gastritis, 
esophagitis or gastroesophageal reflux, and 
others at increased risk of bleeding) 
110mg twice daily 
Edoxaban 
60mg once daily 
Any of: weight <60kg, estimated creatinine 
clearance <50mL/min, or concomitant 
therapy with potent P-glycoprotein inhibitors 
30mg once daily 
Rivaroxaban 
20mg once daily 
Creatinine clearance <50mL/min 
15mg once daily 
* Investigators should follow local CCG (or equivalent) guidance.  Dose and dose adjustment for each DOAC 
should be in line with the respective Summary of Product Characteristics.  Antiplatelet agents should be stopped 
in most patients when commencing a DOAC (please see text in section 3.9).  
 
All medications are oral, with no specific storage requirements.  Drug accountability will be according 
to standard practice for NHS prescriptions, with no additional clinical trial label.  Any product recall will 
be managed via the usual clinical systems.  Patients will not be withdrawn from the trial if they cross 
over to the other arm of the trial (e.g. due to development of other risk factors for stroke and 
commencement of anticoagulation, or discontinuation of DOACs), or switch to an alternative DOAC or 
vitamin-K antagonist.  Investigators and other clinicians may need to pause or discontinue 
anticoagulation for a range of clinical scenarios, including certain intercurrent illness such as bleeding, 
development of new treatment contraindications, adverse events, or requests to withdraw therapy by 
the participant or other clinicians (for example, due to upcoming surgical procedures).  Similarly, there 
may be reasons outside of the trial that require clinicians to start anticoagulation in patients 
randomised to the control arm.  These decisions remain the responsibility of the prescribing clinician.  
Prescription data will be collated automatically from all participants from Primary Care data, and 
participants will be asked to complete anticoagulation and compliance assessments every 6-months 
(see section 5.6).  Where use of anticoagulation differs from randomised allocation, Site Investigators 
will be asked to provide information to the central study team on the clinical reasons for this change.  
Most patients who commence a DOAC should stop antiplatelet therapy such as aspirin, dipyridamole, 
clopidogrel or prasugrel, as per clinical guidelines.  This includes patients who are taking antiplatelets 
for primary prevention reasons and those with stable coronary, cerebral or vascular disease, where 

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monotherapy with a DOAC is recommended in patients with AF.  If a patient with prior acute coronary 
syndrome or percutaneous coronary stenting receives a DOAC, then in most cases antiplatelet 
therapy should cease at 12 months after the event, and thereafter the patient should receive 
monotherapy with a DOAC alone.  Cardiologists will have explicitly stated any exceptions to this rule in 
clinical documentation (for example, patients with unstable complex lesions or plans for further 
intervention).  When prescribing the DOAC, the Investigator is required to review the medical record 
for any antiplatelet agents and make appropriate plans for cessation, including a clear instruction to 
the patient and any relevant changes to the electronic prescription system.   
 
3.12 Blinding 
The trial is open-label and therefore trial participants and their care providers will not be blinded or 
masked with respect to intervention allocation.  Outcome assessment is based on coded health 
outcomes and therefore less susceptible to assessment bias on the part of the research team; 
nonetheless, the Trial Management Group will remain blinded to intervention allocation from an 
analysis standpoint.  The exception to this is where knowledge of allocation in individual participants is 
needed to facilitate communication with patients/GPs, or in cases of valid medical or safety reasons. 
 
3.13 Internal pilot 
DaRe2THINK will operate a staged internal pilot programme, which is focused on the feasibility of 
recruitment (both screening and actual randomisation).  No outcome measures will be analysed to 
avoid jeopardising the full trial.  A traffic light system will be used to operationalise criteria into green, 
amber and red for the benefit of the Trial Steering Committee who will make recommendations to the 
funder on continuation of the trial.  
Pilot stage 1: England-wide national automated screening  
Description:  
Access to data and screening of potential participants that meet inclusion and 
exclusion criteria from over 12 million primary care patients across England 
using the CPRD IRSP.  
Time period:   
2 months (clock starts at first data query by CPRD). 
Measured outcomes:  Defined access to General Practice data to enable patient screening across all 
contributing CPRD sites; Number of potential participants located and notified to 
the lead NIHR CRN.  
 
Green 
Amber 
Red 
Criterion (data access) 
>75% of eligible sites 
providing daily data 
updates to CPRD 
50-75% of eligible sites 
providing daily data 
updates to CPRD 
<50% of eligible sites 
providing daily data 
updates to CPRD 
Criterion (screening) 
>2000 
1000-2000 
<1000 
Outcome 
Progression without 
major modification (whilst 
also resolving any 
identified barriers) 
Progression whilst under 
review for identification 
and modification of trial 
processes 
Detailed review of project 
viability by the Trial 
Steering Committee and 
funder 

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Pilot stage 2: GP surgeries set up and ready to recruit patients 
Description:  
Assessment and engagement with priority primary care sites (i.e. those with 
multiple potential participants), on-boarding of practice investigators, bringing 
the practices to a state of recruitment readiness, and continued access to data.  
Time period:   
3 months. 
Measured outcomes:  Number of primary care practices that have completed sign-up processes with 
CPRD and the NIHR CRN; Continued ongoing access to practice data to 
facilitate patient recruitment into DaRe2THINK. 
 
Green 
Amber 
Red 
Criterion (practices) 
>60 
30-60 
<30 
Criterion (data access) 
Ongoing data collection 
from >75% of practices 
Ongoing data collection 
from 50-75% of practices 
Ongoing data collection 
from <50% of practices 
Outcome 
Progression without 
major modification (whilst 
also resolving any 
identified barriers) 
Progression whilst under 
review for identification 
and modification of trial 
processes 
Detailed review of project 
viability by the Trial 
Steering Committee and 
funder 
 
Pilot stage 3: Recruitment of patients for DaRe2THINK 
Description:  
Conversion to recruitment of eligible patients at primary care centres taking part 
in DaRe2THINK. 
Time period:   
3 months (endpoint month 08). 
Measured outcomes:  Proportion of patients eligible on automated screening that are successfully 
recruited (future feasibility assessment therefore no criterion); Rate of patient 
recruitment (numbers include a 50% reduction in recruitment rate during the 
pilot). 
 
Green 
Amber 
Red 
Criterion (recruitment) 
>60 per month by month 
8 
 
30-60 per month by 
month 8 
 
<30 per month by month 
8 
 
Outcome 
Progression without 
major modification (whilst 
also resolving any 
identified barriers) 
Progression whilst under 
review for identification 
and modification of trial 
processes 
Detailed review of project 
viability by the Trial 
Steering Committee and 
funder 
 
 
 
 

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3.14 Withdrawal  
Participants may withdraw at any time during the trial without giving reasons and without prejudicing 
their further treatment, or if their clinical team feel that continued participation in the trial is 
inappropriate.  This will not affect the patient’s access to any future NHS care. 
As per the consent process, personal data collected up to the point of withdrawal can be used.  For 
participants that wish to withdraw, an option will be given to remove themselves from patient-reported 
outcomes, NHS electronic health record follow-up (no contact with the study team), or both. 
 
3.15 Change of Primary Care provider  
If the enrolled participant changes their Primary Care provider, the flow of electronic health record data 
to CPRD will cease.  The registration end date will be monitored by CPRD for enrolled participants, 
and any instances where this occurs will be reported alongside the safety reporting as described in 
section 6.5 to the Trial Coordinator and CI.  If the participant moves to another Primary Care practice 
that contributes to CPRD, then the new practice and patient identifier will be captured by CPRD and 
the flow of electronic health record data to CPRD will resume.  If the practice does not already 
contribute to CPRD, then they will be approached to join CPRD and the study by the CPRD 
recruitment team.  If the practice is unwilling or unable to join CPRD and the study, then the participant 
will be withdrawn from the trial (discussed explicitly in the Participant Information Sheet).  As an 
additional check, enrolled participants will be asked at the 6-monthly patient-reported outcome 
timepoint if they have moved, or are considering a move to another Primary Care provider.  In this 
circumstance, an automated REDCap alert will be sent to the Trial Coordinator to telephone the 
participant. 
  
3.16 Treatment duration and End of Trial 
If randomised to the DOAC arm, participants will receive treatment at least until the end of the trial 
(see below).  At this point, the Investigator and patient should make a shared decision as to whether 
the DOAC will continue based on the individual clinical circumstances of each patient and an appraisal 
of risk factors at that time for stroke and thromboembolism (as per normal clinical practice). 
‘End of trial’ for regulatory purposes is defined as the last data capture of the last participant for phase 
1 of follow-up (estimated at five years after the trial commences).  As this is an event-driven trial, the 
precise date will depend on the accumulation of outcome events in the intervention and control arms, 
which will be monitored by the independent Data Monitoring Committee (DMC) and Trial Steering 
Committee (TSC).  The Trials Office will notify the MHRA and REC that the trial has ended within 90 
days of the end of trial and provide them with a summary of the clinical trial report within 12 months.  
Participants will also be consented for 10-year follow-up with patient-reported and NHS care outcomes 
(phase 2), and then lifetime follow-up for NHS care outcomes (phase 3; pending further funding) – 
these elements constitute the non-interventional (observational) phase of the trial. 
 
 

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4 
OUTCOMES 
4.1 Timing & assessment of outcomes 
All outcome data will be collated on a yearly basis, except for EQ-5D-5L quality of life and DOAC 
compliance data which is collected 6-monthly.  Primary analysis will take place at 5-years follow-up 
from first patient randomisation, or when the specified event numbers have been reached (see section 
7.1). 
 
4.2 Primary outcome 
The primary outcome for DaRe2THINK is a composite of cardiovascular mortality, ischaemic 
cerebrovascular events (stroke and transient ischaemic attacks), all thromboembolic events (including 
venous and arterial thromboembolism), myocardial infarction and vascular dementia.   
 
4.3 Secondary outcomes 
The key secondary outcome is: 
• 
Change in cognitive function status assessed through validated periodic objective testing with 
the UK Biobank cognitive function panel (primary parameter is the fluid intelligence score).   
Additional secondary outcomes are: 
• 
Individual components of the primary outcome. 
• 
Cumulative event rates for each individual component of the primary outcome. 
• 
Conventional major adverse cardiovascular events (composite of non-fatal stroke, non-fatal 
myocardial infarction and cardiovascular death). 
• 
Any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation. 
• 
Minor bleeding that requires attention from primary care (any bleeding that leads to a primary 
care consultation). 
• 
Haemorrhagic stroke and other types of intracranial bleeding. 
• 
All-cause general practice visits. 
• 
All-cause hospital admissions and duration of stay. 
• 
Heart failure hospitalisation and duration of stay. 
• 
All-cause mortality. 
• 
Patient-reported quality of life using the EQ-5D-5L index score. 
• 
Patient-reported quality of life using the EQ-5D-5L visual analogue score. 
 
4.4 Cost-effectiveness outcomes  
The primary outcome measure for the economic evaluation will be quality-adjusted life-years (QALY) 
gained.  Cost-effectiveness will be measured in terms of the incremental cost per QALY gained from 
the healthcare perspective.  The secondary outcome measure for the economic evaluation will 
consider the societal perspective.  
 
 

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4.5 Process outcomes 
1. Number/proportion of potential participants located by CPRD and notified to the lead NIHR CRN 
(reported monthly).  
2. Number/proportion of primary care practices that have completed sign-up processes (reported 
monthly). 
3. Number/proportion of patients eligible on automated search and thought eligible by the GP 
(reported monthly). 
4. Rate of patient recruitment (reported monthly). 
5. Patient-reported compliance to DOAC therapy in the DOAC arm only (reported annually; see 
section 5.6). 
6. Repeat prescriptions obtained for DOAC therapy in the DOAC arm only, using Primary Care 
prescription data (reported annually). 
7. Missing data rates for patient-reported outcomes (reported annually). 
 
4.6 Rationale for outcomes 
Four focus groups were undertaken (led by the PPI team) to understand what is most important to 
patients with AF and the relevant impact on quality of life.[25]  The patients were clear that they see 
AF as a multisystem disorder that it difficult to separate from other comorbidities.  The impact on their 
physical and emotional wellbeing was not solely due to conventional cardiovascular outcomes (such 
as myocardial infarction), but more broadly related to all thromboembolic complications.  AF is known 
to have a considerable and broad adverse impact on patient quality of life due to the burden of a wide 
range of symptoms and psychosocial consequences.[31]  We are also conscious that this trial is 
based in primary care and so outcomes should reflect the short and long-term burden on GPs from all 
aspects of AF and its associated sequelae, ranging from a near-fatal stroke to a deep vein thrombosis.  
The rationale for the primary outcome composite is the increased incidence of these events in the 
context of AF compared to sinus rhythm, the impact these events have on patient wellbeing, and the 
considerable burden placed on the NHS as a result.   
Although cognitive decline is of key interest in DaRe2THINK, this is a secondary outcome as the true 
impact of DOACs on cognitive function is currently unknown.  The patient-reported approach has 
distinct advantages [32] and in this context allows us to abolish trial visits, enhancing efficiency of the 
programme.  In 2019, 83% of those aged 55-64 in the UK accessed the internet daily or almost every 
day, and only 10% had not used the internet in the previous 3 months; 73% of respondents preferred 
to access the internet via smartphone.[33]  Although our approach will cater for the majority of trial 
participants and will be supported by the PPI team, we anticipate attrition from yearly patient-reported 
testing (see sample size calculation in section 7.3). 
The rationale for the health economic evaluation is to assess the cost-effectiveness of DOACs in 
patients with AF at a low or intermediate expected risk of stroke compared to no treatment.  This will 
include both the English NHS and societal perspectives, due to the substantial impact that AF and its 
consequences have on the community.[34]  The cost-effectiveness analysis will be conducted in 
parallel to the DaRe2THINK randomised trial by an expert team at the London School of Economics. 
 
 

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5 
DATA MANAGEMENT 
5.1 Baseline and follow-up data 
Electronic health record data will be collected directly through the CPRD system, and so there is no 
requirement for Investigators or front-line NHS staff in Primary Care to complete case report forms to 
record demography and patient characteristics.  This includes medical history (such as previous 
vascular/thromboembolic disease, bleeding episodes, diabetes and other comorbidities, and COVID-
19 etc.), medications, clinical measurements and tests, and blood results.  The Statistical Analysis 
Plan will detail each variable collected and relevant descriptions/determinants.   
No follow-up visits are required as data linkage will occur through CPRD of primary care data, 
secondary care data (via HES) and data from the Office for National Statistics (ONS).  Efficacy and 
safety outcomes will be collated from these sources based on a pre-specified clinical code set 
supplemented, where required, with a safety reporting process via IRSP.  The code lists will be 
published in advance of the first endpoint assessment at one year.  No physical patient follow-up is 
required; a remote, digital system will collect cognitive function yearly and patient-reported quality of 
life at six-month intervals, following notification by text and email to consenting individuals.   
 
5.2 Quality of CPRD data 
Adequacy of data:  As CPRD uses real-world data, it does not modify data values but adds quality 
markers to every dataset.  There are three levels of data quality assessment for data validation (see 
Table 2).  Level 1 and 2 checks are undertaken by CPRD as part of their data quality processes.  
CPRD employs over 900 data quality assurance checks covering integrity and format of the data.  This 
includes practice and patient-level quality markers, with the ability to audit all data values to comply 
with Good Clinical Practice.  Additional checks are made for recruitment in the context of interventional 
research.  Patients meeting selection criteria based on the pre-screened electronic healthcare records 
are presented to primary care research staff.  This allows for clinical validation of coded information, 
assessment of fitness to participate by GPs, and incorporation of other non-coded clinical information. 
Level 3 checks are study-specific and will be undertaken by the University of Birmingham.   
 
Table 2: Quality assurance processes 
Quality 
assurance 
Timing 
Purpose & process  
Outcome 
Level 1 
The first series of checks 
that focus on verifying that 
the data meet agreed 
specifications and 
requirements. These are 
undertaken as part of the 
daily Extract, Transform and 
Load (ETL) process when 
data flow into CPRD 
databases. 
To ensure that any received 
data contains only expected 
data files and that all data 
elements are structured 
correctly as per the agreed 
specification. Duplicate 
records are removed and 
sequencing is verified before 
integration into a master 
dataset. 
These checks ensure that data 
are uncorrupted and have both 
structural and referential 
integrity as defined by the 
specification. Any Level 1 
failure results in the data not 
being used and a resupply of 
those data being requested. 
Level 2 
These checks revolve 
around research quality 
validation and cover the 
actual content of the data. 
CPRD provides a patient-level 
data quality marker 
(acceptability flag) based on 
Representativeness of data is 
assessed by comparing the 
prevalence of selected Quality 
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They are generated every 
time CPRD builds and 
releases a research 
database. 
internal data consistency at 
the individual-patient level. 
conditions against national 
figures [35], with quality 
markers produced on the 
entire database. 
Level 3 
Checks on released 
databases provided by 
CPRD to the University of 
Birmingham. 
Study-specific checks that will 
be undertaken as part of good 
data management. For 
example, examining trends in 
clinical coding and 
consistency for outcomes of 
interest over time to inform the 
definitions of code lists. 
Quality indicators tailored to 
specific areas or subsets of 
the data. 
 
Timeliness and scale of data:  CPRD databases used for interventional research receive daily 
updates of primary care data, providing access to up-to-date information across all contributing 
practices, thereby enabling: (1) Pre-screening searches carried out at scale and standardised 
according to the trial protocol; (2) Contemporaneous application of selection criteria with weekly 
refreshes; (3) GP screening through the IRSP interface allowing the study team to actively monitor 
screening activity in real-time and the flexibility to adjust the search algorithm in response to 
recruitment metrics; (4) In-built recording of serious adverse events according to Good Clinical 
Practice and regulatory/ethics requirements via IRSP; and (5) Regular, restricted, safety-focused data 
downloads to monitor safety directly from the electronic healthcare record, configurable to provide 
regular updates to the Data Monitoring Committee. 
UK NHS data coding:  Due to the General Medical Services Quality and Outcomes Framework 
contract that operates in Primary Care, accurate coding is rewarded and incentivised.  This underpins 
how the UK leads the world in accurate healthcare coding, with high accuracy demonstrated in a 
systematic review for primary codes used after 2004.[36]  Multiple studies have validated disease-
specific accuracy of CPRD data, including for complex diseases [37] and behavioural conditions.[38]  
Pharmacotherapy is similarly coded in the Primary Care record; for full transparency Table 3 provides 
the UK British National Formulary (BNF) codes for medical therapy used for the participant criteria.  A 
full list of codes for all outcomes will be published on the trial website and design paper. 
 
Table 3: Drug codes used for the participant selection criteria   
Pharmacotherapy 
BNF code(s) 
Therapy for diabetes (oral; insulin) 
06010100-3; 06010201-4 
Therapy for hypertension (various drug classes) 
02020-100,300,400; 02040000; 02050-100,200, 400; 
02050501-2; 02060200; 02050504 
Therapy for heart failure (loop diuretics) 
02020200 
 
5.3 Validation of clinical events 
A Study-Within-A-Trial (SWAT) will operate alongside the main DaRe2THINK trial involving patients 
under the care of the University Hospitals Birmingham (UHB) NHS Foundation Trust (see Table 4 for 
summary of the SWAT).  Including four hospitals, UHB is one of the largest healthcare providers in 
Europe, treating more than 2.2 million patients each year.  The large geographical footprint and 
provision of secondary, tertiary and quaternary care provides a unique ability to capture a wide variety 

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of endpoints in patients recruited in the West Midlands.  UHB has one of the most sophisticated 
electronic healthcare systems in the world, which has been in active use at for over 10 years.  This 
includes the Patient Information Communication System (PICS), which integrates prescribing, drug 
administration, observation charting, diagnostic coding, laboratory and radiology tests.  These data are 
used to enhance safe and efficient patient care through rules-based clinical decision support.   
For patients recruited in DaRe2THINK, we will search our integrated healthcare record across the four 
hospitals for pertinent data, for example an admission due to stroke or an outcome related to 
dementia.  Searches will be based on NHS number, date of birth and name (recruitment for the trial 
includes informed consent for NHS data mining).  We will systematically identify relevant clinical 
datasets including healthcare records, clinical notes, imaging and time-series data.  These structured, 
semi-structured and unstructured datasets will be aligned, harmonised and integrated across various 
modalities before application of artificial intelligence behind the NHS firewall.  Using Natural Language 
Processing and text mining approaches, we will generate an automated, semantic characterisation of 
clinical endpoints for each patient and code them using the International Classification of Diseases 
(ICD) framework.  This will be compared with the coded data outcomes obtained through CPRD 
(primary care) and HES (secondary care) to generate a statistical representation of the frequency and 
accuracy of outcomes.  In the example on stroke, we will collect information on the validity of the 
stroke outcome, admission duration, the type of stroke (ischaemic or haemorrhagic), confirmatory 
imaging reports, interventions or relevant treatments, and outcomes (discharge status, in addition to 
secondary events such as subsequent myocardial infarction or recurrent stroke).  For dementia, we 
will collect causation (vascular, Alzheimer’s, other), confirmatory imaging for these causes, mini-
mental state examination scores, discharge location, etc.  In the same way, we will extract relevant 
hospital-level data for other components of the primary outcome and safety outcomes, providing a 
broad validation that will be applicable and useful to future NHS-embedded research.   
 
