Title: Optimising rate-control therapy in older patients with AF – a training fellowship and pilot study focused on improving quality of life
Funder: Department of Health and Social Care

Abstract: Background: Atrial fibrillation (AF) is a common heart rhythm disturbance, causing impaired quality-of-life (QoL), a high risk of stroke, frequent hospitalisations and a two-fold increase in death. Co-existing systolic and diastolic heart failure are common, with both AF and heart failure labelled as cardiovascular epidemics of the 21st century. The majority of patients with AF require control of heart-rate, but there is almost no evidence from clinical trials to guide the choice of medication. This limits an informed decision on rate-control therapy. Beta-blockers are often favoured over digoxin in clinical practice due to a presumption of improved prognosis, but they have well-established side effects. My recent work has shown that beta-blockers do not improve prognosis in patients with AF and heart failure, with further pilot data confirming that digoxin does not adversely affect mortality. Hence, there is clear equipoise and a need to compare the impact of different medications, providing an evidence-base for rate-control therapy that reduces symptoms and improves QoL. Plan of Investigation: I propose a controlled pilot trial in patients with permanent AF in need of rate-control, recruited mainly from referrals to secondary care and boosted using primary care Participant Identification Centres. 160 participants will be enrolled into a prospective, randomised, open-label, blinded end-point trial. Participants will receive digoxin or beta-blockers as the initial rate-control agent, with protocol-defined uptitration and additional medication. The primary outcome will be patient-reported QoL, with exploration of ventricular function using ultrasound echocardiography. Additional outcomes will address functional capacity, surrogate markers of clinical prognosis and hospital admission. Follow-up will occur at 6 and 12 months, with specific feasibility components to inform the design of a future large-scale trial assessing QoL, hospitalisation and adverse events. Objectives: The fellowship will be used to plan and execute a pilot study with the following objectives: (1) Provide training in advanced clinical trial methodology to position me as a future leader in this field; (2) Identify appropriate patient-reported outcomes, including the delivery, acceptability and responsiveness of questionnaires using quantitative and qualitative methods; (3) Examine the validity and reproducibility of different cardiac imaging methods for determining left-ventricular systolic and diastolic function in AF; (4) Establish a biobank of AF-specific biomarkers, including genetic determinants, to generate data on personalised rate-control therapy; (5) Derive processes for a subsequent trial, including recruitment, adherence and cross-over rates, economic costs, and the standard deviation of outcome measures. Anticipated benefits: There is a clear gap in the current evidence-base relating to the use of rate-control agents and their effect on symptoms, heart function and clinical outcomes. I aim to identify relevant and valid patient-reported outcomes and define the best method to determine left-ventricular function in AF patients. In the longer-term, I will provide clinicians with evidence-based protocols for safe and cost-effective rate-control. This award will also allow me to conduct exploratory analyses towards stratified rate-control therapy, in concert with local research efforts towards personalised AF management. The Fellowship will deliver a greater understanding of the mechanisms and pathophysiology of symptoms in this co-morbid, elderly and increasingly common patient-group. Improving treatment strategies in AF has the potential for substantial benefit to patients, the NHS and global healthcare agencies. This includes individualisation of management, potentially avoiding adverse treatment effects and reducing the cost to the NHS, as well as improving and simplifying the use of cardiac imaging. With regards to training, I have constructed a comprehensive plan with broad experience including local and international collaborators, aimed at developing my skills and becoming an independent researcher. This includes practical and theoretical training in clinical trials, advanced statistics, large national registries and robust assessment of patient-reported outcome measures.

Lay abstract: Atrial fibrillation (AF) is a common heart condition that causes an irregular and often rapid heart rate. The lifetime risk of developing AF in adults is 1 in 4 and we can expect twice as many people to have this disease over the next 20 years. Patients are typically elderly and often have a number of other medical conditions, including high blood pressure and heart problems. AF causes every 4th stroke and patients with AF suffer from frequent hospital admissions and early death. In addition, AF makes many patients feel unwell and unhappy, with reduced quality of life.An important component of AF treatment is the control of rapid heart rates, which can be achieved with different medications. However we currently lack evidence for the best rate-controlling drugs, making it difficult to choose the right medication for individual patients. This leads to side effects and contributes to reduced quality of life in AF patients. My previous work has highlighted that commonly-used rate-control medications have little effect on reducing the risk of death and so improving symptoms and quality of life is of major importance. Clinical trials test new or existing medications to see if they are safe and effective. This award is designed to compare two strategies of rate-control, based either on initial treatment with digoxin or beta-blockers. 160 patients with AF in need for rate-control therapy will be randomly assigned to these two treatments which are frequently used in clinical practice. The primary focus of the Fellowship is to generate evidence-based research on the effect of treatment on quality of life in patients with AF. We will test whether the quality of life questionnaires are appropriate and responsive to the change in symptoms experienced by patients. The Fellowship will also explore how we use cardiac ultrasound to look at the function of the heart, as well as blood markers and the need for admission to hospital. Taken together, this information will allow me to plan a larger clinical trial that will determine the best and most cost-effective rate-control strategy for AF patients, with the aim of improving quality of life and reducing hospital admissions. The potential benefit of this project for patients and the NHS is substantial, providing evidence on whether particular drugs lead to better quality of life. As around a million people in UK have this condition, the impact of even small improvements in quality of life is huge, both for individual patients and society. Although the proposed trial is a pilot study, it will be the largest head-to-head comparison of rate-control treatments in patients with AF to-date. The Fellowship aims to develop our ability to tailor treatment to the needs of individual patients based on their symptoms, health status and heart function. It will provide the groundwork for a larger study to inform national health policy. Importantly, this process will provide me with the skills and training to become a future leader in AF research, with studies designed to improve patient care in the NHS.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR