Title: IMPRESS-AF: IMproved exercise tolerance in heart failure with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation
Funder: Medical Research Council

Abstract: We hypothesise that in patients with permanent atrial fibrillation treatment with spironolactone will improve exercise tolerance as a surrogate for cardiovascular mortality/morbidity (primary outcome), and will improve quality of life and diastolic function, as well as reduce the rate of all-cause hospital admissions (secondary outcomes). In our local epidemiological screening study (SAFE), the prevalence of atrial fibrillation was 4.7% in general practice in people aged 65 years or more. A third of atrial fibrillation patients suffer symptomatic heart failure, of which most have heart failure with preserved ejection fraction. This puts patients with atrial fibrillation under very high risk of developing of heart failure irrespectively of their systolic function. The targeted patients represent about 3.0% of the UK population 65 years and older and about 1.6% of the population aged 50 years and older (based on the West Birmingham Atrial Fibrillation project). Despite preservation of ejection fraction, morbidity, quality of life and mortality in heart failure with preserved ejection fraction are generally similar impaired to those in heart failure with reduced ejection fraction. Furthermore, improvements in morbidity and mortality with conventional treatments used in heart failure with reduced ejection fraction have not translated to heart failure with preserved ejection fraction. Hence, patients with atrial fibrillation are very commonly encountered in the NHS; they often develop heart failure despite having preserved ejection fraction and require a better understanding of the disease mechanisms and prognostically relevant therapeutic options. Left ventricular diastolic filling is often compromised due to abnormal active and/or passive relaxation (increased cardiac stiffness, may be due to changes in myocardial collagen and development of fibrosis). Aldosterone has profibrotic properties and may contribute to increased left ventricular stiffness in patients with atrial fibrillation eventually leading to heart failure with preserved ejection fraction. This study aims to determine whether the aldosterone antagonist, spironolactone improves exercise tolerance and quality of life compared to placebo (on top of the current guideline-recommended optimised medical care in both groups) in patients with permanent atrial fibrillation and preserved cardiac contractility. We will test the study hypotheses by conducting a double-blind randomised clinical trial in symptomatic participants with permanent atrial fibrillation with preserved left ventricular systolic function and normal levels of the brain natriuretic peptide to ensure homogeneity of the study population. The patients will be randomised to 2-year treatment with spironolactone vs. placebo (both added to the current optimised care). The primary outcome will be exercise tolerance (peak VO2 on cardio-pulmonary exercise testing at 2 years). Secondary outcomes will be (i) exercise tolerance measured by 6-minute walk test (a simple test of exercise performance), (ii) health-related quality of life (assessed using the validated Minnesota Living with Heart Failure [MLWHF] and EuroQol EQ-5D [EQ-5D] questionnaires self-completed by patients), and (iii) left ventricular diastolic function (E/e’ on echocardiography) will be assessed at baseline and at 2 years; also (iv) rates of all-cause hospitalisations during 2-year follow-up.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR