Title: Identifying patients at risk of pacemaker-induced progressive cardiac dysfunction and the advantages of personalised programming in long-term pacemaker patients.
Funder: Health Education England

Abstract: Background: Pacemaker implantation is a common and safe procedure that is life-saving in some patients and is associated with improved quality of life. Around 350,000 people in the UK have a pacemaker and annually 40,000 new pacemakers are implanted. The most frequent long-term complication of right ventricular (RV) pacemaker therapy is left ventricular (LV) systolic dysfunction (LVSD), seen in ~40% of patients. It is thought that dyssynchrony as a result of RV pacing leads to adverse LV remodeling which frequently progresses to LVSD, but there are no longitudinal studies in patients with existing devices demonstrating this. My study will describe factors predicting progressive LVSD, and demonstrate the merit of careful personalised programming limiting pacing on LV function and battery longevity in patients with long-term pacemakers. Aims: I will: 1) determine the incidence, potential predictors and degree of progressive remodeling in patients with long-term standard pacemakers; 2) establish whether remodeling can be reversed or prevented by personalised programming 3) determine the effects on battery longevity of personalised programming Question to be answered: Is pacemaker-associated LV remodelling progressive, and is it possible to reverse or prevent further progression? Plan of investigation: The project consists of two workstreams: Workstream 1: Between 2008 and 2012, 535 patients with existing pacemakers scheduled for battery replacement attended the research unit and underwent clinical assessment and echocardiography. In February 2016 56% of these patients are alive. I will invite ~200 (66%) of this cohort for a repeat scan, quality of life assessment (EQ-5D-5L), blood tests and pacemaker check. I will report these scans without knowledge of the results of the previous scan and compare the two. I will then be able to describe whether LV remodeling in response to RV pacing is progressive, the degree of this progression and associated factors. Workstream 2: Patients (n=70) with long-term (>2 years) permanent pacemakers with avoidable RV pacing will be invited to participate in a single-centre, phase II, randomised, double-blind placebo-controlled trial of optimised pacing programming versus standard care. Those randomised to the intervention arm will have personalised programming to avoid RV pacing, whilst those allocated to standard care will have no programming changes made. All participants will be invited back at 6 months for a repeat echocardiogram, quality of life assessment (EQ-5D-5L), blood tests and pacemaker check. Potential benefits to patients and the NHS: Heart failure (HF) is associated with a poor quality of life, frequent hospitalisations and increased mortality. Around 40% of pacemaker patients have LVSD or HF and cross-sectional studies have described that the amount of RV pacing required is associated with the prevalence and severity of these conditions. It is unknown whether the deterioration in LV function is progressive. Furthermore, no placebo-controlled study has demonstrated whether personalised reprogramming to avoid RV pacing is acceptable to patients, safe or leads to preservation or improved LV function. There is therefore no accepted strategy to avoid RV pacing and tailored reprogramming is rarely undertaken. Patients are frequently offered alternative more complex and more expensive pacing strategies which can improve heart function and symptoms, but are associated with significantly more complications (15%). The amount of pacing delivered (percentage of pacemaker-induced heart beats) has the greatest influence on battery longevity. Careful programming has the additional, underappreciated (and poorly investigated) benefit of extending battery longevity, which is a priority for patients and could improve the cost-effectiveness of all pacemakers. My project will provide the means to stratify patients' risk of developing progressive pacing-related LVSD, determine the underlying mechanisms and demonstrate the benefits of personalised programming. It therefore has the potential to benefit patients and also be cost-saving to the NHS.

Lay abstract: Aim: To describe what predicts heart muscle weakness in patients who have had a pacemaker for a long time and show the benefits of personalised pacemaker settings. Background: Pacemakers are a common treatment for slow heartbeats. In the UK 350,000 people have a pacemaker, and each year another 40,000 receive them. Having a pacemaker is a safe procedure but a paced heartbeat is not a normal heartbeat it is detuned' - and over time, this can cause heart muscle weakness and lead to heart failure. Knowing whether a patient is at higher risk of pacemaker-associated heart muscle weakness and how this is likely to progress over time would allow treatment to be started earlier. Many pacemaker patients use their pacemaker for at least 40% of their heartbeats. These people are more likely to have heart muscle weakness. However, we know that by personalising pacemaker settings, we can lower the amount of paced heartbeats for many people, which can improve heart muscle function without affecting quality of life. The most common question asked by pacemaker patients is how long their pacemaker battery has left. Personalising pacemaker settings reduces the amount of paced heartbeats, so may extend the battery life. This is important because many patients with pacemakers are older and because of their age, around 1 in 5 pacemaker patients have a battery replacement in what turns out to be the last year of their life, so if we could extend their pacemaker battery we might save some people from an operation altogether. Design: My proposal has two sections: 1) Identify factors predicting whether a pacemaker patient will develop heart muscle weakness 2) Describe whether reducing the amount of paced heart beats improves heart muscle function and extends battery life without affecting quality of life Methods: 1) I will invite all approximately 200 pacemaker patients who participated in a study between 2008-2012 to return to Leeds NIHR Cardiovascular Clinical Research Facility around the time of their usual annual pacemaker check. I will check their pacemaker, perform an ultrasound scan of their heart, blood tests, and ask them to fill in a quality of life questionnaire. 2) I will randomly allocate approximately 70 patients into two groups. Group 1 will continue with their normal pacemaker settings and group 2 will receive personalised pacemaker settings to minimise their use of the pacemaker. Neither I nor the patient will know whether their settings have changed. I will invite all patients back after 6 months for a repeat ultrasound scan, blood tests, quality of life questions, and a pacemaker check which will include an estimate of remaining battery life. PPI: I have designed my study with the help of patients and their carers. I described my project at the patient-public involvement meeting at the Cardiovascular Clinical Research Facility at Leeds General Infirmary on the 16th March 2016. This meeting was attended by 19 patients, 5 carers or family members, two retired GPs and local heart failure nurses along with the research staff. They felt that the project would be very worthwhile and practical to do. The patients, two of whom had pacemakers, agreed that the single most frequent question they asked during follow-up visits was how long their battery would last. They were particularly interested in the potential of personalising pacemaker settings to extend battery life. They thought avoiding an operation as long as possible would be a powerful benefit and incentive. A small group met with me later in the month to review the patient information sheets. Dissemination: Once I have the results I will publish them in a well-known scientific journal which has a specific focus on heart conditions to target colleagues. I will present a poster of the findings at conferences focussed on heart devices and heart conditions here in the UK and abroad. There are also a number of patient groups and charities interested in the results who I will work with to inform patients.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR