Evaluating Quality of Life of AF Patients Following a Bleed
Conditions: Atrial Fibrillation
Sponsor: Swansea University

Date: 15-Jan-2021 
IRAS:279646, v1.0 
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Page: 1 
Date: 15-Jan-2021 
  
 
  
Observational Study Protocol  
 EVALUATING QUALITY OF LIFE OF AF PATIENTS FOLLOWING A BLEED (EQUAL-AF)  
V2.0 
 
KEY CONTACTS: 
Funder Representative: 
Name: Steven Lister 
Job Title: Senior Health Economist 
Address: Bristol-Myers Squibb Pharmaceuticals Ltd 
Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH, UK 
Phone: +44 7581 233 996 
Email: steven.lister@bms.com 
Principal Investigator: 
Name: Hayley Hutchings 
Job Title: Professor of Health Services Research 
Address: Swansea Trials Unit, Swansea University, Singleton Park, Swansea 
SA2 8PP, UK 
Phone: 01792 513412 
Email: h.a.hutchings@swansea.ac.uk 
Sponsor Address: 
 Swansea University, Singleton Park, Swansea 
SA2 8PP, UK 
 
 
 
 

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BY REVIEWING THIS DOCUMENT, YOU AGREE TO KEEP IT CONFIDENTIAL AND TO USE AND DISCLOSE IT 
SOLELY FOR THE PURPOSE OF ASSESSING WHETHER YOUR ORGANIZATION WILL PARTICIPATE IN 
AND/OR THE PERFORMANCE OF THE PROPOSED SWANSEA UNIVERSITY STUDY. ANY UNAUTHORISED 
COPYING, DISCLOSURE OR DISSEMINATION OF THIS INFORMATION IS STRICTLY PROHIBITED. ANY 
SUPPLEMENTAL INFORMATION (E.G., AMENDMENTS) THAT MAY BE ADDED TO THIS DOCUMENT ARE 
ALSO CONFIDENTIAL AND MUST BE KEPT IN CONFIDENCE IN THE SAME MANNER AS THE CONTENTS 
OF THIS DOCUMENT. 
 

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DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Change 
Original Protocol 
(v1.0) 
21-Jul-2020 
Not Applicable 
V2.0 
15-Jan-2021 
Update to study design to specify JCRF role in study – 
no ward visits will be conducted, in line with COVID-
19 regulations. 
Model Document Version 22-Apr-2019 
 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
279646 
REC Reference: 
20/PR/0479 
ClinicalTrials.gov ID: 
TBC 
NIHR Portfolio ID: 
4771 
 

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Signature Page 
I, the undersigned, confirm that the following protocol has been read and understood agree to perform 
and conduct the study as described in the following protocol. The PI will adhere to the principles outlined 
in the Declaration of Helsinki, and other appropriate regulatory requirements.  
I agree to ensure that the document will be kept confidential and not be used for any other purpose other 
than the evaluation or conduct of the study 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. 
 
Funder representative: 
                                                                                                                     Date:  
 
Signature:_______________________________________ 
 
Name (print):_____________________________________ 
 
Position:_________________________________________ 
 
 
Principal Investigator (PI): 
                                                                                                                     Date:  
 
Signature:_______________________________________ 
 
Name (print):_____________________________________ 
 
Position:_________________________________________ 
 
dd 
mmm 
yy 
dd 
mmm 
yy 

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COVID-19 IMPACT STATEMENT 
The proposed study design outlined in the following protocol will be appropriately implemented in line 
with current guidelines set out by the UK and Welsh Government for Coronavirus management. Up to 
date Government guidance will be followed throughout the study, which will potentially impact certain 
aspects of study conduct, as described in this protocol. Study visits will be conducted remotely while 
necessary, until such time where face-to-face visits are permitted to recommence. Key members of the 
study team will monitor relevant guidance for GP surgeries and hospitals closely and adjust study conduct 
accordingly, consistent with any new information and/or restrictions as it is released. Where study tasks 
are conducted remotely, recent HRA advice released for conducting clinical trials during COVID-19 
outbreak will be adhered to, where applicable. Any study visits conducted in person will take place with 
all required precautions in place to prevent the spread of the virus. Due to the restrictions and guidance 
in place from the government, recruitment efforts designated to JCRF nurses in Swansea will be limited 
to screening of A&E databases at Morriston hospital and sending recruitment letters via secondary care 
where applicable/appropriate.  
 
Additionally, the study acknowledges that the current pandemic of COVID-19 and resulting 
restrictions and dramatic changes to patient lifestyle has the potential to cause additional adverse impact 
on quality of life issues for the study population being investigated. Quality of life issues directly caused 
due to the global pandemic of Coronavirus will not be investigated as part of this study. However, 
anecdotal information will be collected about how patients manage their diagnosis of AF during relevant 
clinic closures, lockdown environment and social distancing restrictions.  

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SYNOPSIS. 
Protocol Title:  Evaluating QUAlity of Life of AF patients following a bleed (EQUAL-AF) 
 
Study Design:   
A cross-sectional, observational feasibility study which will provide a descriptive evaluation of the quality 
of life (QoL) of atrial fibrillation (AF) patients experiencing a bleed, both in primary care and hospital 
settings (wards and emergency department (ED)). No control patients (i.e. no-bleed patients) will be 
enrolled as part of this feasibility phase. 
 
Objective(s):   
Primary objective 
 
• 
To test the feasibility of identifying patients with both minor and major bleeds as a result of 
anticoagulant treatment for AF and evaluating their QoL through both primary and secondary care 
settings. 
Secondary Objectives 
• 
To describe and interpret the observed differences in QoL by type of bleed. 
• 
To describe the treatment received and the nature of the bleed experienced by the patient. 
• 
To undertake structured qualitative interviews to gain detailed insight into issues from a patient 
perspective, for those who live with AF and have experienced a recent bleed while taking anticoagulants. 
• 
To observe appropriateness of three chosen PROMs (EQ5D, AFEQT and PACT-Q, part 2) in 
capturing QoL data, specifically post a bleeding event for AF patients who are taking anticoagulants. 
 
Outcome measure(s): 
Primary outcome measures 
• 
The study will be considered feasible if recruitment efforts prove successful: 
o A sample size of 50-80 patients will be required for the study in line with the guidance outlined 
in the Lancaster et al (2004) publication regarding feasibility studies1. A minimum of 50 
patients recruited will deem the study as successful. 

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• 
Patient reported outcome measures (PROMs) will be used in the study using a survey design to collect 
QoL data from patients directly in both primary and secondary care settings. Three validated 
questionnaires will be used in this study: EQ5D, AFEQT and PACT-Q. All questionnaires have previously 
been used in atrial fibrillation studies to collect QoL data.  
 
Secondary outcome measures 
• 
Patients will be asked to provide their anticoagulant medication information along with full details of 
the bleed they have experienced, which will be used to later categorise the bleeds as minor or major 
by a medical professional, during the data cleaning and analysis. Medication and bleed details will be 
recorded before each patient completes the selected study PROMs.   
• 
A sub-set of 10 patients will be asked to take part in a qualitative semi-structured interview, which 
will aim to further describe patient QoL after a bleed, while anticoagulated. Patients completing the 
interview will also be asked to provide any comments and opinions regarding the suitability of the 
chosen study PROMs for properly capturing all QoL issues after a diagnosis of AF.  
 
Study Population: 
Primary and secondary care patients with AF (aged ≥18) who are actively prescribed oral anticoagulant 
therapies (OATs) and have recently experienced bleeds, up to a maximum of 4 weeks prior to enrolment. 
No upper age limit will apply but potential study participants must match all inclusion/exclusion criteria, 
detailed fully in section 3.2.1 & 3.2.2.  
 
Data Collection Methods:  
Data sources: Electronic and/or paper records kept at primary and secondary care will be regularly 
searched for identification of suitable patients. Patients routinely attending anticoagulation clinics will be 
asked if they have experienced a recent bleed, and those who present as eligible will be asked to take part 
in the study. Posters placed in appropriate locations in GP clinics will encourage patients who have AF and 
are anti-coagulated to discuss minor bleeds with GPs. Lastly, e-cards will be sent out to patients with AF 
groups on forums, social media pages, web site and newsletters run by online AF support networks. 
Exposure: Anticoagulated to prevent stroke following diagnosis of AF. 

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Data collection: Data will be obtained using questionnaires supplied on paper case report forms or via an 
electronic device, depending on participants’ preference and up to date restrictions due to coronavirus 
outbreak in regards to using touchscreen devices. Data captured via an electronic device will be submitted 
directly to a REDCap database which has been designed for the study. Completed paper versions of the 
survey will later be transcribed into the database by a member of the study team. A random subset of 
enrolled AF patients will also undergo recorded interviews with research nurses in order to capture 
valuable free-form, emotive data regarding effect on quality of life after a bleed and to document patient 
opinion on current available PROMs used in the study.  
 
Data Analyses:  
Descriptive analysis of QoL reported by AF patients following a minor or major bleed while anticoagulated. 
Comparison to age-adjusted population norms may be insightful but no comparisons with controls are 
planned for this feasibility assessment, as no control patients will be enrolled. 
 
Sample Size/Power:  
 
Between 50 and 80 patients are expected1, stratified into major and minor bleeds2. Depending on 
recruitment efficacy, a maximum of 200 patients will be enrolled.  
 
Limitations/Strengths:  
The main limitation of the study is the lack of access to a suitable PROM, which specifically captures the 
true impact of bleeding on quality of life (QoL). The study will instead utilise previously validated generic 
and disease specific health-related quality of life (HRQoL) measures and compare them with population 
norms. 
As this is a feasibility study it is unknown how successful chosen recruitment strategies will be for the 
study in the study sites and populations selected.  
This study will enhance currently limited research into how bleeding specifically affects QoL in patients 
diagnosed with AF. 

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TABLE OF CONTENTS 
TITLE PAGE 1 
DOCUMENT HISTORY .......................................................................................................................3 
RESEARCH REFERENCE NUMBERS ...................................................................................................3 
COVID-19 IMPACT STATEMENT .......................................................................................................5 
SYNOPSIS. 6 
TABLE OF CONTENTS........................................................................................................................9 
1 
INTRODUCTION ...........................................................................................................10 
1.1 
Study Rationale ...........................................................................................................10 
1.2 
Feasibility Questions ...................................................................................................11 
2 
OBJECTIVES .................................................................................................................12 
2.1 
Primary Objectives ......................................................................................................12 
2.2 
Secondary Objectives .................................................................................................12 
3 
STUDY DESIGN ............................................................................................................12 
3.1 
Overview of Study Design ...........................................................................................12 
3.2 
Study Population .........................................................................................................20 
3.2.1 
Inclusion Criteria .........................................................................................................20 
3.2.2 
Exclusion Criteria.........................................................................................................20 
3.3 
Data Source/Data Collection Process .........................................................................21 
3.3.1 
Patient Reported Outcome (PRO) Measures ..............................................................22 
3.4 
Definitions of Study Variables ....................................................................................23 
3.4.1 
Outcomes/Endpoint Variables ....................................................................................25 
4 
STATISTICAL ANALYSIS ................................................................................................25 
4.1 
Progression Criteria ....................................................................................................26 
5 
STUDY LIMITATIONS/STRENGTHS ..............................................................................26 
6 
STUDY CONDUCT ........................................................................................................27 
6.1 
Ethics Committee Review and Informed Consent ......................................................27 
6.1.1 
Ethics Committee Review ............................................................................................27 
6.1.2 
Informed Consent........................................................................................................27 
6.2 
Responsibilities within the Study ................................................................................27 
6.2.1 
Sponsor Roles and Responsibilities .............................................................................27 
6.2.2 
Principal Investigator Roles and Responsibilities ........................................................28 
6.2.3 
Steering Committee ....................................................................................................28 
6.3 
Confidentiality of Study Data ......................................................................................28 
6.4 
Quality Control ............................................................................................................29 
6.5 
Database Retention and Archiving of Study Documents ...........................................29 
6.6 
Registration of Study on Public Website ....................................................................29 
7 
ADVERSE EVENT REPORTING ......................................................................................29 
8 
LIST OF ABBREVIATIONS .............................................................................................30 
9 
SCIENTIFIC PUBLICATIONS ..........................................................................................31 
10 
REFERENCES ................................................................................................................32 
 

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1 
INTRODUCTION  
1.1 
Study Rationale 
Atrial Fibrillation (AF) is the most common cardiac arrhythmia. The overall prevalence of AF is reported to 
be 0.4-1%3. However, many clinicians debate the true global prevalence, stating that it is likely to be 
underestimated as many individuals are asymptomatic and possibly undiagnosed4. Rates of AF are also 
highest in patients aged over 605. Previous studies have concluded that for males aged 75-79, rates of AF 
doubled in comparison to those aged 65-696. As the general population continues to age, AF is likely to 
become much more of a public health burden7, with predicted numbers of AF patients estimated to reach 
a minimum of 1.3 million patients in the UK by 20608. 
Patients can develop further AF-related complications, for example, significant risks of stroke and systemic 
thromboembolism and increased mortality9 10. Strokes triggered as a result of AF are a major complication 
in patients and are associated with significant morbidity and mortality 11.  
The general symptom burden on AF patients and the subsequent reduced ability to undertake daily 
activities has been widely examined in numerous studies12-14. People living with AF have a much lower 
quality of life (QoL) than patients who do not have the disease11 15.  
With the steady increase in AF prevalence and its impact on patients, it is becoming increasingly necessary 
to deliver adequate treatment and/or therapies, which can improve health related quality of life (HRQoL) 
in patients. Identifying any underlying causes of AF may be the first step in any treatment plan16, as 
treating the cause may be enough to treat and rectify the related AF. Once a detailed history of the form17 
18 and significance of AF in the patient is established, a treatment plan should then be considered19. 
Treatment plans usually involve controlling the heart rate or rhythm.  
Oral anticoagulation therapies (OATs) (for example warfarin and apixaban) are prescribed in conjunction 
with rate management in order to limit the risk of stroke and systemic thromboembolism. They are, 
however, associated with the serious side effect of bleeding. These bleeding complications include 
intracranial, gastrointestinal, genitourinary and respiratory tract bleeding haematuria20. Bleeding risk can 
be determined using calculated risk scores such as HAS-BLED21. A higher HAS-BLED score indicates that 
the patient is more at risk of a major bleed, which has previously influenced patient and clinician decisions 
not to offer or to withdraw anticoagulant treatment22. However, the European Society of Cardiology 2016 
guidelines advise that it is s better to treat with OATs (despite the risk of bleeding) than not use OATs 23.  

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Bleeding while anticoagulated is believed to have a significant impact on patient quality of life (QoL)24. 
Quality of life and health status are considered to have a colinear relationship, but this is typically difficult 
to define. There are already a multitude of validated measures which attempt to quantify Health Related 
Quality of Life (HRQoL)25-27. HRQoL tools can also be disease- or injury-specific and aim to capture both 
benefits and undesirable aspects of different diseases from a patient perspective, including consequences 
of living with the disease28. More and more focus is being directed towards improving patient reported 
quality of life when delivering quality and value-based healthcare29 30.  
There is currently limited research into how bleeding events impact QoL in AF patients, especially those 
who experience minor bleeds, for which no medical care is sought (as per Bleeding Academic Research 
Consortium (BARC) definition)31. Likewise, there are no existing and/or validated patient-reported 
outcome measures (PROMs) developed for use in assessing how bleeding influences patient QoL. 
This feasibility study will examine how patient QoL is affected when they experience either a major or 
minor bleed, defined by the International Society on Thrombosis and Haemostasis (ISTH)32, while taking 
OATs for the management of AF. 
 
1.2 
Feasibility Questions 
• 
Can sufficient numbers of patients with AF be identified and recruited onto a study to 
investigate the impact of bleeding events, related to anticoagulant use, on quality of life?  
• 
Can quality of life impact be measured for patients who are prescribed anticoagulants and 
experience bleeding as a side effect?  
 
We hypothesise that there is a considerable and sustained impact on AF patient’s quality of life (QoL) 
when they experience a bleed while anticoagulated, whether that bleed is major or minor in severity. 
Understanding the nature and extent of this impact on patients’ QoL is expected to guide physicians’ risk 
assessment when seeking to effectively anticoagulate patients with AF. 
 

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2 
OBJECTIVES 
2.1 
Primary Objectives 
To test the feasibility of i) identifying and recruiting patients with both minor and major bleeds32 as a 
result of anticoagulant treatment for AF associated events, and ii) measuring their QoL in both primary 
and secondary care settings.  
 
2.2 
Secondary Objectives 
• 
To describe and interpret the observed differences in QoL by type of bleed. 
• 
To describe the treatment received and the nature of the bleed experienced by the patient. 
• 
To undertake structured qualitative interviews to gain detailed insight into issues from a patient 
perspective, for those who live with AF and have experienced a recent bleed while taking 
anticoagulants. 
• 
To observe appropriateness of three chosen PROMs (EQ5D, AFEQT and PACT-Q, part 2) in 
capturing QoL data, specifically post a bleeding event for AF patients who are taking 
anticoagulants. 
 
3 
STUDY DESIGN  
3.1 
Overview of Study Design  
A descriptive evaluation of the QoL of patients with AF experiencing a bleed, both in primary care and 
secondary care settings (hospital wards and the emergency department (ED)).  
 
Patient Recruitment & Study Sites 
All patients will be targeted based on strict inclusion and exclusion criteria, as detailed further below 
(Section 3.2.1 & 3.2.2). Recruitment strategies will vary considerably in order to limit unconscious 
recruitment bias (for example, taking care not to direct all efforts only towards those patients who are 
more disposed to seek medical care when experiencing bleeds). Initially, eligible patients will be identified 
from regular searches in secure databases in both primary (GP surgeries) and secondary care 

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(ward/emergency department [ED]). JCRF staff will provide recruitment support by regular screening of 
A&E databases at Morriston hospital. Letters of invite will be sent out to patients who appear eligible via 
secondary care. NO on-site visits will take place by JCRF staff due to restrictions surrounding COVID-19 
and social distancing. Patients will be subsequently approached about the study by means of a face-to-
face referral in clinics where viable, in line with current consultation arrangements during the COVID-19 
period, or, alternatively, study information will be posted to capture patients with AF who may not have 
recently visited clinics, wards, or emergency department (ED). Where appropriate, study posters will be 
placed in optimal locations such as general practice (GP) clinics to display information about the study, in 
lay terms, to encourage discussion with GPs concerning all recent minor bleeds (as defined by ISTH32), 
which the patient may not have thought relevant enough to mention otherwise. Leaflets and study cards 
will be provided, which will allow potential participants to take away study information for consideration, 
including by friends and family members. Patients interested in participating in the study will be instructed 
to contact the clinical research team directly to streamline screening and enrolment process, and to limit 
time burdens on healthcare staff. 
Based on data provided by anticoagulation clinics within the Swansea City Health Cluster (eight general 
practices in the Swansea area), it is estimated that there are approximately 500 patients with AF who are 
currently taking prescribed anticoagulants. All eligible patients identified within the Health Cluster, will be 
contacted via post and, if willing, asked to report on any bleeds within the recruitment period.  A further 
recruitment drive will take place synchronously in hospital settings, where all patients who attend the 
emergency department (ED) of Morriston Hospital or admitted to the wards due to bleeds, will be 
approached for participation in the study. These patients will be identified following admission, but 
existing in-patients at study outset will be approached if it is appropriate to do so. Lastly, e-cards will be 
sent to specific patient groups as required, on forums, social media, web site and newsletters run by online 
AF support networks. Finally, patients will be informed of the study via online AF support groups on 
forums, social media pages and from a large database of patients, managed by the support group.  
Approximately 60,000 patients are held on the database in total, which will be accessed and filtered to 
identify eligible AF patients. Consent will be received digitally and an online link to the questionnaires will 
be sent to those who wish to participate. Follow-up data collection for these patients will also be 
conducted digitally.  
Recruitment is anticipated to commence in September 2020 and will continue for 6 months – a key 
decision made in light of the COVID-19 outbreak. Although the study will aim to recruit between 50 and 

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80 patients in the first instance, all suitable patients who are willing to partake in the study will be 
included. A maximum of 200 patients will be permitted to enroll if successfully screened. 
The research team will not have any contact with the patient unless the patient registers their interest in 
the study or if they reply following invitation from the healthcare provider. 
 
