OPTimising a Screening Program to Detect Pacemaker-associated Heart Failure Using Artificial Intelligence
Conditions: Heart Failure, Pacemaker
Sponsor: University of Leeds

Straw S. OPT-AI. V1.1. Sep 2025. 2025-NCT11. IRAS: 347225 
 
 
1 
TITLE PAGE 
 
This protocol has regard for HRA guidance 
 
  
 
 
 
           
 
_________________________________________________________________________ 
 
Study protocol 
 
Title:  
 
OPTimising a screening program to detect pacemaker-associated  
heart failure using Artificial Intelligence (OPT-AI) 
Chief Investigator:  Dr Sam Straw (s.straw@leeds.ac.uk; 0113 3928240) 
Sponsor: 
 
The University of Leeds 
Protocol version: 
1.1 
Date:  
 
05/09/2025 
IRAS number: 
347225 
Sponsor number: 
2025-NCT11 
 
 

Straw S. OPT-AI. V1.1. Sep 2025. 2025-NCT11. IRAS: 347225 
 
 
2 
SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Chief Investigator agrees to conduct the study in compliance with the approved protocol 
and will adhere to the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, 
and other regulatory requirements. 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose than the evaluation or conduction 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: 
...................................................................................................... 
 
Date: 
01/12/2024 
Name: (please print): Dr Sam Straw 
......................................................................................................
 
 
 
 
 
 
 

Straw S. OPT-AI. V1.1. Sep 2025. 2025-NCT11. IRAS: 347225 
 
 
3 
LIST OF CONTENTS 
 
TITLE PAGE  
 
 
 
 
 
 
 
 
 
1 
SIGNATURE PAGE  
 
 
 
 
 
 
 
 
2 
LIST OF CONTENTS  
 
 
 
 
 
 
 
 
3 
KEY STUDY CONTACTS 
 
 
 
 
 
 
 
 
4 
STUDY SUMMARY  
 
 
 
 
 
 
 
 
5 
FUNDING 
 
 
 
 
 
 
 
 
 
 
5 
SPONSOR INDEMNITY STATEMENT 
 
 
 
 
 
 
5 
STUDY PROTOCOL  
 
 
 
 
 
 
 
 
6 
BACKGROUND 
 
 
 
 
 
 
 
 
 
6 
PILOT DATA  
 
 
 
 
 
 
 
 
 
7 
HYPOTHESIS 
 
 
 
 
 
 
 
 
 
7 
RESEACH QUESTION 
 
 
 
 
 
 
 
 
8 
STUDY SETTING 
 
 
 
 
 
 
 
 
 
8 
IDENTIFICATION OF POTENTIAL PARTICIPANTS  
 
 
 
 
8 
RECRUITMENT PROCESS   
 
 
 
 
 
 
 
8 
EXPERIMENTAL DESIGN 
 
 
 
 
 
 
 
 
9 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
9 
OUTCOMES  
 
 
 
 
 
 
 
 
 
10 
STATISTICAL ANALYSIS 
 
 
 
 
 
 
 
 
10 
ETHICAL AND REGULATORY CONSIDERATIONS  
 
 
 
 
10 
EXPECTED VALUE  
 
 
 
 
 
 
 
 
13 
DISSEMINATION POLICY 
 
 
 
 
 
 
 
 
13 
AMENDMENT HISTORY 
 
 
 
 
 
 
 
 
15 
REFENCES 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 

Straw S. OPT-AI. V1.1. Sep 2025. 2025-NCT11. IRAS: 347225 
 
 
4 
KEY STUDY CONTACTS 
 
Chief Investigator:  
 
Dr Sam Straw  
s.straw@leeds.ac.uk 
0113 392 8240 
 
Co-Investigator: 
 
Dr Maria Paton 
m.paton@leeds.ac.uk 
0113 392 8240 
 
Co-Investigator: 
 
Dr John Gierula 
 
 
 
 
j.gierula@leeds.ac.uk 
0113 392 8240 
 
Co-Investigator: 
 
Dr Klaus K Witte 
 
 
 
 
k.k.witte@leeds.ac.uk 
0113 392 8240 
 
Co-Investigator: 
 
Ms Charlotte Cole 
 
 
 
 
charlotte.cole4@nhs.net 
 
 
 
 
0113 392 8240 
 
Co-Investigator: 
 
Ms Ruth Burgess 
 
 
 
 
ruth.burgess1@nhs.net 
 
 
 
 
0113 392 8483 
 
Co-Investigator: 
 
Dr Stephe Kamalathasan 
 
 
 
 
stephe.kamalathasan@nhs.net 
 
 
 
 
0113 392 8240 
 
Sponsor: 
 
 
The University of Leeds  
governance-ethics@leeds.ac.uk 
 
 
 
 
0113 343 7587 
 
Funder: 
 
 
The Leeds Hospitals Charity 
 
 
 
 
hello@leedshospitalscharity.org.uk 
 
 
 
 
0113 539 7020 
 
 
 
 

Straw S. OPT-AI. V1.1. Sep 2025. 2025-NCT11. IRAS: 347225 
 
 
5 
STUDY SUMMARY 
 
Study title: 
 
 
OPTimising a screening program to detect pacemaker- 
associated heart failure using Artificial Intelligence (OPT-AI) 
Study design:  
 
Prospective, observational, pilot study 
Study participants: 
 
Patients with pacemakers for bradycardia. 
Planned sample size:  
150 participants. 
Follow up duration: 
 
Not applicable. 
Planned study period:  
July 2025-June 2026 
Aims:  
 
 
To determine whether new technologies can improve the  
detection of pacemaker-associated heart failure. 
 
FUNDING 
 
Leeds Hospitals Charity: 
Research and Innovation Funding. 
 
ROLE OF STUDY SPONSOR AND FUNDER 
 
The University, when acting as Sponsor assumes overall responsibility for the initiation and 
management of the study. 
 
Neither Sponsor or the Funder have any role in the study design, data analysis and 
interpretation, manuscript writing, conduct, and dissemination of results, nor have final 
decision regarding any of these aspects of the study.
 
 

Straw S. OPT-AI. V1.0. Jun 2025. 2025-XXXXX. IRAS 347225. 
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STUDY PROTOCOL 
OPTimising a screening program to detect pacemaker-associated heart failure using Artificial 
Intelligence (OPT-AI) 
 
 
1.  
BACKGROUND 
1.1 
PACEMAKERS FOR THE TREATMENT OF BRADYCARDIA 
Permanent pacemaker implantation for the treatment of bradycardia (slow heart rates) 
improves quality of life and normalises life expectency.1,2 Around 600,000 people undergo 
implantation of a pacemaker device each year, and there are around 3 million people currently 
living with pacemakers worldwide. Typical pacemaker devices for bradycardia consist of a 
generator implanted into a pre-pectoral pocket, with a lead in the right ventricular (RV) apex, 
with or without a second lead in the right atrial appendage. Usually, battery life is around 8-12 
years, after which time a generator replacement is required. 
 
1.2  
RIGHT VENTRICULAR PACING AND HEART FAILURE 
Although pacemakers can transform a patient’s quality of life, there are some disadvantages. 
Compared with intrinsic electrical conduction, RV apical electrical stimulation results in 
electrical and mechanical dyssynchrony, leading to acute changes in LV performance, and 
over the long-term adverse left ventricular (LV) remodelling, progressive systolic dysfunction 
and, in some, the clinical syndrome of heart failure. Patients with pacemakers for bradycardia 
often have co-morbidities, such as ischaemic heart disease or hypertension which can make 
this problem more likely. Pacemaker-associated heart failure is the most common long-term 
complication of device implantation, however this is often unrecognised, and although certain 
patient characteristics make it more likely, it is not currently possible to identify individuals who 
might develop heart failure in the future.3 
 
1.3 
ALTERNATIVE STRATEGIES TO PREVENT HEART FAILURE 
The burden of RV apical pacing is positively correlated with the risk of HF hospitalisation. RV 
pacing avoidance algorithms can reduce this burden ,4 however, this is often unavoidable for 
patients with high-degree atrioventricular (AV) block.5 Alternative strategies such as the 
implantation of devices capable of delivering biventricular pacing (cardiac resynchronisation 
therapy), septal or conduction system pacing are available. However, each had its own 
limitations including longer procedure times, premature lead failure, financial costs, the higher 
risk of upfront complications, and more fundamentally, that none of these strategies have not 
been proven to improve clinical outcomes.6  The RV apical position continues to be far and 
away the most common site for ventricular lead implantation for patients implanted with 
pacemakers for bradycardia. 
 
1.4 THE PACEMAKER CARE PATHWAY AND THE OPPORTUNITY TO INTERVENE 
The implant procedure itself is only one aspect of the pacemaker pathway of care. Following 
implantation patients are required to have ongoing follow-up to assess device functionality 
and battery longevity. Standard practice is for patients to attend a clinic in person, even for 
those who now benefit from the provision of remote monitoring. Additionally, towards the end 
of a device’s lifespan, patients are required to undergo a day case procedure to undergo 
generator replacement. Both of these offer the opportunity to assess for pacemaker-
associated heart failure during a patient’s routine hospital contact. 
 
1.5 THE ROLE OF CARDIAC ULTRASOUND IN DIAGNOSIS AND CLASSIFYING HEART 
FAILURE  
Cardiac ultrasound, or echocardiography, is fundamental to the diagnosis and management 
of heart failure. A diagnosis of heart failure requires assessment of cardiac structure and 
function, and although alternative imaging modalities are available, cardiac ultrasound is 
almost always the initial imaging modality used to make the diagnosis. Furthermore, heart 
failure is currently classified by left ventricular ejection fraction (LVEF) into heart failure with 

Straw S. OPT-AI. V1.0. Jun 2025. 2025-XXXXX. IRAS 347225. 
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reduced (HFrEF) or preserved ejection fraction (HFpEF). Optimal care for people with HFrEF 
now includes four classes of medications proven to reduce hospitalisation and mortality risk.7 
Each of these pharmacological therapies result in incremental benefits to patients, and 
guidelines now recommend these are initiated in parallel, as soon as possible following the 
discovery of heart failure.8 This is unlike the situation in HFpEF, where these therapies have 
either proven neutral, or have resulted in marginal improvements to outcomes. An assessment 
of LVEF with echocardiography is therefore essential. Until recently the effect of these agents 
for pacemaker-associated heart failure was unknown, and most phase III clinical trials of 
medical therapy for HFrEF did not report the effect of these agents for patients with 
pacemakers. Additional strategies to improve outcomes include device ‘upgrade’ procedures, 
in which an additional LV lead is implanted to deliver biventricular pacing (cardiac 
resynchronisation therapy), with or without a defibrillator. 
 
2.  
PILOT DATA 
2.1  
RIGHT VENTRICULAR PACING RESULTS IN IMMEDAITE ADVERSE EFFECTS 
ON LEFT VENTRICULAR FUNCTION, AND ADVERSE REMOLLING IN THE LONG-TERM 
We performed a single-centre, observational study of patients previously implanted with 
pacemakers for bradycardia and used cardiac magnetic resonance (CMR) imaging to 
determine the immediate effects of RV pacing on LV systolic function. We recruited 84 patients 
with an LVEF ≥40% into two observational studies. In 34 patients with preserved atrio-
ventricular conduction, we programmed two pacing modes to deliver asynchronous atrial 
pacing (with intrinsic conduction) or asynchronous dual chamber pacing (forced RV apical 
pacing) during CMR. In a second study, patients with high degree AV block underwent a CMR 
at baseline and then again after 6-months 
2.2  
SCREENING FOR AND TREATING HEART FAILURE IN PATIENTS WITH 
PACEMAKERS IMPROVES OUTCOMES  
OPT-PACE 
(OPTimising 
PACEmaker 
therapy) was a multi-centre, randomised 
controlled 
trial 
enrolling 
people 
with 
pacemakers 
implanted 
for 
bradycardia. 
Participants 
were 
randomised 
1:1 
to 
echocardiography screening or usual care. 
For participants in the screening arm found to 
have LVSD (LVEF <50%), we then compared 
patients managed by their primary care 
physician with those managed in a combined 
heart failure and devices clinic. The primary 
outcome was the time to death or first 
hospitalisation due to heart failure. We randomized 1201 participants were randomised, 600 
to echocardiography screening and 601 to usual care. Patients in the echocardiography 
screening arm who were managed within a combined heart failure and devices clinic had 
better optimisation of medical therapy for heart failure and were at around a third lower risk of 
the combined primary endpoint (hazard ratio 0.67 [0.46-0.98]). 
2.3  
SUMMARY AND LIMITATIONS OF THE AVAIABLE EVIDENCE 
Pacemaker-associated heart failure with the most common long-term complication of 
pacemaker implantation. We now have robust evidence that show that echocardiography 
screening identifies heart failure in one third of patients attending routine pacemaker follow 
up, and that where this is identifies and then treated clinical outcomes are improved. However, 
this approach has limitations. First, an echocardiogram takes approximately 45 minutes to 
perform, analyse and report. Second, the technicians running the pacemaker clinics are not 
usually skilled in echocardiography. Third, each scan costs around £120, or approximately 
£540,000 to assess all 4,500 patients currently under the care of Leeds Teaching Hospitals 
Trust. A new approach is needed. 
 
3.  
HYPOTHESIS 
Figure: Screening for heart failure reduces the risk of all-
cause mortality or heart failure hospitalization (Paton et 
al. Nat Med. 2024 

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Artificial intelligence (AI) can detect pacemaker-associated heart failure with similar levels of 
accuracy compared to echocardiography. 
 
4.  
RESEARCH QUESTION 
4.1  
PRIMARY RESEARCH AIM 
To determine the accuracy of AI derived LVEF compared to standard cart-based 
echocardiography with left ventricular ejection fraction (LVEF - the percentage of blood 
pumped during each heart beat) measured by biplane method, assessed by correlation 
coefficient. 
 
4.2  
SECONDARY RESEARCH AIMS 
To determine the accuracy of AI determined abnormal left ventricular ejection fraction (LVEF 
<50%) compared to standard cart-based echocardiography measurement of LVEF <50% by 
biplane method, determined by sensitivity, specificity, positive and negative predictive values.  
To determine the incremental improvement of a model to predict LVEF <50% in a population 
with pacemakers of the addition of AI derived LVEF, point of care NT-proBNP, or both.  
To determine the proportion of participants in whom it was not possible to determine AI derived 
LVEF, LVEF measured by biplane method, or subjective visual estimation of LVEF. 
 
5. 
STUDY SETTING 
We will recruit potential participants from those attending routine pacemaker clinic follow-up 
at the Leeds Teaching Hospitals NHS Trust. All study procedures will be undertaken at the 
Leeds National Institute for Health and Care Research Cardiovascular Clinical Research 
Facility (CRF). The Leeds Cardiovascular CRF has facilities and equipment available for 
echocardiography and pacemaker interrogation, as well as appropriately trained staff to 
conduct the study procedures. 
 
6 
IDENTIFICATION OF POTENTIAL PARTICIPANTS 
6.1 
ELIGIBILITY CRITERIA 
We require patients to have standard pacemakers implanted for the management of 
bradycardia, and for at least 20% of heart beats to be paced (right ventricular pacing burden 
>20%) as these patients are at risk of developing pacemaker-associated heart failure. Patients 
with specialised types of pacemakers which reduce the risk of developing heart failure 
(conduction system pacemakers) or have been implanted for the management of known heart 
failure (cardiac resynchronisation therapy pacemakers/defibrillators, implantable cardioverter 
defibrillators) are not eligible for inclusion. 
 
6.2  
INCLUSION CRITERIA 
Adult patients aged ≥18 years. 
Patients with existing pacemakers who have a RV pacing burden ≥20%. 
Ability to provide informed consent. 
 
6.3 
EXCLUSION CRITERIA 
Patients who are unwilling or unable to provide informed consent. 
Patients known to have heart failure 
Patients with any previous measurement of LVEF <50%. 
Patients with conduction system pacemakers. 
Patients with cardiac resynchronisation therapy pacemakers/defibrillators. 
Patients with implantable cardioverter defibrillators. 
Patients with leadless pacemakers. 
 