Table 4: Data validation Study-Within-A-Trial 
SWAT design 
Details 
Population 
Sub-study of DaRe2THINK patients with data held within the UHB network. 
Clinical events 
of interest 
Mortality, cerebrovascular events, thromboembolic events, myocardial infarction, vascular 
dementia, intracranial bleeding or any other clinically-relevant bleeding. 
Methodology of 
data extraction 
Automated machine learning approaches behind the NHS firewall, including all clinical 
noting, imaging reports, clinical measurements, laboratory results and therapeutics 
(medications and interventions); staff blind to randomised treatment.  
Comparators 
Coded data obtained from primary and secondary care (CPRD and HES). 
Time period 
Same patient timeframe as the DaRe2THINK trial. 
Outcomes 
1. Accuracy of the primary care database; percentage of patients with correct coding. 
2. Accuracy of HES; percentage of patients with correct coding using a) primary codes, b) 
secondary codes and c) both primary and secondary codes. 
3. Additional unreported events; percentage of patients with clinical events of interest that 
are missing from either primary or secondary care datasets. 
 

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Adjudication 
An independent clinical team will adjudicate any discrepancies identified between the UHB 
network data and those coded in CPRD or HES. 
Statistical 
analysis 
Summary data, inter-curator agreement and kappa statistics. 
Impact & Value 
1. To the DaRe2THINK team to assist the process of trial outcome analysis and reporting 
at the end of the trial. 
2. To global researchers on the value of NHS coded data and relevant limitations. 
3. Potential enrichment of patient outcomes using a systematic and automated process 
than can be applied to future research and clinician decision support. 
Registration 
The SWAT has been prospectively registered with the MRC Northern Ireland Hub for Trials 
Methodology research (SWAT#158).  
Dissemination 
Interim (internal) report at month 36; Final (published) report submitted after trial data 
collection has completed at month 60. 
 
5.4 Patient-reported cognitive function 
DaRe2THINK will use technology solutions to provide ‘no-visit’ follow-up of cognitive function, which 
will substantially lower participant burden in order to maximise response rates.  To limit any 
technology bias, the system is designed for use by a range of devices including all smartphones, 
tablets, laptops and personal computers.  Should a patient not have access to such a device, they will 
be able to complete these tests at a library, or through a friend or family member’s device.  Proxy 
completion of cognitive testing will not be permitted.  A PPI-led focus group of public advisors will 
appraise and help to improve our technology approaches. 
DaRe2THINK will use the Online Questionnaire Sharing Service developed by the Nuffield 
Department of Population Health at the University of Oxford.  In brief, this system will allow a bespoke 
and simple web-based interface for patients to access and complete a range of cognitive function tests 
that measure different cognitive domains.  These tests are based on those performed as part of the 
UK Biobank study.[39]  The results of the cognitive function test will not be returned to participants and 
we will make it clear that these tests are for research purposes only, and will not be reviewed by 
external parties or the Primary Care team. 
Patients will access the online questionnaire through a customised web-link (provided by the 
University of Oxford) that is texted and emailed to consenting study participants.  Due to the nature of 
the tests, only online completion of cognitive testing is available, with source data provided entirely by 
the participant with no editing capability by the Sponsor.  No personal data (for example, mobile phone 
number or email address) will be shared with the University of Oxford (or any other entity) and will 
remain restricted behind our firewall.  The web-link incorporates a timestamp and a numeric 
participant ID, and only the DaRe2THINK study team will be able to link the corresponding study ID 
with a participant.  Data from the online cognitive function questionnaires are stored on a secure 
server at the University of Oxford and are made available to the DaRe2THINK research team via a 
Secure File Transfer Protocol on a periodic basis.  
The cognitive testing battery assesses several aspects of cognition known to be sensitive to ageing 
and which are often precursors to the diagnosis of a range of neurodegenerative conditions 
(particularly dementia), such as processing speed and non-verbal reasoning.  Items have been 

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selected from existing cognitive batteries (e.g. the Cardiff Cognitive Battery and COGNITO [40,41]) 
and have been developed by recognised experts for use in large-scale population-based cohorts, such 
as UK Biobank.  The specific tests that DaRe2THINK will use include: 
1. Fluid intelligence/reasoning test: This test gathers data on verbal and numerical reasoning.  
Respondents are asked fourteen logical verbal and numerical questions. Each question has five 
possible answers.  The score is the number of correct answers provided within two minutes, with 
incorrect or unattempted questions scored zero. 
2. ‘Trail making’ test: This test assesses visual attention and provides information on visual search, 
scanning, speed of processing, mental flexibility, and executive function.  Respondents must link 
circles in order by clicking on the next item in the sequence.  There are two presentations; one 
using numbers and one using numbers and letters.  
3. Symbol digit substitution: This code-breaking test measures complex processing abilities.  
Respondents are presented with one grid linking symbols to single-digit integers and a second grid 
containing only the symbols.  They are then asked to indicate the numbers attached to each of the 
symbols in the second grid, using the first one as a key.  
4. Matrices: This test measures non-verbal fluid reasoning.  Respondents are presented with a 
logically constructed design that is missing a piece.  They must choose the piece that completes 
the design from different alternatives.  The items start easy and become progressively more 
difficult. 
 
5.5 Patient-reported quality of life 
Similar to cognitive function, questionnaires will be delivered directly to patients via text message to 
their mobile phone and email to their nominated address (but on a 6-monthly basis).  This can be filled 
in by participants using any digital device or computer with internet access, at home or place of 
participant preference.  Where data are not received, the system will automatically send reminders to 
the patient for timely completion.  After 3 reminders, the Trial Coordinator will telephone the participant 
to ensure receipt and willingness to continue in the study.  Proxy completion by someone other than 
the trial participant is not permitted.  Data will be housed securely within a REDCap database at the 
University of Birmingham.  The system requires a mandatory set of questions to be completed to avoid 
missing data.  It will be made clear to all participants (in the participant information sheet, consent form 
and on the electronic system) that patient-reported outcomes are for research purposes only, and will 
not be reviewed by medical staff to inform their care.  In rare cases where online completion of quality 
of life cannot be completed (e.g. disability or blindness), alternative arrangements such as verbal or 
paper responses will be explored.  Any transcribed data will be clearly noted as such on the case 
report system and logged with the users access details (see section 9.1).  
The EQ-5D-5L questionnaire is a valid, reliable, responsive measure, where respondents rate their 
health on 5 dimensions on the day of completion (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression), in addition to a visual analogue scale of health perception.[42,43]  It is a 
generic health questionnaire available in a range of languages and widely used across different 
disciplines and for quantification of health economic benefit.  Although not specific to AF, we have 
already used and tested this questionnaire within an RCT, with focus groups in patients with AF 
confirming ease of completion.[25]  AF-specific questionnaires are much more complex, may not be 

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suitable for completion without assistance from research staff, and have a number of concerns 
regarding validation and methodology.[44]  
 
5.6 Additional patient-reported events 
Concurrent with the questions on quality of life at 6-monthy intervals collected remotely on REDCap, 
all participants will be asked: 
1. If they are currently prescribed any blood thinning (anticoagulant) therapy (specifying 
acenocoumarol, apixaban, dabigatran, edoxaban, phenindione, rivaroxaban and warfarin to ensure 
participants do not confuse with antiplatelet therapy).  If ticked, participants will then be asked 
whether their compliance with medication in the previous two weeks is (a) taking all tablets; (b) 
missing one dose; (c) missing more than one dose; (d) stopped/paused on their own decision 
without medical advice; or (e) stopped/paused on medical advice.  If options (c) or (d) are selected, 
then participants will automatically be advised that safe and effective treatment (in particular 
prevention of stroke and blood clots) requires good adherence to tablets, and to speak to their GP 
if they have concerns.   
2. If they have moved to another GP, or are considering a move to another GP in future.  If ticked, 
participants will automatically be advised that the Trial Coordinator will arrange a telephone call to 
discuss the implications on their participation in the trial.   
 
5.7 Coordination of data processes 
All aspects relating to data, data processing and security will be managed by a specific group of 
experts in their respective fields who will convene at regular intervals.  The Data Coordination Team 
(see members on page 7) will also have remit to ensure that any processes developed for this trial can 
be applied to future DaRe2 studies. 
 
 
 
 

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6 
SAFETY REPORTING 
6.1 Overview 
DaRe2THINK will employ a risk-adapted and pragmatic approach to adverse event reporting.  The 
rationale for this is: (1) Collection of HES outcomes will only occur on a yearly basis; (2) Events are 
captured from routine NHS care coding, meaning that events have already been identified and 
managed within the NHS; (3) Hospitalisation, prolongation of hospitalisation and death are specified 
outcomes or components of outcomes in the trial; (4) GPs in England are already experienced in the 
prescription and monitoring of patients taking DOAC therapy, for AF as well as other clinical 
indications such as venous thromboembolism; and (5) the DOACs used as interventional therapy in 
this trial have an established safety profile in patients with AF.  This includes RCTs, where DOACs 
have been extensively studied in numerous large phase III trials, including 42,411 participants 
receiving a DOAC compared to 29,272 randomised to warfarin in the landmark trials for apixaban, 
dabigatran, rivaroxaban and edoxaban in AF (ARISTOTLE, RE-LY, ROCKET AF and ENGAGE AF 
TIMI 48).[8] . Real-world safety data have also been extensively reported on, as summarised by the 
European Medicines Agency Committee for Medicinal Products for Human Use.  DOAC use was 
assessed in eight databases which include a total of 186,405 new users with AF, 156,636 users in a 
meta-analysis of population-based AF cohorts, and 407,586 new users of DOACs across other clinical 
indications.[45]  These data reflect that the DOAC class have been one of the most intensively studied 
group of therapeutics in the contemporary era.  As indications for DOAC therapy continue to broaden 
[46], clinicians across the NHS have daily experience in their use allowing a risk-proportionate 
approach in this trial.   
 
6.2 Definitions 
Standard definitions for different types of adverse events are listed in Table 5. 
 
Table 5: Definitions of adverse events 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal product has 
been administered, including occurrences which are not necessarily caused by or 
related to that product. 
 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an investigational 
medicinal product which is related to any dose administered to that 
participant. 
The phrase "response to an investigational medicinal product" means that a 
causal relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as adverse reactions. It is important to note that this is entirely 
separate to the known side effects listed in the Summary of Product Characteristics 
(SmPC). It is specifically a temporal relationship between taking the drug, the half-
life, and the time of the event or any valid alternative aetiology that would explain 
the event. 
 

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Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the 
above consequences. 
• NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which 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. 
 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the trial 
treatments, based on the information provided. 
 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the information about the medicinal product in question set out in the 
reference safety information: 
• in the case of a product with a marketing authorisation, this could be in the 
SmPC for that product, so long as it is being used within its licence. If it is 
being used off label an assessment of the SmPCs suitability will need to be 
undertaken. 
• in the case of any other investigational medicinal product, in the investigator’s 
brochure (IB) relating to the trial in question 
 
 
6.3 Operational use within a pragmatic NHS-embedded trial 
To limit unnecessary time spent by frontline NHS staff for a class of drugs with an established safety 
profile, DaRe2THINK will operate a risk-adjusted approach to safety reporting.   
SAEs and SARs will not be reported in an expedited fashion.  In particular, major and minor bleeding, 
hospitalisation (any cause), prolongation of hospitalisation and death will not be reportable SAEs as 
they are nominated outcomes of the trial.  The RSI for DaRe2THINK will be Section 4.8 of the SmPC 
for apixaban, as the exemplar of the DOAC class with the most clinical experience within the UK 
(available at https://www.medicines.org.uk/emc/product/2878/smpc).  Operationally, outcomes from 
CPRD/HES will be matched against this list on a yearly basis and a summary table of SAEs/SARs 
generated and reported to the Data Monitoring Committee, Trial Steering Committee, Sponsor and 
MHRA.  If SAEs are reported beyond a pre-defined limit, this will trigger more frequent reporting.  The 
precise trigger points for this eventuality will be set by the independent Data Monitoring Committee at 
their first meeting, and ratified by the Trial Steering Committee, but would be expected to be twice the 
rate observed in the SmPC (for example major gastrointestinal bleeding rate of 1.52% per year).  A 
multifaceted ‘safety net’ process will also occur to ensure that important safety events are not missed 
(detailed below) and to develop trial processes for future DaRe2 pipeline randomised trials. 
The CPRD IRSP allows Investigators to directly input a potential SAE for any recruited participant.  
This entry is then automatically flagged to the CPRD team and Trial Coordinator to process the 
potential SAE, with expectedness determined by the Chief Investigator, Deputy Chief Investigator or 

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delegate, as described in section 6.8.  Source data for the SAE form is controlled by the Investigator 
with no editing rights by CPRD, Sponsor or CI.  Any amendments or updates by the Investigator lead 
to the creation of a new linked SAE form with a clear audit trail.   
Specific procedures are in place to deal with incident intracranial events, major bleeds and dementia 
outcomes.  Identification and delineation of strokes will be made using a bespoke system within the 
CPRD Interventional Research Services Platform (IRSP), which will ask Site PIs to classify any new 
intracranial events according to type: (1) ischaemic stroke; (2) epidural hematoma; (3) subdural 
hematoma; (4) subarachnoid haemorrhage; and (5) intracerebral haemorrhage.  A similar process will 
occur for categorisation of non-intracranial major or clinically relevant bleeds, depending on the 
anatomical site and clinical consequences.  For dementia outcomes, categories are: (1) Alzheimer's 
disease; (2) vascular dementia; (3) Lewy Body disease; (4) Fronto-temporal dementia; (5) mixed 
dementia; and (6) other causes (e.g. due to alcohol, Parkinson’s disease and viruses).  As with other 
events, further detail will be collated from CPRD and HES.   
Due to the age criteria of the trial and the exclusion of WOCBP, it is unlikely that pregnancy will occur 
in the recruited population.  Nevertheless, pregnancy is not considered an adverse event unless a 
negative or consequential outcome is recorded for the mother or child/foetus (which if serious would 
be considered an SAE).  DOACs are not used (or should be replaced) in women who become 
pregnant or are breastfeeding, in favour of low molecular weight heparin. 
As with any potential adverse reaction in the NHS, Investigators will be encouraged to complete an 
MHRA Yellow Card submission, but these will not be collected as part of trial data.  The MHRA’s 
Yellow Card Scheme is a national system for collecting and monitoring information on suspected 
adverse drug reactions by health professionals and patients.  Since February 2020, reporting of 
suspected ARs to the Yellow Card Scheme has been rolled out across England, and is integrated into 
practices that use the EMIS web medical record platform.   
 
6.4 Reporting of SUSARs 
Due to the immense volume of safety data collected on this class of drugs, and their common use in 
NHS routine practice, it is improbable that new SUSARs will be identified for DOACs in this trial.  Data 
collection in DaRe2THINK will operate entirely from NHS coded outcomes from primary and 
secondary care; the purpose of which is to enable a more efficient approach to clinical trials within the 
NHS.  As such, it is not likely that further details of any SAE will be available to the central study team, 
and any action/outcomes may only be known at the next yearly data collation point.  Although this 
limits the value of expedited reporting from either a safety or regulatory perspective, the processes in 
place still meet the Sponsor’s legal obligations in terms of SUSAR reporting.    
If an Investigator believes a particular SAE in a participant receiving DOACs is both unexpected and 
potentially due to the DOAC, they will be asked to complete a SAE report page on IRSP as soon as 
possible after becoming aware of the event.  Once recorded on IRSP, a report is generated which is 
immediately sent to the Sponsor, Trial Coordinator and the CPRD study team.  The Investigator will 
also be required to telephone the Trial Coordinator within 72 working hours of becoming aware of the 
event.  On receipt of the report, CPRD, in collaboration with the Trial Coordinator, will liaise with the CI 
to formally assess the event, and where assessed as a possible SUSAR, will be reported in line with 
regulatory guidelines.  As in most cases this will be the result of a hospital admission being coded into 

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the Primary Care record, this will provide time for receipt of documentation from the secondary care 
provider and to account for part-time GPs.   
All SUSARs occurring from the time of randomisation until the end of the study must be recorded on 
the relevant form and sent to the Sponsor by the Chief Investigator/Deputy Chief Investigator or 
delegate within 7 days of the research staff becoming aware of the event.  Any SUSAR will need to be 
reported to the Sponsor irrespective of how long after administration the reaction has occurred until 
resolved.  The sponsor will inform the MHRA and REC within the required expedited reporting 
timescales. 
For each SUSAR the following information will be collected: 
• 
Full details in medical terms and case description (if applicable and known). 
• 
Event duration (start and end dates, if applicable and known). 
• 
Vital status of the patient (where known). 
• 
Opinion on causality (i.e. relatedness to the DOAC). 
• 
Seriousness criteria. 
• 
Confirmation that the event is unexpected. 
 
6.5 Safety net to capture adverse events 
To guard against unreported events, DaRe2THINK will operate a safety net process to capture 
additional potential SAEs.  CPRD receives daily data collections from General Practices, which are 
processed into a secure database.  For participants recruited into DaRe2THINK, this data will be 
made available for regular, frequent searches.  Such searches could identify key new events occurring 
in the patient’s coded electronic health record, including potential SAEs such as major bleeding.  Upon 
identification of such events, the Site PI will be notified by email and asked to undertake additional 
activity, for example to record details of the potential SAE within the IRSP.  This process will work in 
concert with the extraction of coded data within primary and secondary care, and will feed into the 
safety reporting processes described above.  It will also assist the development of the DaRe2 pipeline 
for future trials with higher-risk CTIMPs.  As a backup procedure, paper SAE forms will also be 
available at all sites and held as part of the Site File content (for example, in case of system/internet 
failure, or if a participant moves their Primary Care provider to another CPRD practice).  Training 
regarding SAE reporting via IRSP and via the back-up paper route will be provided to all Investigators 
as part of site initiation.  If a SAE needs to be reported via the back-up route, the Investigator will 
complete a paper SAE form and return it as a PDF to CPRD and the Trial Coordinator.  A copy would 
also be sent to the Sponsor.  All data from both SAE reporting routes will be transcribed into a SAE 
line listing document, with data entry being entered and checked by two different members of the 
CPRD team.  All correspondence and PDFs associated with reported SAEs will be held in the Trial 
Master File. 
 
6.6 Responsibilities of the Principal Investigator 
1. Ensuring that any AEs or ARs are accurately recorded in the GP record when participants attend 
for treatment/follow-up, and the CPRD IRSP where applicable. 

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2. Completion of SAE documentation as soon as practicable, and to communicate any potential 
SUSARs to the Trial Coordinator within 72 working hours. 
3. For incident intracranial events, major bleeding and dementia, using medical judgement in 
assigning seriousness, causality and aetiology. 
4. Standard adverse reaction reporting as per clinical norm, using the MHRA Yellow Card system. 
 
6.7 Responsibilities of the Clinical Practice Research Datalink team 
1. Configuring and maintaining IRSP to support the reporting of SAEs by Investigators. 
2. Configuring and maintaining the IRSP to support intracranial events, major bleeds and dementia 
reporting by Investigators. 
3. Collating the information required to produce safety reports for the Chief Investigator, Sponsor and 
oversight committee(s). 
4. Providing the annual data extract to support SAE analysis.   
5. Following up SAEs, intracranial events, major bleeds and dementia reports with the Investigator 
until resolution or end of trial (as applicable). 
6. Supporting timely and accurate submission of SUSARs. 
7. Collaborate with the CI to submit the Development Safety Update Report (DSUR). 
8. Generating the Trial Monitoring Plan and Safety Monitoring Plan. 
 
6.8 Responsibilities of the Chief Investigator/ Deputy Chief Investigator or delegate 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing review of 
the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness and causality (in line with the 
Reference Safety Information) where it has not been possible to obtain local medical assessment.  
This includes expectedness of SARs against the RSI. 
3. Immediate review of all SUSARs.  
4. Review of specific SAEs and SARs such as intracranial haemorrhage, in accordance with the trial 
risk assessment and protocol as detailed in the Trial Monitoring Plan. 
5. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding to SAEs. 
6. Provide a DSUR once a year throughout the clinical trial, or as necessary, to the Competent 
Authority (MHRA), and where relevant the REC and sponsor.  The report will be submitted within 
60 days of the Developmental International Birth Date (DIBD) of the trial each year until the trial is 
declared ended.  In the context of this pragmatic NHS-embedded trial (and where hospitalisation is 
common in this patient group), the DSUR will provide a condensed format of SAEs.  
7. Central data collection of safety data according to the trial protocol onto a database. 
8. Annual checking of updates to the Reference Safety Information. 

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9. Give immediate written notice to the MHRA and the relevant REC of any urgent safety measures 
taken and the circumstances giving rise to those measures. 
 
6.9 Responsibilities of the Sponsor 
1. Ensuring reporting safety information to the CI, delegate or independent clinical reviewer for the 
ongoing assessment of the risk / benefit according to the Trial Monitoring Plan. 
2. Ensuring reporting safety information to the independent oversight committees identified for the 
trial (Data Monitoring Committee and / or Trial Steering Committee) according to the Trial 
Monitoring Plan. 
3. Ensuring expedited reporting of SUSARs to the MHRA and REC within required timelines. 
4. Ensuring  standard tables and other relevant information for the DSUR are prepared in 
collaboration with the CI and ensuring timely submission to the MHRA and REC. 
 
6.10 Responsibilities of the oversight committees  
In accordance with their relevant Charters, the DMC are responsible for periodically reviewing overall 
safety data to determine patterns and trends of events, or to identify safety issues which would not be 
apparent on an individual case basis; and the TSC are responsible for periodically reviewing safety 
data and liaising with the DMC regarding safety issues.  As noted, the primary source of safety 
reporting will be annual outcome data combining CPRD, HES and ONS matched against the SmPC 
for apixaban.  In addition, the safety net reporting process described in section 6.5 will also be 
presented to the DMC and TSC.  
 

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7 
STATISTICAL CONSIDERATIONS 
7.1 Sample size derivation 
The sample size has been calculated using actual NHS primary care data on 16,574 patients with AF 
not receiving anticoagulation and selected by our inclusion and exclusion criteria (2005-2018; THIN 
dataset).  This provides real-world control group outcomes in patients similar to those we will recruit in 
DaRe2THINK.  Rates of mortality, stroke, thromboembolism, myocardial infarction and vascular 
dementia per 100 person-years in patients matching enrolment criteria were 2.60, 0.78, 1.18, 0.40 and 
0.10, respectively.   
 
7.2 Primary outcome on composite clinical events 
Applying these numbers conservatively to account for lower risk patients tending to enter clinical trials, 
our sample size calculation is based on a total of 4.0 events per 100 person-years (which includes a 
cardiovascular death rate of 1.5).  The reduction in primary composite outcomes with DOAC therapy is 
estimated at 35% (includes a weighted mortality reduction of 17%).  This is consistent with previous 
trial data [47] and is biologically plausible given the results of historical trials using warfarin versus no 
therapy [26].  The sample size calculation is for a time-to-event superiority analysis with 2 years of 
recruitment.  To detect a hazard ratio of 0.65 with 90% power and a 2-sided alpha of 0.05, a total of 
391 events will be required from an expected total of 2978 patients randomised (rounded up to 3000 
patients).  The sample size calculation includes a progressive crossover to anticoagulation in the 
control group (5%, 10%, 15%, 20% and 35% at the end of years 1 through 5 respectively), 15% 
cumulative withdrawal for DOACs, and loss to follow-up of 1% (negligible as data are collected 
through NHS care).  The upper age limit of 73 years will ensure that at least 2 years of follow-up is 
possible in all patients until they reach the current age requirement for anticoagulant therapy of 75 
years.  However, we expect that mean age will be in the mid 60’s thereby providing sufficient follow-up 
time during the trial for primary outcome assessment.  The sample size of 3000 patients will still 
provide 85% power if event rates are lower than expected (3.5% per year; other parameters identical; 
335 events and 2896 patients).   
 
7.3 Key secondary outcome on cognitive function 
Cognitive function over time will be measured using the UK Biobank panel of tests that cover 
reasoning, visual attention, complex processing and reaction time (see Data Collection section on 
page 35 below).[39]  Our analysis of UK Biobank data on 22,160 AF patients and 480,456 without AF 
shows the cognitive impact of AF is the same as 5 years of additional ageing.[unpublished]   Using 
these values and accounting for missing data, 2000 patients would provide 80% power (2-sided alpha 
of 0.05) to detect an effect size of 12.5% of standard deviation using UK Biobank data (0.25 mean 
score difference in fluid intelligence), and 92% power to detect an effect size of 15% of standard 
deviation (0.30 mean score difference).  Power will be enhanced by adjusting for baseline values; 
however this is a secondary outcome as the true impact of DOACs is currently unknown.  
 
7.4 Data analysis overview 
A Statistical Analysis Plan (SAP) will be drafted by the trial statistician, reviewed by senior statisticians 
at the Birmingham Clinical Trials Unit, and approved by the Trial Steering Committee.  In view of the 

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open-label design of the trial, the SAP will be completed before participants are recruited.  A brief 
outline of the analysis methods are given below.  
The primary comparison groups will be composed of those who are randomised to intervention arm 
versus those randomised to the control arm.  All analyses will be based on the intention to treat 
principle, i.e. all participants will be analysed in the groups to which they were randomised regardless 
of withdrawals or crossovers.  
For all major outcomes, summary statistics and differences between groups (e.g. hazard ratio, mean 
differences, relative risks, etc.) will be presented with 95% confidence interval from two-sided tests.  
Analyses will be adjusted for the randomisation variables and baseline scores (where appropriate). 
There will be no adjustment for multiple testing. 
 
7.5 Analysis of the primary outcome 
Primary outcome data will be analysed as time-to-first event and will compare between treatment 
groups using survival analysis methods.  Kaplan-Meier survival curves will be constructed for visual 
presentation of time-to-first-event comparisons.  A Cox proportional hazard model will be fitted, and 
results will be expressed as the adjusted hazard ratio with 95% confidence intervals.  
As a sensitivity analysis, we will perform a competing risk analysis for the primary outcome using the 
method of Fine and Gray; this will account for the competing risk of death where other outcomes (e.g. 
non-fatal thromboembolism or hospital admission) cannot occur in those patients that have died.  A 
further sensitivity analysis will censor patients when reaching the age of 75 years, due to the indication 
for DOACs at this time point.  A ‘per-protocol’ analysis as well as an ‘as-treated’ analysis will be 
performed for the primary outcome using prescription data from Primary Care.  The ‘as-treated’ 
analysis will assess use of any anticoagulant, regardless of randomisation. 
 
7.6 Analysis of secondary outcomes 
Time to event outcomes (individual components of the primary outcome, all-cause mortality, etc.) will 
be analysed using the same methods as described for the primary outcome.   
For continuous outcomes (cognitive function and EQ-5D-5L), a mixed-effects repeated measures 
analysis will be carried out on all data across follow-up.  Results will be expressed as the adjusted 
mean difference with 95% confidence interval.  Cognitive function analysis will formally compare 
completion rates between groups using survival analysis methods to determine if differential 
completion is evident. If this is the case, then further sensitivity analyses for this will be conducted, 
which will include imputation of missing data using pattern mixture models.  EQ-5D-5L data will be 
scored according to the current NICE guidance (updated October 2019) [47].  Imputation of missing 
data will not be performed.  
Count data (all-cause general practice visits, all-cause hospital admissions, etc.) will be analysed 
using a Poisson regression model (or negative binomial regression if there is evidence of 
overdispersion).  An offset for the length of time the participant was in the trial will be included in the 
model.  Results will be expressed as the adjusted incidence rate ratio with 95% confidence interval. 
 
 

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7.7 Planned Subgroup Analyses 
Subgroup analyses will be performed for the primary outcome according to the DOAC agent 
prescribed, an age cut-off of 65 years, presence at baseline of heart failure, hypertension, chronic 
kidney disease and diabetes, COVID-19 diagnosis, the median baseline fluid intelligence cognitive 
function score, and by gender.  The effect of these subgroups will be examined by including a 
treatment group by subgroup interaction parameter in the model.  The results of subgroup analyses 
will be treated with caution and will be used for the purposes of hypothesis generation only. 
 
7.8 Interim analyses and impact on sample size 
Interim assessment of event rates will be performed on a yearly basis as part of the interim analysis 
for DMC to carefully map the event rate estimates with actual events.  This information will allow the 
Data Monitoring Committee to make recommendations to the Trial Steering Committee on the need to 
reduce or expand the trial population without impacting on the primary outcome alpha.  The Trial 
Steering Committee will remain blind to randomised group in any presented material.  
 
7.9 Stopping Criteria 
Appropriate criteria of proof beyond reasonable doubt cannot be specified precisely, but a difference 
of at least p<0.001 (similar to a Haybittle-Peto stopping boundary) in an interim analysis of a major 
endpoint may justify halting, or modifying, the study prematurely.  If this criterion were to be adopted, it 
would have the practical advantage that the exact number of interim analyses would be of little 
importance, so no fixed schedule is proposed.  Given the proposed use of the Haybittle-Peto 
boundary, no adjustment for multiple testing (to control the overall type I error rate) is proposed; 
hence, the threshold for statistical significance at final analysis will still be p=0.05. 
A separate DMC reporting template will be drafted and agreed by the DMC including an agreement on 
which outcomes will be reported at interim analyses.  The statistical methods stated in the Statistical 
Analysis Plan will be followed for the agreed outcomes. 
 
7.10 Health economic evaluation 
Type of economic evaluation: Cost-effectiveness will be assessed by the incremental cost per quality-
adjusted life-years (QALY) gained. 
Model structure and modelling framework: The probabilistic decision analytical model will comprise of 
two components; (1) a decision tree that captures the short-term clinical outcomes and costs 
associated with the treatment strategies for the duration of the trial follow-up period; and (2) a long-
term Markov cohort model, which extrapolates the costs and outcomes over a lifetime horizon.  The 
Markov model will characterise the course of the disease in terms of health states (for example, 
stroke, myocardial infarction, systemic embolism, major bleeding, clinically relevant non-major 
bleeding, etc.) and the possible transitions between them using 6-week cycles, where patients will 
accrue healthcare costs, life years, and QALYs. 
Identification, measurement and valuation of outcomes: Clinical event rates in the model will be 
obtained from the DaRe2THINK trial and converted to risks per cycle, informing the transition 
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and gender-specific general UK life tables and a hazard ratio adjusting for the impact of AF.  Patients 
will be assigned utility values according to their health states.  EQ-5D-5L scores, measured from the 
trial at baseline, will be used to establish baseline utilities.  In addition to EQ-5D-5L data collected 
periodically during the trial period, utility inputs for the Markov model will be obtained from a UK-based 
utility catalogue [48], with utility weights obtained using the NICE-recommended mapping function.[49]  
Identification, measurement and valuation of resource use: The model will accrue costs in several 
resource categories including treatment costs, management costs, acute care costs associated with 
clinical events, cost associated with other cardiovascular hospitalisations, and long-term social care 
costs.  Resource use data collected in the DaRe2THINK trial will include dates on inpatient and 
outpatient care for clinical events, number of nights in hospital and interventional procedures (via 
linkage to HES), plus general practice visits and primary care treatment (via CPRD).  Long-term social 
care and loss of productivity will be estimated from established literature.  Baseline measures of 
resource use will be used to reduce the variance in incremental cost estimates.  Cost data will be 
obtained from the NHS drug tariffs, the Monthly Index of Medical Specialties and NHS reference costs.  
The cost of productivity loss will be calculated using a human capital approach, which assumes that 
the production loss to society is equal to the value of lost earnings.  This is a comprehensive approach 
where the maximum of potentially-possible production loss to society is estimated, and will be 
combined with extensive sensitivity analyses.  Additionally, the treatment of elements of productivity 
costs other than paid work-time will be considered and discussed. 
Analysis for health economic evaluation: Baseline characteristics of the patients in the intervention and 
standard of care groups will be summarised according to intention-to-treat.  Differences in resource 
use and costs between the two groups will be tested using two-sample t-tests and Chi-squared tests 
for continuous and categorical variables, respectively.  Cost-effectiveness of the intervention versus 
standard of care will be assessed using the incremental cost-effectiveness ratio (ICER) and the results 
will be presented in terms of point estimates, cost-effectiveness planes and cost-effectiveness 
acceptability curves.   The standard NICE willingness to pay threshold for the NHS of £20,000 - 
£30,000 per QALY will be used for the base case analysis, with health and cost outcomes discounted 
by 3.5%.  Univariate deterministic sensitivity analysis will be performed where each parameter will be 
varied according to the 95% confidence intervals and standard deviations (where applicable), while 
holding other parameters constant.  Since main DOAC patents are set to expire during the trial period, 
a scenario analysis will also consider the impact of generic provision.  Probabilistic sensitivity analysis 
will be performed to account for variability in outcomes due to statistical uncertainty in inputs.  The 
values of key input parameters will be assigned a probability distribution and varied concurrently to 
generate ICERs by varying event rates, costs, utilities and risks simultaneously. 
 
7.11 Analysis of virtual control data 
Anonymised linked data will be provided by CPRD on individuals that meet the pre-screening 
automated selection criteria.  Summary data will be compared between these ‘virtual’ control patients 
and patients in the randomised control group to assess for external validity of the trial cohort and to 
improve data processes and data flows for future studies.  Full detail on statistical methods will be 
provided in the trial SAP. 
 
 

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8 
ETHICAL, REGULATORY & GOVERNANCE ISSUES 
8.1 Ethical framework 
DaRe2THINK is designed to operationalise a national approach to NHS-embedded research.  
Extensive support will be provided by the NIHR CRN network, led by the West Midlands Primary Care 
team.  Existing governance procedures are in place to ensure Good Clinical Practice, training and site 
initiation for multiple GPs and Practice Nurses at each site plus the Practice Manager.  In addition, 
there are established processes for mail-out to screened patients, and potential additional 
opportunistic enrolment at GP appointments.  The CRNs provide informed consent training and have 
ongoing relationships with community pharmacies for drug dispensing and in-practice monitoring.  
Each local CRN Primary care team is able to offer Research Facilitators and Research Nurses to 
assist with engagement with individual practices and stakeholders (Clinical Commissioning Groups, 
Super Partnerships, Federations, and more recently Primary Care Networks established as part of the 
Government’s General Practice Forward View).  These local teams will complete HRA approvals, 
facilitate delivery of the trial through their experience of clinical software systems, continually ensure 
recruitment targets are met throughout the lifecycle of the portfolio, and can screen, consent and 
collect patient data within a high-quality and ethical framework.   
The DaRe2THINK protocol has been developed in accordance with the Standard Protocol Items for 
Randomized Trials (SPIRIT) [50] and SPIRIT-PRO guidelines.[51]   
 
8.2 Ethical review 
Before the start of the trial, approval will be sought from a Research Ethics Committee (REC) & local 
R&D for the trial protocol and other relevant documents.  The study will be performed in accordance 
with World Medical Association recommendations, the Research Governance Framework for Health 
and Social Care, and applicable UK Statutory Instruments, which include the latest Data Protection 
legislation, the Human Tissue Act, and Guidelines for Good Clinical Practice (GCP). 
Substantial amendments that require review by REC will not be implemented until the REC grants a 
favourable opinion for the trial (note that amendments may also need to be reviewed and accepted by 
the MHRA and/or NHS R&D departments before they can be implemented in practice at sites).  All 
correspondence with the REC will be retained in the Trial Master File/Investigator Site File.  An annual 
progress report (APR) will be submitted to the REC and Sponsor Research Governance office within 
30 days of the anniversary date on which the favourable opinion was given, and annually until the trial 
is declared ended.  It is the responsibility of the Chief Investigator or delegate to produce the annual 
reports as required and notify the REC and Sponsor of the end of the trial.  If the trial is ended 
prematurely, the Chief Investigator or delegate will notify the REC and Sponsor, including the reasons 
for the premature termination.  Within one year after the end of the trial, the Chief Investigator or 
delegate will submit a final report to the REC with any results, including any publications/abstracts. 
 
8.3 Protocol review  
Expert, independent review of the trial programme has been undertaken as part of the funders grant 
procedures.  This protocol has been reviewed within the Sponsor’s institution (University of 
Birmingham, including the Birmingham Clinical Trials Unit), our NHS partner (University Hospitals 
Birmingham NHS Trust), CPRD and the NIHR CRN West Midlands Primary Care team.   

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8.4 Public and Patient Involvement (PPI) 
A PPI team of three individuals was set up in 2016 to initiate a range of studies and trials for patient 
benefit, coordinated by the University of Birmingham Institute of Cardiovascular Sciences.  We are 
grateful to the NIHR CRN West Midlands and the NIHR Academy for providing funds to initiate and 
support ongoing PPI work.   
This protocol has been developed in line with work performed by the PPI team on the DaRe2THINK 
trial and DaRe2 pipeline.  Their involvement has centred on four specific areas: (1) Development of 
the overall concept of a data-enabled NHS trial, considering the needs of patients as research 
participants, the needs of the NHS and society in general, and the balance of give and take with 
respect to time (personal and family) and commitment involved in taking part in clinical research; (2) 
Issues relating to ethical concerns, data dissemination and data security; (3) Potential benefits to 
patients and the public of these innovations in trial process; and (4) The no-visit follow-up plans, 
including access, comfort and limitations to utilising technology solutions.   
During DaRe2THINK, the PPI team will: (1) Advise the Trial Management Group on any potential 
concerns raised by participants; (2) Help to revise any patient resources after feedback from 
participants; (3) Co-design and help to evaluate the interpretation of trial results, especially patient-
reported outcomes; (4) Invited to all Trial Steering Committee meetings, with two PPI members having 
permanent voting positions; and (5) Assist with dissemination of results and plain English summaries.  
 
8.5 Regulatory compliance 
DaRe2THINK will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA 
with favourable REC opinion.   This protocol, and the conduct of any intervention testing, will comply 
with the Medicines for Human Use (Clinical Trials) Regulations 2004 and any relevant amendments. 
Before any site can enrol patients into the study, the Chief Investigator/Principal Investigator or 
designee will ensure that appropriate approvals from participating organisations are in place.  Specific 
arrangements are in place at Primary NHS Care sites in order to comply with the relevant guidance.   
For any amendment to the study, the Chief Investigator or designee, in agreement with the sponsor, 
will submit information to the appropriate body in order for them to issue approval for the amendment.  
The Chief Investigator or designee will work with sites (R&D departments at NHS sites as well as the 
study delivery team) so they can put the necessary arrangements in place to implement the 
amendment to confirm their support for the study as amended. 
 
 
 
 

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9 
DATA SECURITY 
9.1 Data security at the University of Birmingham (coordinating institution) 
DaRe2THINK will utilise the Research Electronic Data Capture (REDCap) system, originally 
developed by Vanderbilt University with ongoing support from the US National Institutes of Health.  
REDCap is a browser-based data capture software, supported by an experienced local team at the 
University of Birmingham.  The system as deployed at the University of Birmingham is compliant with 
the Data Protection Act, and includes access restricted to nominated study staff, with clear audit trails 
for data/user monitoring.  User rights per project are governed by the lead PI or nominated REDCap 
administrator.  All access, changes and addition details are logged within a project’s logging section. 
REDCap is operated across two virtual servers hosted on the University network: a web application 
server and a MySQL database server.  All University virtual severs are built to a secure standard.  
Daily backups of the server infrastructure are taken to allow fall backs to previous versions if required.  
A documented build process for installing REDCap and all security settings is followed by local college 
IT staff.  The University servers sit behind a site firewall that helps protect access.  The web 
application server has a secure connection through a specific firewall rule to the MySQL database 
server.  The authentication to REDCap is via a University user account (LDAP), along with utilising 
REDCap’s User allowlist.  An administrator has to provide access to REDCap and a secure 
verification process is required before users can log on.  Regular server security scans and reports are 
produced to identify any missing security patches.  The report is emailed to system administrators with 
the relevant information for patches, upgrades or bug fixes.  An external website security scan is 
checked via a third party website, the results are stored and can be viewed upon request.  The 
REDCap database is backed up via the College Backup system using CommVault software.  Backups 
occur daily, weekly and monthly and are stored in an offsite fireproof safe. 
All incoming data In REDCap gets intentionally filtered, sanitized, and escaped.  This includes all data 
submitted in an HTTP Post request and all query string data found in every URL while accessing 
REDCap, among other modes through which user-defined data gets submitted in the application.  
Server environment variables that are vulnerable to forgery by users are also checked and sanitized.  
All user submitted data is properly filtered for any possibly harmful mark-up tags (e.g. <script>) and is 
then escaped before ever being displayed on a web page within the application.  SQL queries sent to 
the database server from REDCap are all properly escaped before being sent.  If any values used in 
an SQL query originated from user-defined values, they would have already been sanitized 
beforehand as well, as described above.  User-defined data used within SQL queries also have their 
data type checked to prevent any mismatching of data types (e.g. making sure a number is really a 
number). These processes of sanitization, filtering, data type checking, and escaping all help to 
protect against methods of attack, such as Cross-Site Scripting (XSS) and SQL Injection.  To 
specifically protect against Cross-Site Request Forgery (CSRF), REDCap utilizes a “nonce” (a secret, 
user-specific token) on every web form used in the application.  The nonce is generated anew on each 
web page as the user navigates within REDCap during a session. 
With regards to remote e-consent, DaRe2THINK will utilise built-in features within REDCap, supported 
by the REDCap team at the University of Birmingham.  The system displays the latest version of the 
REC-approved PIS and ICF, with the potential participant able to scroll through each document before 
electronically accepting and providing their name, date and e-signature (see also section 3.8).  A PDF 
of the ICF is stored within the database for viewing by access-authorised users and automatically 

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emailed to the participant.  The participant’s NHS number is entered by the Investigator at the time of 
confirming the participant’s consent on REDCap. 
 
9.2 Data security at University Hospitals Birmingham (lead NHS institution) 
Personal data for consented participants will be stored in a dedicated sever within the University 
Hospitals Birmingham NHS Foundation Trust infrastructure and behind the Health and Social Care 
Network (HSCN) firewall.  This includes a copy of identifiers and patient-reported EQ-5D-5L collected 
on REDCap, outcome and safety data from CPRD/HES/ONS, and cognitive function data from the 
University of Oxford Online Questionnaire Sharing Service.  All data and results will be backed up 
within the same environment and will be allocated to isolated data containers.   
All patient level data will be stored for a minimum period of 5 years as per NHS requirements.  Data 
access will be monitored and limited to authorised users who will be granted password restricted 
audited access through Secure Shell (SSH; a cryptographic network protocol).  A Data Privacy Impact 
Assessment has been completed.  No identifiable data will be moved, manipulated or stored outside of 
this environment.   
 
9.3 Data security at CPRD 
The CPRD platform enables secure screening of patients for recruitment and does not require sharing 
of any patient identifiers outside the practice.   
The CPRD IRSP environment is self-contained, within its own set of Azure Subscriptions and 
managed by NTT Data Business Solutions (UK) Ltd. Access to the server infrastructure is managed 
using an Azure Bastion, which is only available through the Microsoft Azure Portal, and limited to 
MHRA, NTT Data and specific IP address ranges. CPRD IRSP servers are hosted on Azure in 
Microsoft’s UK South Cloud-Hosted Data Centre. No non-Microsoft employees can gain access to the 
data centres. Any vendor that is allowed to access the data centre follows very stringent protocols for 
any access they are granted 
The CPRD network is segmented into two parts; an internal subnet that contains the machines in the 
irsp.cprd.com Windows domain, and a demilitarized zone which contains the standalone internet-
facing servers (e.g. webservers). There is also a link to CPRD infrastructure. Strict firewall policies 
control the flow of traffic between the various zones, to control potential lateral movement on the part 
of an attacker, and to prevent unnecessary exposure of services.  
User access to the IRSP environment is managed by the CPRD Interventional Research team. 
Access is granted based on the user’s role (either within the Team, or as Study Investigators or patient 
end-users). IRSP uses a two-factor authentication for external users (Investigators and Patients) and a 
Single Sign On for internal users (MHRA staff) using their MHRA account and password. 
CPRD SOPs and policies are in place that define the policies and procedures for data access and 
external data transfer.  A full list is defined in the trial Data Management Plan. 
 
9.4 Data security for cognitive function 
Data is collected by a dedicated Linux server protected by the main watchguard firewall at the Nuffield 
Department of Population Health (NDPH; University of Oxford).  Information collected is stored within 

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a protected relational database on a separate system which is not directly accessible from the internet.  
The hardware storage components are part of the NDPH virtual system which is bolted into locked 
racks and in a location protected by three physical layers of entry checks.  All information is linked 
solely to unique one-off session keys which have no relationship to participant identifiers.  The linkage 
between these session keys and participant identifiers is held remotely by the DaRe2THINK research 
team and is unknown to both the online server and the NDPH staff managing the service.  Information 
gathered is pre-coded wherever practicable during the input process and any residual free-text 
information is protected by AES 256 encryption.   
 
9.5 Data security for health economic analysis 
Pseudonymised data provided to the health economics team will reside within secure servers at the 
London School of Economics (LSE) Primary Data Centre.  LSE encrypts the data link between its on-
campus firewalls and its firewalls hosted within its own equipment in the Data Centre; there is no 
facility for the traffic to be intercepted and decrypted.  LSE encrypts the traffic using AES 256 between 
client machines and servers storing the data.  All ingress to and egress from the LSE network is 
controlled by use of next-generation firewalls which are Common Criteria EAL4 compliant.  Access to 
LSE resources is governed by the stringent Access Control Policy of the university. 
 
9.6 Data protection and patient confidentiality  
All investigators and trial site staff must comply with the requirements of the Data Protection Act and 
General Data Protection Regulation with regards to the collection, storage, processing and disclosure 
of personal information and will uphold the Act’s core principles.  Access will be limited to the minimum 
number of individuals necessary for quality control, audit and analysis.  The controller of the data is 
the University of Birmingham, and all staff are expected to comply with this institution’s Standard 
Operating Procedures. 
In brief, all data will be used in line with the Act, for example the principles of: (1) Fair, lawful and 
transparent use by only using anonymised data for analysis; (2) Explicit use of this data for the 
purposes of health improvement in specified patient subgroups; (3) Relevant and limited use of data to 
what is necessary to answer the research questions; (4) Applying of our established data pipelines to 
ensure accuracy, and identify and rectify anomalies; (5) Keeping data for no longer than is necessary 
and permit collaboration/data sharing with other research groups, where applicable, to ensure the full 
extent of value from the data obtained; (6) Handling data in a way that ensures security and prevents 
loss or misuse; and (7) Technical and organisational procedures in place to ensure accountability, in 
addition to PPI input on research questions and data use.  These approaches are also consistent with 
the European General Data Protection Regulation.   
 
 
 
 

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10 
OVERSIGHT & MONITORING 
10.1 Trial Management Group 
The Trial Management Group (TMG) will be responsible for the day-to-day running and management 
of DaRe2THINK and will convene at regular intervals (see members on page 7).  The TMG will 
delegate specific work around data processes and data security to the Data Coordinating Team. 
 
10.2 Trial Steering Committee 
The role of the Trial Steering Committee (TSC) is to provide the overall supervision of the trial, monitor 
trial progress and conduct, and advise on scientific credibility of potential interventions.  The TSC will 
meet at least annually, and comprise of at least 75% independent members (including an independent 
chair and PPI representatives), as per the funder’s policies.  The TSC will consider and act, as 
appropriate, upon the recommendations of the Data Monitoring Committee (DMC).  Further details of 
the remit and role of the TSC are available in the respective charter (see members on page 7). 
 
10.3 Data Monitoring Committee 
An independent DMC will be established to oversee the safety of participants in the trial.  The DMC 
will meet prior to the trial opening to the first intervention, and then meet at least annually, or as per a 
timetable agreed by the committee at the first meeting.  Data analyses will be supplied in confidence 
to the DMC by the trial statistician.  The DMC will be asked to give advice on whether the accumulated 
data from the intervention, together with the results from other relevant research, justifies the 
continuing recruitment of further participants.  The DMC will operate in accordance with their 
respective charter and will consist of an independent Chair, and independent clinician and an 
independent statistician (see members on page 7). 
 
10.4 Expert Advisory Group 
An Expert Advisory Group (EAG) will support the TMG by providing expertise in pragmatic clinical 
trials and integration with the NHS, with a focus on developing sustainable methods.  The EAG 
consists of UK leaders in health data research, anticoagulation, cognition and clinical trials (see 
members on page 7).  The EAG will formally meet every 6 months, or as specified by the Chair. 
 
10.5 Protocol deviations 
Prospective, planned deviations or waivers to the protocol are not allowed under UK regulations on 
Clinical Trials and must not be used; for example, it is not acceptable to enrol a participant if they do 
not meet the eligibility criteria or restrictions specified in this protocol. 
Only major deviations from the protocol will be collated and registered, for example a deviation from 
consent processes or in the administration of the intervention.  To ensure patients that are randomised 
to treatment receive it, daily data flows to CPRD will be periodically tracked to facilitate study 
monitoring. 
Where needed, processes are in place to escalate breaches for immediate action by the central 
coordination team.   

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A “serious breach” is a breach which is likely to effect to a significant degree either (a) the safety or 
physical or mental integrity of the participants of the trial; or (b) the scientific value of the trial.  Where 
this occurs during the trial, the Sponsor will be notified immediately, and the Sponsor will ensure the 
licensing authority is notified in writing of any serious breach of (a) the conditions and principles of 
GCP in connection with that trial; or (b) the protocol relating to that trial, as amended from time to time, 
within 7 days of becoming aware of that breach.  The Chief Investigator Agreement identifies tasks 
delegated to the CI on the sponsor’s behalf. 
 
10.6 Data access 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring/audits/inspections, in line with consent. 
 
10.7 Archiving 
Archiving will be authorised by the Sponsor following submission of the end of trial report, and will 
include relevant trial documents, the trial database and all essential material for a minimum of 25 
years after completion of the trial.  Archiving and destruction of documents will follow the Sponsor’s 
Standard Operating Procedures. 
 
10.8 Trial monitoring 
A Trial Monitoring Plan will be developed and agreed by the Trial Management Group based on the 
trial risk assessment.  Monitoring will be kept to the minimum needed to ensure compliance and 
patient safety, relating to participant enrolment, consent, eligibility, allocation and reporting of harm. 
Risk adapted trial monitoring will be carried out centrally and remotely via the CPRD IRSP based on 
an ongoing risk assessment process.   
Central monitoring in the trial will be carried out through the IRSP and includes monitoring of 
recruitment, electronic case report form completion of SAEs, protocol deviations, and reportable 
outcomes. 
Central site and recruitment monitoring will be undertaken via trial specific dashboards on IRSP.  
Site visits will only be carried out where ‘for cause’ criteria are triggered (as defined in the Trial 
Monitoring Plan) but may include: (1) Quality concerns at site following central monitoring checks; (2) 
Identification of a potential risk to the trial; (3) Investigation into a potential serious breach of the trial 
protocol/GCP; and (4) Other reasons as recommended by the Sponsor. 
Monitoring will be carried out by the CPRD study team who operate independently from the Sponsor 
and Principal Investigators.  Where a triggered on-site monitoring visit is required, this will be carried 
out by CPRD staff not directly part of the day-to-day management team (Clinical Data Manager or 
equivalent).  Monitoring reports will be compiled for each oversight committee as required. 
 
10.9 Clinician responsibility 
This study has no impact on any individual clinicians’ responsibility to take immediate action if thought 
necessary to protect the health and interest of patients. 
 

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11  
FINANCIAL CONSIDERATIONS 
11.1 Trial funding 
DaRe2THINK is funded through a Health Technology Assessment grant from the National Institute for 
Health Research and the UK Department of Health and Social Care (HTA 19/109 - NIHR130280).  
The funder has no role in trial design, conduct, data analysis, interpretation or manuscript writing, but 
will review any manuscripts prior to dissemination to ensure that they meet the funder’s policies.   
 
11.2 Payment to participants 
Participants will not be paid for enrolment in the trial. 
 
11.3 Insurance 
The University of Birmingham has in place Clinical Trials indemnity coverage for this trial which 
provides cover to the University for harm which comes about through the University’s, or its staff’s, 
negligence in relation to the design or management of the trial and may alternatively, and at the 
University’s discretion provide cover for non-negligent harm to participants.  
With respect to the conduct of the trial at the Clinical Sites and other clinical care of the patient, 
responsibility for the care of the patients remains with the NHS organisation responsible for the 
Clinical Site and is therefore indemnified through the NHS Litigation Authority.  
The University of Birmingham is independent of any pharmaceutical company, and as such it is not 
covered by the Association of the British Pharmaceutical Industry (ABPI) guidelines for participant 
compensation. 
 
 
 
 

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12 
DISSEMINATION POLICY 
12.1 Study teams 
Regular newsletters will keep research staff and collaborators informed of the progress of the trial, and 
regular meetings will be held to report the progress of the trial and to address any problems 
encountered in the conduct of the trial.  The Deputy CI will coordinate dissemination of data to the 
Primary Care research teams through the NIHR CRN.  
 
12.2 Publications 
All publications and presentations relating to the main trial, including abstracts, will be authorised by 
the TSC.  All findings of clinical relevance will be submitted to a suitable medical journal for publication 
after peer review.  The PPI team will provide a short lay summary of results that will be published 
alongside the scientific paper.  Named authors on any publication must satisfy the International 
Committee of Medical Journal Editors (ICMJE) criteria for authorship (contribute to drafting of the 
article or revision for important intellectual content), provide timely approval of the final version to be 
published and supply detailed statements on any potential conflict of interest or financial relationships.  
Members of the group who do not fulfil ICMJE criteria for authorship will be listed in the article 
appendix.   
 
12.3 Study participants 
Participants will be sent a text message and email at the end of the trial providing a brief, plain English 
summary of the results written by the PPI team.  We will also work with our local teams (patient 
engagement, volunteers and media) to publicise important results relevant to our community and 
through national press. 
 
12.4 Community engagement 
Relevant and accessible summaries of findings and presentations will be aimed at key stakeholder 
groups such as CCGs, Primary Care Networks (PCNs), General Practices, Royal Colleges, Medical 
Schools, professional societies (such as the British Cardiovascular Society and European Society of 
Cardiology), charities (such as the British Heart Foundation) and patient support groups (including the 
AF Association). 
 
 
 

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13 
DaRe2THINK sub-studies 
13.1 Validation of clinical events 
Section 6.3 provides information on the Study-Within-A-Trial (SWAT) that will be used to validate 
clinical events. 
This sub-study is funded within the original DaRe2THINK grant (NIHR Health Technology 
Assessment; NIHR-130280).  The number of participants will depend on trial recruitment in the West 
Midlands local to the University Hospitals Birmingham NHS Foundation Trust.  
 
13.2 Neuro-vascular imaging  
DaRe2THINK-NeuroVascular(NV) is an observational sub-study of 160 patients, funded by the NIHR 
Efficacy and Mechanism Evaluation programme (NIHR-132974). 
Background:  Whilst it is clear that silent brain infarcts in patients with AF lead to a decline in 
cognitive function [52] and a higher risk of dementia [53], there is inconsistent evidence for the 
association of AF and specific changes on brain magnetic resonance imaging (MRI).[54]  These 
studies were unable to account for anticoagulation use and the general vascular disease seen in 
patients with AF.  Due to the randomisation to DOACs or usual care, DaRe2THINK provides an 
opportunity for unbiased assessment of the mechanistic effects of DOACs, as well as markers of 
future dementia risk.  In a pooled analysis of three studies of 175 patients with AF at a median age of 
60 years, 14 (8%) had evidence of a silent infarction on brain MRI prior to the procedure and white 
matter hyperintensities (WMH) were seen in 81 (46%).[55]  In the SWISS-AF cohort of 1,390 AF 
patients with a mean age of 72 years but no history of stroke or transient ischaemic attack, infarcts 
were seen in 446 patients (32%) and WMH in 1,372 (99%). Of these, 694 (50%) had moderate WMH 
lesions (Fazekas scale ≥2).[56]  Thus, brain injury is commonplace in patients with AF, and these 
lesions progressively accumulate over time leading to potential cognitive decline.[57]  In a meta-
analysis of eight observational cohorts (age range 71-82 years), patients with AF receiving 
anticoagulation had a lower incidence of cognitive impairment compared to those not prescribed an 
anticoagulant (relative risk 0.72; 95% CI 0.69-0.75).[16]  However, observational data should be 
interpreted with caution due to considerable prescription biases; in a randomised controlled trial, 
warfarin did not reduce the rate of cognitive decline compared to aspirin in older patients with high risk 
of thromboembolism.[11]  This sub-study will allow us to investigate if and how DOAC therapy used in 
younger patients with AF can prevent cerebrovascular disease and resultant cognitive impairment.  
Retinovascular imaging using optical coherence tomography (OCT) and OCT angiography will be 
used to determine if the mechanism of DOACs is related to cerebral lesions or due to effects on the 
general vasculature. 
Approach:  Patients randomised in DaRe2THINK and geographically near to the study site will be 
invited to a visit at baseline and at 3 years.  Each visit (approximately 2 hours in duration) will include 
a brain MRI scan, retinal scans, cognitive function assessment using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB), blood tests for cardiac biomarkers and a 12-
lead electrocardiogram (ECG).  Table 6 provides a detailed synopsis of the DaRe2THINK-NV study.  
Unless otherwise stipulated, all process will follow those noted for the main trial, including consent 
processes, data security, ethical approval, oversight and dissemination.  
 

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Table 6: DaRe2THINK-NV sub-study 
Design 
Details 
Population 
160 participants randomised in DaRe2THINK (80 participants from each arm with baseline 
imaging tests). 
Inclusion 
criteria 
Consents to join DaRe2THINK-NV after randomisation in DaRe2THINK. 
Exclusion 
criteria 
1. Claustrophobia prohibiting the use of MRI. 
2. Contraindication to MRI scanning due to implanted metal clips or devices with the 
potential to cause tissue damage in a magnetic field (e.g. aneurysm clips and certain 
cardiac pacemakers). 
3. Weight over 30 stone or 190 kg (maximum limit for MRI scanner). 
4. Women of childbearing potential (updated check by local study team). 
Time period 
Participants of the main trial will be invited to baseline assessment within 3 months if 
randomised to the intervention (DOAC) arm, or within 12 months if randomised to the 
control (no anticoagulation) arm.  A follow-up visit will be performed at 3 years. 
Site(s) 
Queen Elizabeth Hospital; University Hospitals Birmingham (UHB) NHS Trust 
Recruitment 
DaRe2THINK participants who have agreed to additional studies on their consent form who 
reside within/near the West Midlands will be approached through text, email and telephone 
by the UHB study team.  A patient information leaflet and video have been generated in 
collaboration with the PPI team.  Remote e-consent will be performed as stipulated in 
section 3.7 using a specific DaRe2THINK-NV consent form after appropriate time to review 
the patient information leaflet.   
Hypothesis 
To elucidate if the mechanism of action of DOACs, in an effort to preserve cognitive 
function in patients with AF, is due to the prevention of cerebral white matter lesions, 
reduction in incident silent brain infarcts, protection of cognitive neural tracts, or an overall 
decrease in the burden of vascular disease. 
Primary 
outcome 
New cerebral infarction or at least moderate WMH (defined as Fazekas scale ≥2) on brain 
MRI at follow-up. 
Key secondary 
outcome 
Retinal capillary density of the radial peripapillary capillary network on OCT angiography at 
follow-up. 
Other 
secondary 
outcomes 
Neuroimaging outcomes: 
• 
Grey/white matter volume and regional variation in cortical thickness/volume using high 
resolution T1 imaging 
• 
WMH lesion count, volume and damage metric using T2/FLAIR imaging 
• 
Microstructural integrity and tractography using diffusion-weighted imaging 
• 
Cerebral microbleed count and vascular abnormalities on susceptibility-weighted 
imaging 
Retinovascular outcomes:  
• 
Vascular tortuosity, calibre, fractal dimensions, bifurcation angle and retinopathy on 
retinal fundus photography 

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• 
Retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness, and macular 
volume using swept source or spectral domain OCT 
• 
Vessel and perfusion density of the superficial, and deep vascular plexus on spectral 
domain OCT angiography 
Cognitive outcomes: 
• 
CANTAB cognitive testing battery, addressing executive function, attention, speed of 
processing and memory function 
Health data outcomes: 
• 
High-sensitivity troponin; B-type natriuretic peptide 
• 
ECG: AF or other cardiac arrhythmias; heart rate; PR/QRS/QTc duration 
Analysis 
Image interpretation will follow standardised reporting templates for both cerebral and 
retinal images, using an established protocol that will be published on the trial website.  A 
Statistical Analysis Plan (SAP) will be generated by the DaRe2THINK TMG and approved 
by the TSC/DMC prior to any analysis.   
Analyses will follow an intention-to-treat approach based on the original randomised group, 
comparing the outcomes stipulated above between the DOAC and control groups.  As we 
are primarily interested in the actual effects of anticoagulant therapy, each analysis will also 
use a modified ‘as-treated’ approach.  Statistical methods are as described in Section 7.   
Sensitivity analyses will be performed to exclude patients with existing moderate WMH for 
the primary outcome, and existing eye disease for the key secondary outcome (glaucoma, 
retinal vein occlusion or proliferative diabetic retinopathy).  Additional sensitivity analyses 
will be performed of comorbidities with sufficient numbers of patients (e.g. hypertension). 
Sample size 
calculation 
Sample size is based on the aforementioned cohort studies [55,56] and our analysis of the 
THIN observational database of AF patients matching our trial criteria.  With a conservative 
control prevalence for the primary outcome of 50%, a 50% reduction in cerebral 
thromboembolic disease from DOACs [26,47], 0.85 power and 2-sided alpha of 0.05, a 
total of 126 patients are required. A sample size of 160 patients would account for death/ 
withdrawal prior to the follow-up scan (estimated at 10%), cessation of DOAC therapy due 
to adverse events (estimated at 6%), and provide sufficient power for the key secondary 
outcome (>0.99 for an absolute difference of 6% in temporal radial peripapillary capillary 
density and 0.92 for a delta of 4%, informed by a prospective cross-sectional study [58]. 
 
 

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14 
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15 
SCHEDULE OF ASSESSMENT 
Procedures 
Baseline 
6 
months 
12 
months 
18 
months 
24 
months 
30 
months 
36 
months 
42 
months 
48 
months 
54 
months 
60 
months 
10 
years 
Confirmation of selection criteria 
by the Investigator 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent taken and 
recorded 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation & allocation 
through the CPRD IRSP 
X 
 
 
 
 
 
 
 
 
 
 
 
DOAC prescription by GP for 
participants randomised to the 
intervention group 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient-reported cognitive tests 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Patient-reported quality of life 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient self-report of compliance 
to DOAC therapy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EHR extraction – CPRD 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
EHR extraction – HES/ONS 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Shaded rows are for the participants randomised to DOAC therapy only.  Due to a 2-year recruitment window, not all participants will have 
regular reassessment up to 60 months.  10-year outcome is part of the non-interventional phase of the trial. 
CPRD = Clinical Practice Research Datalink; DOAC = Direct oral anticoagulant; EHR = Electronic health record; GP = General Practitioner; 
IRSP = Interventional Research Services Platform; ONS = Office for National Statistics; HES = Hospital Episode Statistics. 
//