Screening & Enrolment 
The study will aim to enroll all patients who have AF and are anticoagulated, and who have experienced 
a bleed within a maximum of 30 days at point of enrolment. Patients experiencing bleeds over 30 days 
prior to enrolment will not be considered for the study at this stage. Numbers of minor and major bleeds 
reported will be monitored to ensure equal numbers of patients experiencing both types of bleeds are 
included, as far as feasible. Should an unequal proportion of n numbers occur between type of bleed, 
patients will not be turned away if they are willing to participate. Researchers will monitor numbers 
closely and attempt to achieve an equal proportion of minor and major bleed patients. If a balance of 
major and minor bleeds cannot be achieved within the chosen study population, it will be noted for 
informing study design of any related future studies. 
Patients who meet all study criteria will undertake an informed consent process, where they will be 
provided with full study details in a patient information sheet (PIS) and asked to sign appropriate 
documentation to indicate agreement to take part. Patients will have at least 24 hours to deliberate if 
needed and will have the opportunity to ask any questions before consenting to take part. For surveys 
which are completed online via a survey link, e-consent will be received according to HRA advice. Patients 
must agree to provide current contact details for the study team to be kept confidentially by the study 
team for follow-up purposes. Basic patient demographic information will be collected by qualified 
research nurses and recorded on case report forms (CRFs), along with details of any bleed(s) experienced. 
Additional anecdotal questions will be asked relating to ongoing patient management of atrial fibrillation 
during the current pandemic of Coronavirus, such as the ease of seeking medical care in a situation of a 
lockdown and social distancing where visits to anticoagulation clinics are limited or entirely stopped. All 
study documentation will comply with Good Clinical Practice (GCP) guidelines and General Data Protection 
Regulation (GDPR).  
  
Patient Questionnaires 

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All patients will be asked to complete three questionnaires for the study: EQ-5D-5L, Perception of 
Anticoagulant Treatment Questionnaire, Part 2 only (PACT-Q, Part 2) and Atrial Fibrillation Effect on 
QualiTy-of-life (AFEQT), which should take no longer than 30 minutes in total to complete23, 39. 
Considerations have been made, as far as possible, to minimize impact on patient’s time. Questionnaires 
will be conducted at two time-points for this study; an initial round will be completed at point of 
consent/enrolment and a second identical set of questionnaires at 90±14 days post-enrolment. Patients 
will complete the initial round of questionnaires immediately after consent process, to ensure that loss 
to follow-up is controlled. An option to take part in a further qualitative interview, after the 90-day 
follow up, will be included in both questionnaire sets. Initial questionnaires will be provided 
electronically via tablet devices or on paper copies, if patients prefer. Follow-up questionnaires will be 
sent out either through the post 3 weeks prior to the 90-day follow-up date, along with a stamped 
addressed envelope for ease of return or enrolled patients who prefer to complete data collection 
electronically will be sent a survey link. Patients will be asked in an accompanying letter to complete and 
return the questionnaires within the 90±14 day time-frame. If no reply is received within 2 weeks of first 
correspondence, a reminder letter along with a second copy of all questionnaires will be delivered.  
The PROMs for the study have been carefully selected based upon study requirements and desired 
outcomes as far as possible, in lieu of having access to a validated bleed-specific QoL questionnaire. Data 
collected using the chosen questionnaires will also allow comparable analysis with more substantial 
databases, as data will line up with previously collected QoL data in AF patients, where identical 
questionnaires have been widely used.  
 
Patient Interviews  
To capture valuable, emotive data in the form of patient thoughts and feelings in relation to the study 
objectives, a small subset of patients will complete short, structured interviews, which will be conducted 
by research staff at Swansea Trials Unit. It is anticipated that 10 interviews will be sufficient to identify 
key themes from patients.  Interviews will stop if saturation is reached before then and no new themes 
are identified; interviewees will be randomly selected from all patients who have indicated that they 
would be willing to take part. Any patient who has consented to be interviewed and completed initial 
questionnaires as a minimum, will be contacted (i.e. patients who fail to complete a second set of 
questionnaires at 90±14 days can still take part in study interviews, if contacted successfully).  However, 
patient interviews will only take place after the 90-day follow-up point post-enrolment. Interview 

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questions will be designed in close collaboration with the study’s consultant haematologist to ensure that 
appropriate questions are asked in a concise and respectful way. Patients will be asked to expand more 
specifically on bleeding events and consequent level of impact on quality of life at time of event (bleed) 
in comparison to the effect 3 months (90 days) later. Additionally, patients will be asked to give opinions 
on the chosen study PROMs on relevance to the true burden of AF and if the questionnaires have 
overlooked any important quality of life concerns for patients with AF. Recall bias will be managed as far 
as conceivable by ensuring that interviewers are sufficiently experienced in conducting interviews 
efficiently and interview questions are impartial. Any information given by patients during an interview 
will be verified where possible.  
All interviews will be recorded upon patient consent and transcribed at a later date. Interview questions 
will be identical across all patients.  
 
Data Handling & Storage 
Paper copies of CRFs and questionnaires will be transcribed into the study database, where the data will 
be checked for consistency and accuracy, alongside other data collected electronically. 
Data will be hosted securely on the REDCap data management system (licensed to Swansea Trials Unit 
(STU)). Study data will be held anonymously within REDCap and any identifying data (including protected 
characteristics) will be kept separately, secured by access restrictions.  
 
Data Analysis and Reporting 
Descriptive analysis of QoL reported by AF patients following a minor or major bleed while anticoagulated. 
Comparison to age-adjusted population norms may be insightful but no comparisons with controls are 
planned for this feasibility assessment. 
A brief thematic analysis (Braun and Clarke, 200633) will be conducted on transcribed interview data, to 
draw out important common themes relating to the study question, which will not be directly captured 
through the chosen PROMs. Specific qualitative data analysis software, NVivo 12, will be used for 
additional insight and to identifying trends in unstructured data captured during study interviews.  

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A final report will be submitted to the funder, BMS, in month 18 of the study.  Alongside this, publications 
in the form of at least one conference presentations and one peer-review publication will be prepared 
and submitted between months 16 and 20. 
 

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Project timescales 
Start date: 01st January 2020 
First Patient First Visit (anticipated):01st September 2020 
End date: 01st September 2021 
Duration: 20 months (16 months data collection, analysis and study report, 4 months peer review publication and dissemination) 
EQUAL-AF Project timescales- Phase 1 feasibility study 
TASK 
Months 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
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14 
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16 
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20 
Work Package 1 
  
Identify appropriate PROMs, arrange 
licenses for PROM use, finalise protocol, 
completion of IRAS application for Ethics 
and R&D approvals 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
RedCap database development, 
production of tablet and app versions of 
questionnaires, CRF design 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Site set up -Primary care, ED and ward 
(delay due to COVID-19)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Work Package 2 
  
Patient recruitment (delayed in light of 
COVID-19 outbreak) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Work Package 3 
  
Database cleaning and locking 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Data analysis 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Final report to BMS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Publications, peer review reporting and 
dissemination 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Study Flowchart 
 
Patient 
identified
Database search - in 
anticoagulation clinics, Morriston 
Ward F and Morristion ED
Leaflet/poster/card drop 
Eligibility/Screening 
assessment
Eligibility 
confirmed
PIS provided/Informed 
consent process
Consent 
received
PROM Questionnaires 
supplied via preferred 
method – tablet/post/
online link
Database search - Online AF 
Support Network (Heart Rhythm 
Alliance)
Data checked and 
transcribed into secure 
study database 
(REDCap)
Patients contacted 90±14 
days after initial 
questionnaire completion 
to collect follow-up data 
Data checked and 
transcribed into secure 
study database 
(REDCap)
Data cleaning/ 
analysis, reporting 
and dissemination
Subset of patients to 
undergo qualitative 
interviews, post 90 
days

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3.2 
Study Population   
Adult patients (≥18) who have AF are actively prescribed oral anticoagulant therapies (OATs) and have 
recently experienced bleeds, up to a maximum of 4 weeks prior to enrolment. No upper age limit will be 
applied, but patients must match all other inclusion/exclusion criteria (section 3.2.1). Patients will be 
selected from the Swansea area only, who attend/have attended either anticoagulation clinics within the 
Swansea City Health Cluster, Morriston emergency department or have been admitted to wards at 
Morriston Hospital due to a bleed.  
 
3.2.1 
Inclusion Criteria 
• 
Adult patients (>= 18 years old) 
• 
Patients who can understand all study information and literature to provide fully informed 
consent 
• 
Atrial fibrillation (AF) as the primary diagnosis 
• 
Having a major or minor bleed up to a maximum of 30 days prior to point of enrolment 
• 
Receiving oral anticoagulation therapy for AF 
 
3.2.2 
Exclusion Criteria 
• 
Pregnant women  
• 
Patients with active cancer 
• 
Patients unable to consent for themselves 
• 
Patient on concomitant antiplatelet therapy 
 
 
 
 

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3.3 
Data Source/Data Collection Process 
Data sources 
As part of this feasibility study, we will explore the most appropriate mechanism to identify patients who 
have experienced recent minor and major bleeds.  We will extend recruitment across both primary and 
secondary care, including wards and the ED.  Patients attending anticoagulation clinics at the Swansea 
City Health Cluster (made up of eight separate general practices) will be identified by the practice 
pharmacist or nurse.  They will be given information about the study and will consent for a research nurse 
to contact them to complete the study questionnaires.  Research nurses based in Swansea University’s 
Joint Clinical Research Facility (JCRF) will undertake regular exploration of Morriston Ward F audit data 
(Stroke ward) to identify patients who have experienced a recent bleed.  Our GP investigator will also 
identify patients from ED records at Morriston hospital.  Lastly, e-cards will be sent to specific patient 
groups on forums, social media, web site and newsletters, which are run by online AF support networks. 
Outcomes 
Quality of life and the impact of the anticoagulation treatment will be collected via validated patient-
reported outcome measures (PROMs). We will also include a small number of additional relevant 
questions regarding when the bleed occurred, the nature of the bleed, and current treatment for the 
patient.  We will also collect the documented cause and location of bleed as identified in discharge 
summary (for secondary care) in patients with major bleeds. Patient reported bleeds will be posthumously 
classified into minor or major bleeds by a clinician. 
Exposure 
Oral anticoagulant to prevent stroke following diagnosis of AF. 
Data collection 
Cases will be identified from i) routine anticoagulation clinics in primary care, ii) from hospital records for 
ward patients and from ED records. QoL data will be collected directly from patients via questionnaires. 
We envisage that data will be collected from patients via an electronic tool, ideally via patients’ phones 
or tablets.  We will also produce paper versions of questionnaires for patients who do not have access to 
a smartphone/tablet or would prefer this method of questionnaire completion.  In order to maximise data 
collection, we will collect data directly from patients attending primary or secondary care if feasible or by 
phone or post. 

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A subset of patients with AF will also be invited to participate in structured interviews in order to capture 
emotive data and to draw out any common themes in issues relating to burden of side effects, specifically 
higher bleeding risks, from anticoagulants. Interview questions have been informed by public and patient 
representatives who have close experience with those who have AF or live with the condition themselves. 
Additionally, questions have been designed with input from relevant clinical staff, including a consultant 
hematologist. In order to limit any potential bias, each interviewer selected to perform patient interviews 
will be experienced in delivering qualitative interviews in similar settings and will also be mindful of 
possible potential bias when delivering the interview questions, such as refraining from asking leading 
questions. Each patient will be asked an identical set of questions, which will be void of emotive language 
and closed questions where possible. Questions have been chosen and approved based upon clinical 
guidance based upon previous information given by patients with AF who experience bleeds while 
prescribed anticoagulants. 
 
3.3.1 
Patient Reported Outcome (PRO) Measures 
An extensive literature search at the outset of study design confirmed that there is currently no known 
validated Patient Reported Outcome Measure (PROM) which specifically captures impact of bleeding on 
Quality of Life (QoL). In lieu of having access to such PROM, three previously validated and widely used 
PROMs will be used to allow for comparisons with larger databanks. The questionnaires that will be 
completed for the study consist of: 
• 
EQ-5D-5L; 
• 
Perception of Anticoagulant Treatment Questionnaire (PACT-Q); and 
• 
Atrial Fibrillation Effect on QualiTy-of-life (AFEQT).  
 
EQ-5D-5L 
The EQ5D has been developed by the EuroQoL group for use in clinical studies as a patient reported 
outcome measure, commonly used for reporting the current health status of an individual. Patients rate 
their health from 1 to 5 based on 5 components: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. A 5-digit number will be generated (e.g. 11111), giving an indication of the patients’ 
current health status. The 5L version of EQ5D has been selected for use in this study as it is considered to 

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have improved sensitivity compared with the 3L version when capturing quality of life issues in patients 
living with different health conditions34. The 5L version has also been accepted for use in previous studies 
investigating quality of life in patients with atrial fibrillation taking oral anticoagulants35.  
As part of the EQ5D assessment, patients will also indicate pain levels using a visual analogue scale (VAS) 
which asks the patient to place a cross over a graduated line from 0 (no pain) to 100 (worst pain 
imaginable).  
 
PACT-Q 
PACT-Q is a two-part PROM, which is used in AF studies to capture patients’ perception of treatments 
before and after initiation. The questionnaire comprises of 7 items for Part 1 (treatment expectations) 
and 20 items in Part 2 (convenience, burden of disease and treatment, anticoagulant treatment 
satisfaction, taking an average of 20 minutes total to complete (10 minutes per section). Patients are 
asked to mark answers on a Likert scale from 1 to 5. For the purpose of this study, only Part 2 will be 
completed by all patients. 
 
AFEQT 
The AFEQT is a self-reported measure which directly measures impact of atrial fibrillation (AF) on quality 
of life. The aspects of quality of life aspects covered in the questionnaire detail impact of AF on hobbies, 
relationships, activities including walking or sports, mental health, and side effects from treatment 
(including side effects such as nosebleeds, bleeding gums, heavy bleeding from cuts and bruising), over 
the last 4 weeks prior to point of completion. Patients will answer each question on a Likert scale from 1-
7. The AFEQT consists of 20 items in total.  
 
3.4 
Definitions of Study Variables 
As defined by the International Society for Thrombosis and Haemostasis2 32 for non-surgical patients 
Major bleed  
1. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarticular, or pericardial, or intramuscular with compartment syndrome. 

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2. Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion 
of two or more units of whole blood or red cells. 
Minor bleed 
All non-major bleeds will be considered minor bleeds. Minor bleeds will be further divided into those that 
are clinically relevant and those that are not. Some examples of minor bleeds include but not limited to: 
• 
Nose bleeds 
• 
Bloody stools 
• 
Small, manageable cuts (e.g shaving cuts) 
• 
Noticeable and/or persistent bruising 
Clinically Relevant Minor Bleed 
A clinically relevant minor bleed is an acute or subacute clinically overt bleed that does not meet the 
criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: 
• 
A hospital admission or attendance at A&E for bleeding, or 
• 
A physician guided medical or surgical treatment for bleeding, or 
• 
A change in antithrombotic therapy (including interruption or discontinuation of oral 
anticoagulant). 
 
Other variables collected in the study will be the following: 
• 
Recruitment pathway 
• 
Medication type 
• 
Co-morbidity/ies, if present 
• 
Location of bleed 
• 
Impact of COVID-19 pandemic and resulting restrictions and closures on ability to seek medical 
care for a bleed 
 

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Collecting the above confounding variables, each of which also has the potential to have some impact on 
QoL for patients with AF who experience bleeding (while anticoagulated), will allow researchers to reflect 
on and account for any resulting confounder bias. Confounding variables will be reported on within the 
end of study descriptive analysis.  
 
3.4.1 
Outcomes/Endpoint Variables 
Quality of life data and the impact of the anticoagulation treatment will be collected via validated patient-
reported outcome measures (PROMs). We will also include a small number of additional relevant 
questions regarding when the bleed occurred, the nature of the bleed and their current treatment.  We 
will also collect the documented cause and location of bleed as identified in discharge summary (for 
secondary care) in patients with major bleeds. 
 
4 
STATISTICAL ANALYSIS 
Due to the feasibility aspect of the study and the low number of cases, a full statistical analysis is not 
planned.  A descriptive analysis of QoL reported by AF patients following a minor and/or major bleed, 
while anticoagulated, will be performed.  Patients who experience multiple bleeds over the course of 
study participation and consequently report these to research staff will be included, and multiple bleeds 
will be posthumously categorised into minor or major bleeds by a clinical professional and included as 
part of the descriptive analysis. Recorded treatment type (anticoagulant used) will be compared with type 
of bleed (minor/major) to determine if there is any possible linkage which could warrant further testing. 
Comparison to age-adjusted population norms may be insightful but no comparisons with controls are 
planned for this feasibility assessment.   
A brief thematic analysis (Braun and Clarke, 2006)33 will be conducted on transcribed interview data, to 
draw out important common themes relating to the study question, which will not be directly captured 
through the chosen PROMs. Specific qualitative data analysis software, NVivo 12, will be used for 
additional insight and to identifying trends in unstructured data captured during study interviews.  
Lastly, CRF’s and online survey links will include sections for eligible patients to provide open-ended 
feedback regarding each of the PROMs used in this study and how far the PROM captured bleed-specific 
QoL issues for anticoagulated AF patients. As previously stated, this information will not be used to 

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conduct a full statistical analysis but will allow researchers to gauge each PROM performance in capturing 
QoL post-bleed(s) for these patients. 
 
4.1 
Progression Criteria 
The feasibility of the trial methods, recruitment strategies, and its potential to be further developed and 
into a full qualitative study will be measured on key progression criteria. These criteria have been 
approved by our Trial Steering Committee and study managers, where applicable: 
• 
Minimum requirements met for recruitment (50 eligible patients) 
• 
Retention of at least 50% of enrolled patients at follow-up 
• 
70% PROMs data completion at baseline and 40% completion of PROMs at follow-up 
 
5 
STUDY LIMITATIONS/STRENGTHS  
The study will enhance limited, existing knowledge of the level of impact that bleeding while 
anticoagulated have on patients who have been diagnosed with AF taking anticoagulants. 
As this is a feasibility study, it is difficult to predict how successfully eligible patients will be identified and 
subsequently enrolled, based on the study inclusion/exclusion criteria. There is also uncertainty around 
optimal ways to promptly identify patients within the primary care and hospital settings. Patients who 
experience minor bleeds do not always routinely discuss these events with GPs and identifying these 
patients could prove challenging. Recruitment measures will be tested during this pilot study to inform 
best strategies for a possible larger-scale study in the future. 
 As yet, there is no known validated PROM which specifically investigates the impact of bleeding on quality 
of life which would be suitable for use with AF patients. The study will instead utilize three previously 
validated general and disease-specific HRQoL measures EQ-5D, Perception of Anticoagulant Treatment 
Questionnaire (PACT-Q) and Atrial Fibrillation Effect on QualiTy-of-life (AFEQT).  
 

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6 
STUDY CONDUCT 
6.1 
Ethics Committee Review and Informed Consent  
6.1.1 
Ethics Committee Review 
The required approval from the <<name of committee>> Research Ethics Committees, and Swansea Bay 
University Health Board R&D approvals will be obtained before study site initiation. All approvals will be 
sought through Health and Care Research Wales using the Integrated Research Application System (IRAS).  
The 
study 
research 
governance 
sponsor 
will 
be 
Swansea 
University 
(researchgovernance@swansea.ac.uk).  
 
 
6.1.2 
Informed Consent 
In accordance with local regulations, subjects should provide written consent before enrollment into the 
study. Investigators must ensure that patients, are clearly and fully informed about the purpose of the 
study, potential risks, and the patient’s rights and responsibilities when participating in this study.  
 