7  
RECRUITMENT PROCESS 
7.1 
PARTICIPANT IDENTIFICATION 
To make participation as simple as possible, and to avoid unnecessary visits to the hospital, 
patients will be approached prior to their routine pacemaker clinic appointment. Patients who 

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have pacemakers attend the hospital every 6-12 months in person to undergo a check of their 
pacemaker’s battery life and functionality. All potential participants will be identified by a 
member the patient’s direct care team according to the study inclusion criteria. Potential 
participants will be sent an Invitation Letter and the Patient Information Sheet, offering them 
the opportunity to attend an appointment in the Leeds Cardiovascular Clinical Research 
Facility instead of their usual pacemaker clinic appointment. This will then be followed up by 
a telephone call from the direct care team, and only those who are potentially interested and 
confirm their agreement to have their information passed to the research team will be 
approached to arrange an appointment. 
 
7.2 
CONSENT PROCESS 
The Chief Investigator retains overall responsibility for the conduct of research at this site, this 
includes the receiving of informed consent of participants at the site. They must ensure that 
any person delegated responsibility to participate in the informed consent process is duly 
authorised, training and compete to participate according to the ethically approved protocol, 
principles of Good Clinical Practice (GCP) and Declaration of Helsinki.  
 
On the day of the appointment, a member of the research team will approach the patient, 
explain the study and offer the opportunity to ask questions. Participants will have already had 
at least one week to read the Participant Information Sheet and to consider whether they wish 
to take part. If willing to participate, they will then provide written consent to undertake the 
study procedures. All patients, regardless of whether they consent to participate in the 
research study, or not, will have a pacemaker safety check completed as part of their usual 
clinical care by an accredited cardiac physiologist. 
 
8.  
EXPERIMENTAL DESIGN 
A single centre, prospective, observational study enrolling patients with existing pacemakers. 
 
9.  
STUDY PROCEDURES 
9.1 
BASELINE STUDY PROCEDURES 
Participants will attend an appointment at the Leeds Cardiovascular Research Facility. They 
will have already received the Participant Information Sheet at least a week prior to their 
appointment, if willing to participate they will provide informed written consent. We will then 
collect demographic and clinical data from the participant’s electronic healthcare record prior 
to undergoing the study procedures. Participants will undergo a routine device interrogation 
by an accredited cardiac physiologist as per usual clinical care to confirm device functionality 
and RV pacing burden ≥20%.Participants will undergo point-of-care blood testing for NTpro-
BNP, a hand-held echocardiogram and a standard cart-based echocardiogram. The 
appointment is expected to last around one hour. Following the appointment a member of the 
research team will arrange their next scheduled pacemaker clinic appointment with their usual 
care team. 
 
9.2 
POINT OF CARE NTPRO-BNP BLOOD TESTING 
LumiraDx (LumiraDx Ltd, Cayman Islands) is a quantitative point-of-care, fingerpick blood test 
capable of measuring various biomarkers using a micro-sample of blood obtained from a 
finger prick. The LumiraDx can measure NTpro-BNP with only 20L of blood, is highly 
portable, with a turn-around time of only 12 minutes – feasible within the time constraints of a 
standard pacemaker follow-up appointment. Their technology has been validated in a study 
of 659 samples compared to gold-standard commercially available laboratory equipment 
(Roche Cobas Elecsys proBNP II assay) and found to have comparable accuracy (slope 0.86, 
intercept -4.12, r 0.97). 
 
9.3  
STANDARD CART-BASED CARDIAC ULTRASOUND 
participants will undergo a transthoracic echocardiogram by a senior cardiac physiologist 
accredited by the British Society of Echocardiography (or equivalent international body) using 

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a GE Healthcare Vivid E95 Ultra Edition Cardiac Ultrasound. A minimum dataset will be 
obtained with LVEF measured by the biplane method where possible, as well as assess for 
any (at least) moderate valvular disease or other finding which could result in a change to 
patient management. 
 
9.3 
HAND-HELD CARDIAC ULTRASOUND USING ARTIFICIAL INTELLIGENCE 
Participants will undergo a focussed hand-held echocardiogram with AI derived LVEF using 
the Kosmos platform (EchoNous Inc., Redmond, USA) a point-of-care, hand-held ultrasound 
device capable of cardiac imaging, which uses US2.AI (Ultrasound Anyone Anywhere, 
Singapore) integrated AI driven software capable of automated measurement of LVEF. 
Existing data suggest the Kosmos platform is able to reliably detect abnormal LVEF in patients 
referred with suspected heart failure, however there are no data describing its use in a 
population with pacing-induced LV dysfunction. Hand-held echocardiography will be done by 
a specialist nurse or cardiac physiologist who does not hold accreditation in echocardiography. 
 
10  
OUTCOMES 
10.1 
PRIMARY OUTCOME 
The accuracy of AI derived LVEF compared to standard cart-based echocardiography with 
LVEF measured by biplane method, assessed by correlation coefficient. 
 
10.2 
 SECONDARY OUTCOMES 
- The accuracy of AI derived LVEF <50% compared to standard cart-based echocardiography 
measurement of LVEF <50% by biplane method, determined by sensitivity, specificity, positive 
and negative predictive values.  
- The incremental improvement of a model to predict LVEF <50% in a population with 
pacemakers of the addition of AI derived LVEF, point of care NT-proBNP, or both.  
- The proportion of participants in whom it was not possible to determine AI derived LVEF, 
LVEF measured by biplane method, and subjective measurement of LVEF.  
 
10.3  SAFETY OUTCOMES 
- The proportion of patients with a new diagnosis of at least moderate valve disease, or any 
other echocardiography finding which resulted in a change to patient care. 
 
11.  
STATISTICAL ANALYSIS 
11.1  
POWER CALCULATIONS 
For this pilot study all analyses are exploratory, no statistical hypothesis has been prespecified 
and no formal sample size calculation has been performed. Based on previously published 
work assessing the accuracy of AI derived LVEF and sonographer determined LVEF we 
anticipate the inclusion of 150 participants would provide adequate statistical power to 
compare the two imaging modalities. 
 
11.2 
PRIMARY OUTCOME 
The comparison of AI derived LVEF and sonographer measured LVEF will be determined by 
correlation coefficient.  
 
11.3 SECONDARY OUTCOME 
The comparison of AI derived LVEF <50% will be reported as the sensitivity, specificity, positive 
and negative predictive values comparing sonographer measurement of LVEF <50% by cart-
based echocardiography. The improvement in the model will be reported as a comparison of 
the area under the curve comparing models with and without the addition of AI derived LVEF, 
alongside their 95% confidence intervals. The useable images and safety outcomes will be 
reported as proportions. 
 
11.4 DEFINITON OF THE END OF THE STUDY 
The end of the study will occur at the completion of the final participant’s research visit. 

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12  
ETHICAL AND REGULATORY CONSIDERATIONS 
All investigators and study site staff will comply with the requirements of the Data Protection 
Act 2018 with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
 
12.1 
ASSESSMENT AND MANAGEMENT OF RISK 
This study enhances usual clinical care, and it is likely that the intervention of 
echocardiographic screening will result in new findings and changes to patient management. 
One potential issue is the discovery of important heart muscle weakness, or other abnormal 
findings on echocardiography. All new findings will be reviewed by the Chief Investigator, or 
delegated to another Investigator in his absence, and managed according to current clinical 
practice recommendations. We will report as a safety outcome the proportion of patients with 
a new diagnosis of at least moderate valve disease, or any other echocardiography finding 
which resulted in a change to patient care - whether this be a change in treatment, or a referral 
for further tests. We will inform the patient's General Practitioner of any abnormal findings and 
the action we have taken as a result of this. Cardiac physiologists work within the National 
Health Service as technicians who perform echocardiography and as part of their role will 
interpret the images and measure heart structure and function. The Chief Investigator is a 
Cardiologist who is familiar with echocardiography and appropriately trained to interpret and 
action the results. Any changes to participant management will fall outside of this study, and 
the Chief Investigator will either action these changes himself, or refer to the clinical team 
within the National Health Service, as appropriate. 
 
12.2 
RESEARCH ETHICS COMMITTEE (REC) AND OTHER REGULARTORY REVIEW 
AND REPORTS 
Before the start of the study a favourable opinion will be sought from a REC for the study 
protocol, consent forms, and other relevant documents. Substantial amendments that require 
review by NHS REC will not be implemented until that review is in place. All correspondence 
with the REC will be retained. It is the Chief Investigator’s responsibility to produce the annal 
reports, as required. The Chief Investigator will notify the REC of the end of the study. If the 
study is ended prematurely, the Chief Investigator will notify the REC, including the reasons 
for the premature termination. Within one year after the end of the study, the Chief Investigator 
will submit a final report with the results, including any research outputs, to the REC. Before 
any patients are recruited, the Chief Investigator will ensure that appropriate approvals from 
participating organisations are in place. Specific arrangements on how to gain approval from 
participating organisations are in place and 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. It is a decision for the Sponsor as to whether an amendment is substantial or 
non-substantial. The Chief Investigator will work with the study site so they can put the 
necessary arrangements in place to implement the amendment to confirm their support for the 
study as amended. 
 
12.3 
PEER REVIEW 
The study rationale was reviewed by the Funder and externally by two independent, expert 
reviewers. The study protocol has been reviewed by the Sponsor, and independently by two 
members of the Leeds Cardiovascular Patient and Public Involvement and Engagement 
group. 
 
12.4 
PATIENT AND PUBLIC INVOLVEMENT AND ENGAGEMENT 
The study rationale was presented to the Leeds Cardiovascular Patient and Public 
Involvement and Engagement (PPIE) group. The group found the project interesting and that 
the study design would be acceptable to patients. The PPIE group advised participants were 

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 12
likely to wish to combine all study procedures within a single visit, although some may require 
a second visit if they did not have sufficient time on the day and should be offered this 
opportunity. The PPIE group agreed that the inclusion and exclusion criteria should be kept 
minimal to reflect the population with pacemakers. Two members of the Leeds Cardiovascular 
PPIE group agreed to review the Patient Information Sheet, Consent Form, and Invitation 
Letter in detail. Using their feedback, we ensured the information provided was succinct and 
easily understandable. The members suggested amendments so it was easily understandable 
to as wide a range of people as possible. In line with their guidance, we also provide large 
print versions of these documents and will make use of translation services available at the 
Trust where required. 
 
12.5 
PROTOCOL DEVIATION AND SERIOUS BREACHES 
All protocols deviations will be reported by Dr Sam Straw to the study sponsor (goverance-
ethics@leeds.ac.uk) within one working day of the research team’s awareness. All serious 
breaches of the protocol or Good Clinical Practice (a breach likely to affect to a significant 
degree the safety or physical or mental integrity of participants, or the scientific value of the 
research) will be reported to the study sponsor within one working day, and to the Research 
Ethics Committee within seven days. 
 
12.6  REPORTING OF ADVERSE EVENTS 
An Adverse Event (AE) is an untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurres which are not necessarily 
caused by or related to that product. 
An AE is therefore not anticipated to occur during this study, which is observational in nature. 
A Serious Adverse Event (SAE) is an untoward occurrence that either: 
- results in death 
- is life-threatening 
- requires hospitalisation or prolongation of existing hospitalisation 
- results in persistent or significant disability or incapacity 
- consists of a congenital anomaly or birth defect 
- is otherwise considered medically significant by the Investigator. 
A Related Unexpected Serious Adverse Event (RUSAE) is an event that meets the definition 
of serious and in the opinion of the Chief Investigator is: 
- related i.e. the event has occurred because of the research procedures 
- unexpected, i.e. the type of event is not listed in the protocol as an expected occurrence. 
 
The Chief Investigator will review all AEs occurring during the study visit within one working 
day to determine if they meet the definition of a SAE or RUSAE. Any SAE or RUSAE occurring 
in a research participant, where, in the opinion of the Chief Investigator the event was related 
to the administration of any of the research procedures will be reported to the Sponsor 
(governance-ethics@leeds.ac.uk) within one working day of the research team’s awareness. 
All RUSAEs will be reported to the REC within their required timeline of 15 days. 
 
The following information will be reported by the Chief Investigator to the Sponsor: 
- the full details of the SAE/RUSAE in medical terms 
- event duration (start and end dates, if applicable) 
- action taken 
- outcome 
- seriousness criteria 
- causality (i.e. relatedness to research investigation), in the opinion of the Chief Investigator 
- whether the event would be considered expected. 
 
Untoward events which occur after the study visit has been completed or are not directly 
related to the study visit will not be reported. It is anticipated that during this study we will 
identify important heart muscle weakness, or other abnormal findings on cardiac ultrasound. 

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These findings, and any untoward event which occur as a consequence of new 
diagnoses/findings (such as hospitalisation) will not be reported to the Sponsor or REC as 
these are regarded as being part of the patient’s usual clinical care. 
 
12.7  DATA PROTECTION AND PATIENT CONFIDENTIALITY 
All investigators and study site staff will comply with the requirements of the Data Protection 
Act 2018 with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. Identifiable patient data will be collected 
by members of the research team and stored on a secure NHS server for a maximum of 3-
years. We will collect demographic information, as well as access the electronic healthcare 
record to obtain information of relevant past medical history and currently prescribed 
medications. Raw image files obtained from echocardiography imaging studies will be stored 
on a secure NHS server for a maximum of 3-years. The fingerpick blood test obtained a small 
quantity of blood, which is transferred to a barcode chip. Following analysis the barcode chip 
is disposed of (in an appropriate biohazardous waste bin) so that no human tissue samples 
are stored. 
 
All potentially identifiable data will be accessible only to members of the study team. Where 
new diagnoses may result in changes to patient management, these data may be shared with 
other members of the clinical team at the Leeds Teaching Hospitals with the patient’s 
agreement. We will create a pseudonymisation key which will be stored on a secure NHS 
service for a maximum perform of 3-years. Only pseudoanonymised data (with a unique 
identifier) will be transferred to the University system for the purpose of statistical analysis. 
Consent forms will be stored in the site file located within a secured cabinet in the 
Cardiovascular Research Facility, Leeds General Infirmary – only accessible by members of 
the research team and stored for a maximum period of 3-years. For this study we will not 
collect data on future outcome events. Fully anonymised data will be stored for a maximum 
period of 7-years to allow adequate time for analysis and publication. 
 
12.8 
ACCESS TO THE FINAL STUDY DATASET 
The Chief Investigator and Co-Investigators will have access to the final study dataset. 
 
12.9 
SPONSOR INDEMNITY STATEMENT 
The University, when acting as Sponsor, has insurance cover in force, which meets claims 
against it and where those claims arise from the University’s own negligence in its role and 
activities relating to the study (and which is subject to the terms, conditions and exceptions of 
the relevant policy). Clinical negligence indemnification will rest with the participating NHS 
Trust under standard NHS arrangements. 
 
13  
EXPECTED VALUE 
We now have evidence that where pacing-associated heart failure is discovered and then 
treated with standard therapies, patient outcomes are improved. However, there remain 
significant barriers to implementing a screening program including cost, time, and staff training 
and skills. AI promises to streamline healthcare delivery and facilitate a screening program to 
detect pacing-associated heart failure embedded within the existing follow-up schedule for 
patients with pacemakers. 
 
14 
DISSEMINATION POLICY 
This is an investigator-initiated study. The protocol has been designed by the Investigators. 
No funders, industry partner or third party has been involved in the design of this study, nor 
will any third party have access to the data, contribute to manuscript preparation, or be 
involved in the decision to publish. On completion of the study, a study report will be prepared 
for dissemination at international cardiovascular conferences and submitted for publication in 
a peer-reviewed journal. Funding bodies will be acknowledged within the publication. All 

Straw S. OPT-AI. V1.0. Jun 2025. 2025-XXXXX. IRAS 347225. 
 14
participants will be informed of the results of the study, on completion, and will be forwarded 
a copy of the manuscript. 
 

Straw S. OPT-AI. V1.0. Jun 2025. 2025-XXXXX. IRAS 347225. 
 15
AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
1.1 
05/09/2025 
Dr Sam 
Straw 
To specify that in the absence of the 
Chief Investigator, the actioning of 
urgent findings would be delegated to 
another Investigator. 
 
 
 
 

Straw S. OPT-AI. V1.0. Jun 2025. 2025-XXXXX. IRAS 347225. 
 16
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