6.2 
Responsibilities within the Study 
The Principal Investigator (PI) of this study is Professor Hayley Hutchings, Swansea Trials Unit (STU). 
Swansea University (SU).  Swansea University will be the Sponsor of this study under the UK Policy 
Framework for Health and Social Care Research.   BMS have agreed to fund the study and will provide 
oversight of the scientific quality and value for money of the protocol.   
The study shall be conducted as described in this approved protocol. All revisions to the protocol must be 
discussed with, and authorised by, the study sponsor Swansea University and the funder BMS. 
 
6.2.1 
Sponsor Roles and Responsibilities 
The Sponsor will assume overall responsibility for the study design, conduct, analysis and interpretation, 
as well as report writing and dissemination of results. 
A representative from the funder, will sit on the Trial Steering Committee and will ensure that the protocol 
is well designed, scientifically valid and provides value for money. 

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6.2.2 
Principal Investigator Roles and Responsibilities  
The PI is ultimately responsible for the conduct of the study as a whole, regardless of dissemination of 
study tasks. The PI will ensure that the study is conducted in accordance with the protocol and that tasks 
are delegated appropriately. The PI will oversee research staff and ensure wellbeing of study participants. 
 
6.2.3 
Steering Committee  
Trial Steering Committee (TSC) 
Members of the trial steering committee will include sponsor representatives, study PI, research nurses, 
PPI representatives, trial manager and governance staff. The TSC will provide supervision of the study, 
make timely decisions on study set-up and conduct and monitor key milestones set out for the study. 
Meetings will occur monthly upon study set up (months 1-3) and quarterly (or as needed) for the 
remainder of the study.  
Patient and Public Involvement 
Two patient and public involvement (PPI) representatives will be selected at study outset and invited to 
contribute to study design, selection of appropriate data collection methods/tools and to attend study 
steering meetings.  PPI’s will be selected based on appropriate relatedness to the condition, such as those 
currently living with AF and prescribed anticoagulants and/or those involved with AF support groups (e.g. 
Heart Rhythm Alliance). 
 
6.3 
Confidentiality of Study Data 
The confidentiality of records that could identify patients within the database must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
For the purposes of protecting a patient’s identity, a unique study code will be assigned to each patient, 
such as a series of numbers and/or letters.  The data that is recorded with the patient’s assigned code is 
called “key-coded data”.  Key-coded study data will be managed by the sponsor and/or its delegates in a 
study-specific electronic database (the “study database”). Only the site staff will have access to the link 

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between patient’s assigned code and the patient’s identity. However, in case of an audit or inspection, 
subject to local laws and regulations, government officials, REC representatives and sponsor 
representatives may access this information at the study site. If the study requires on-site monitoring, 
subject to local laws and regulations, sponsor representatives will also access the primary data source at 
the study site (see section 6.4). Data that could directly identify the patient will not be collected in the 
“study database”. 
Data will be processed in accordance with the Data Protection Act (2018) and GDPR (2016). All information 
collected about participants will be kept strictly confidential. 
6.4 
Quality Control 
Representatives of   the study sponsor must be allowed to visit all study site locations to assess the data 
quality and study integrity. On site, they will review study files and, patient medical notes to compare 
them with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
6.5 
Database Retention and Archiving of Study Documents  
The investigator must retain all study records and source documents for 10 years. The investigator must 
contact Swansea University prior to destroying any records associated with the study. Location of 
database and supporting documentation will be outlined in the final observational study report. Data will 
be securely stored and only accessible by the research team and will be carefully maintained and available 
for a minimum of ten years after completion of the study. 
6.6 
Registration of Study on Public Website 
This study will be registered on ClinicalTrials.gov. The study will also be adopted into the NIHR CRN 
portfolio. 
 
7 
ADVERSE EVENT REPORTING 
This study is not designed to capture safety events on any medicinal product and therefore, adverse event 
collection and reporting is not required.  
Consideration has been taken for the possibility that patients may become distressed or emotional during 
completion of patient questionnaires by the recollection of previous experiences associated with bleeds.  
Patients may also experience low mood or anxiety associated with their condition. Both primary and 

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secondary care researchers have clinical experience of working with patients with low mood, anxiety and 
distress.  If a participant reports, or shows signs of low mood, distress or anxiety they will be encouraged 
to discuss this with their primary or secondary care researcher and will be signposted to local relevant 
services or to contact their GP  
Patients will have the right to withdraw at any point of the study.  This will not affect their NHS care and 
this will be explained in the patient information sheet and any discussions.  Should a distressed patient 
wish to continue participation, they will be given adequate time to complete questionnaires, taking into 
account any breaks the patient may wish to take.  The patient information sheet contains contact details 
for researchers involved in the study and for the patient advice and liaison service (PALS) with information 
on how to contact both.   
 
8 
 LIST OF ABBREVIATIONS 
Term 
Definition 
A&E 
Accident and Emergency 
AF 
Atrial Fibrillation 
BARC 
Bleeding Academic Research Consortium 
BMS 
Bristol-Myers Squibb 
CRF 
Case Report Form 
EC 
European Commission 
ED 
Emergency Department 
ESC 
European Society of Cardiology 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulations 
GP 
General Practice/General Practitioner 
HRA 
Health Research Authority 
HRQoL 
Health Related Quality of Life 
ICMJE 
International Committee of Medical Journal Editors 
IRAS 
Integrated Research Application System 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 

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JCRF 
Joint Clinical Research Facility 
NYHA 
New York Heart Association 
OAT 
Oral Anticoagulant Therapy 
PI 
Principal Investigator 
PROM 
Patient Reported Outcome Measure 
QoL 
Quality of Life 
REDCap 
Research Electronic Data Capture 
STU 
Swansea Trials Unit 
TIA 
Transient Ischaemic Attack 
TSC 
Trial Steering Committee 
VAS 
Visual Analogue Scale 
 
9 
SCIENTIFIC PUBLICATIONS 
Scientific Publications (such as abstracts, congress podium presentations and posters, and manuscripts) 
of the study results will be a collaborative effort between the study Sponsor, funder and the external 
authors.  No public presentation or publication of any interim results may be made by the PI, sub-
investigator or any other member of the study team without the prior written consent of the Sponsor.   
Authorship of publications for this study is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (i.e., ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for authorship: 
Substantial intellectual contribution to the conception or design of the work; or the acquisition of data 
(e.g., evaluable subjects with quality data or data generation), analysis, or interpretation of data for the 
work (e.g., problem solving, advice, evaluation, insights and conclusion); AND 
Drafting the work or revising it critically for important intellectual content; AND 
Final approval of the version to be published; AND 
Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy 
or integrity of any part of the work are appropriately investigated and resolved. 
Those who make the most significant contributions, as defined above, will be considered for authorship 
of the publication. 

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10 
REFERENCES 
1. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good 
practice. J Eval Clin Pract 2004;10(2):307-12. 
2. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, et al. Definition of major 
bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J 
Thromb Haemost 2005;3(4):692-4. 
3. Liu GJ, Wang YF, Chen PY, et al. The efficacy and safety of novel oral anticoagulants for the preventive 
treatment in atrial fibrillation patients: a systematic review and meta-analysis. Drug Deliv 
2014;21(6):436-52. 
4. Nileshkumar J Patel, Varunsiri Atti, Raul D Mitrani,Juan F Viles-Gonzalez, Jeffrey J Goldberger. Global 
rising trends of atrial fibrillation:a major public health concern. Heart 2018;(0):1–2 
5. Darby-Stewart A, Dachs R, Graber MA. Rivaroxaban vs. warfarin for stroke prevention in patients with 
nonvalvular atrial fibrillation. Am Fam Physician 2012;85(6):577-86. 
6. Chugh, Sumeet S et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 
Study. Circulation2014;129(8): 837-47.  
7. Xue Li, Vicki C. Tse, Lung Wai Au-Doung, Ian C.K. Wong, Esther W. Chan. The impact of ischaemic stroke 
on atrial fibrillation-related healthcare cost: a systematic review. EP Europace 2017;19(6):937–
947 
8. Deirdre A. Lane, Flemming Skjøth, Gregory Y. H. Lip, Torben B. Larsen, Dipak Kotecha Temporal Trends 
in Incidence, Prevalence, and Mortality of Atrial Fibrillation in Primary Care.  
Journal of the 
American Heart Association Cardiovascular and Cerebrovascular Disease 2017;6(5):e005155 
9. Hansen PW, Sehested TSG, Fosbol EL, et al. Trends in warfarin use and its associations with 
thromboembolic and bleeding rates in a population with atrial fibrillation between 1996 and 
2011. PLoS One 2018;13(3):e0194295. 
10. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions 
for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82(8A):2N-9N. 
11. Sérgio Barra, Simon Fynn. Untreated atrial fibrillation in the United Kingdom: Understanding the 
barriers and treatment options. Journal of the Saudi Heart Association 2015;27(1): 31-43 

EQUAL-AF Study Protocol  
V2.0 
Date:15-Jan-2021 
IRAS:279646, v2.0 
33 
12. Kara E. Montbleau, Deandre King, Lori Henault, Jared W Magnani & Albert Lee (Reviewing Editor). 
Health literacy, health-related quality of life, and atrial fibrillation. Cogent Medicine 2017; 4(1) 
13. Graham Thrall, Deirdre Lane, Douglas Carroll, Gregory Y.H. Lip. Quality of Life in Patients with Atrial 
Fibrillation: A Systematic Review. The American Journal of Medicine 2006; 119(5) 448.e1-448.e19 
14. Spertus, J., et al. Development and Validation of the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) 
Questionnaire in Patients With Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology 
2011;4(1): 15-25. 
 
15. Hagens VE et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results 
from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol. 
2004;43(2):241-7. 
16. National Clinical Guideline Centre. Atrial fibrillation: the management of atrial fibrillation. Clinical 
guideline: Methods, evidence and recommendations. June 2014. 
17. Anderson, J. L., et al. Management of Patients With Atrial Fibrillation (Compilation of 2006 
ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations). Circulation  2013 127(18): 1916-
1926. 
18. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients 
with atrial fibrillation: A report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:2246–
2280. 
19. Xu J, Luc JG, Phan K. Atrial fibrillation: review of current treatment strategies. J Thorac Dis. 
2016;8(9):E886–E900.  
20. Wallis CJD, Juvet T, Lee Y, et al. Association Between Use of Antithrombotic Medication and 
Hematuria-Related Complications. JAMA 2017;318(13):1260-71. 
21. Gorman EW, Perkel D, Dennis D, Yates J, Heidel RE, Wortham D. Validation Of The HAS-BLED Tool In 
Atrial Fibrillation Patients Receiving Rivaroxaban. J Atr Fibrillation 2016;9(2):1461. 
22. Dar T, Yarlagadda B, Vacek J, et al. Management of Stroke risk in atrial fibrillation patients with 
bleeding on Oral Anticoagulation Therapy-Role of Left Atrial Appendage Closure, Octreotide and 
more. J Atr Fibrillation 2017;10(4):1729. 

EQUAL-AF Study Protocol  
V2.0 
Date:15-Jan-2021 
IRAS:279646, v2.0 
34 
23. Paulus Kirchhof et al, 2016 ESC Guidelines for the management of atrial fibrillation developed in 
collaboration with EACTS. European Journal of Cardio-Thoracic Surgery 2016;50(5): e1–e88 
24. Res LCS, Lubberts B, Shah SH, et al. Health-related quality of life after adverse bleeding events 
associated with antithrombotic drug therapy - A systematic review. Hellenic J Cardiol 
2019;60(1):3-10. 
25. Herdman, M., Gudex, C., Lloyd, A. et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res 2011; 20: 1727–1736.  
26.  Ware, J. E., Jr. (1999). SF-36 Health Survey. In M. E. Maruish (Ed.), The use of psychological testing for 
treatment planning and outcomes assessment:1227-1246 
27. Badia, X., Arribas, F., Ormaetxe, J.M. et al. Development of a questionnaire to measure health-related 
quality of life (HRQoL) in patients with atrial fibrillation (AF-QoL). Health Qual Life Outcomes 2007 
5(37) 
28. Xiao-Jun Lin, I-Mei Lin, Sheng-Yu Fan. Methodological issues in measuring health-related quality of life. 
Tzu Chi Medical Journal 2013;25(1):8-12, 
29. Bae JM. Value-based medicine: concepts and application. Epidemiol Health. 2015;37:e2015014.  
30. Riva S and Pravettoni G. Value-Based Model: A New Perspective in Medical Decision-making. Front. 
Public Health 2016 4:118 
31. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky 
E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, 
Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus 
report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736–47. 
32. Rodeghiero, F.; Tosetto, A.; Abshire, T.; Arnold, DM.; Coller, B.; James, P.; Neunert, C.; Lillicrap, D. 
ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new 
bleeding score for inherited bleeding disorders. J Thromb Haemost 2010;8 (9): 2063–5 
33. Virginia Braun & Victoria Clark. Using thematic analysis in psychology, Qualitative Research in 
Psychology, 2006 3(2): 77-101 
34. Buchholz, I., Janssen, M.F., Kohlmann, T. et al. A Systematic Review of Studies Comparing the 
Measurement Properties of the Three-Level and Five-Level Versions of the EQ-5D. 
PharmacoEconomics 2018 36, 645–661 

EQUAL-AF Study Protocol  
V2.0 
Date:15-Jan-2021 
IRAS:279646, v2.0 
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35. De Caterina R, Brüggenjürgen B, Darius H, et al. Quality of life and patient satisfaction in patients with 
atrial fibrillation on stable vitamin K antagonist treatment or switched to a non-vitamin K 
antagonist oral anticoagulant during a 1-year follow-up: A PREFER in AF Registry substudy. Arch 
Cardiovasc Dis. 2018;111(2):74-84.