Spironolactone to improve exercise tolerance in people with permanent atrial fibrillation and preserved ejection fraction: the IMPRESS-AF RCT
Authors: Shantsila Eduard , Shahid Farhan , Sun Yongzhong , Deeks Jonathan J , Haynes Ronnie , Calvert Melanie , Fisher James P , Kirchhof Paulus , Gill Paramjit S , Lip Gregory YH 
Published: July 2020

Introduction
Patients with atrial fibrillation frequently suffer from heart failure despite having a normal ejection fraction. There is no proven therapy to improve physical capacity and quality of life in patients with permanent atrial fibrillation with preserved cardiac contractility.

Objective
The IMproved exercise tolerance in heart failure with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation (IMPRESS-AF) trial addressed whether or not 2 years of treatment with spironolactone, as compared with placebo, improves exercise tolerance, quality of life and diastolic function in patients with permanent atrial fibrillation and preserved left ventricular ejection fraction.

Design
A randomised, single-centre, double-blind, placebo-controlled trial.

Setting
Two hundred and fifty ambulatory patients [mean age 72.3 years (standard deviation 7.4 years); 23.6% female] with permanent atrial fibrillation and left ventricular ejection fraction ≥ 55% [mean 60.5% (standard deviation 5.5%)].

Interventions
Treatment with either 25 mg of spironolactone (n = 125) or placebo (n = 125) daily.

Main outcome measures
The primary efficacy end point was exercise tolerance at 2 years as measured by peak oxygen consumption (VO2) on cardiopulmonary exercise testing. Secondary end points were quality of life, the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E′) (E/E′; a marker of diastolic dysfunction), all-cause hospital admissions and spontaneous return to sinus rhythm. Treatment effects were estimated by adjusting for baseline values.

Study ethics
The study was approved by the National Research and Ethics Committee West Midlands – Coventry and Warwickshire (reference 14/WM/1211). All patients provided informed written consent.

Results
There was no difference in the peak oxygen consumption at 2 years between the spironolactone group [analysed, n = 103; mean VO2 14.03 ml/minute/kg (standard deviation 5.38 ml/minute/kg)] and the placebo group [analysed, n = 106; mean VO2 14.45 ml/minute/kg (standard deviation 5.14 ml/minute/kg)] (adjusted treatment effect –0.28 ml/minute/kg, 95% confidence interval –1.27 to 0.71 ml/minute/kg; p = 0.58). The findings were consistent across all sensitivity analyses. For secondary efficacy end points, there was no significant change in the mean 6-minute walking distance (treatment effect –8.47 m, 95% confidence interval –31.87 to 14.93 m; p = 0.48). This also held true for the mean ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E′) (i.e. E/E′), a measure of left ventricular diastolic function (treatment effect –0.64, 95% confidence interval –1.48 to 0.20; p = 0.13). The study treatment was also not associated with a significant treatment effect for quality-of-life scores [p = 0.67 for the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), questionnaire and p = 0.84 for the Minnesota Living with Heart Failure (MLWHF) questionnaire at 2 years]. The findings remained consistent after adjustment for age, sex and body mass index. Spontaneous return to sinus rhythm on electrocardiography, performed at 2 years, was uncommon in both study groups [4% (standard deviation 3.8%) in the placebo group and 8% (standard deviation 7.9%) in the spironolactone group; p = 0.21]. At least one hospitalisation for any reason was required by 15.3% of patients in the spironolactone group and 22.8% in the placebo group (p = 0.15; after adjustment for age, sex and body mass index, p = 0.12). The estimated glomerular filtration rate was reduced by 6 ml/minute/1.73 m2 at 2 years in patients allocated to spironolactone (with no reduction in those receiving placebo, resulting in a reduction in the p-value of the difference in the estimated glomerular filtration rate between patients in the spironolactone group and those in the placebo group of < 0.001).

Limitations
This was a relatively small study.

Conclusions
Spironolactone therapy does not improve exercise capacity, cardiac function or quality of life in patients with atrial fibrillation and preserved ejection fraction.

Future work
Further testing of spironolactone in patients with atrial fibrillation and preserved ejection fraction would be difficult to justify.

Trial registration
Current Controlled Trials ISRCTN10259346, European Union Clinical Trials Register 2014-003702-33 and ClinicalTrials.gov NCT02673463.

Funding
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 4. See the NIHR Journals Library website for further project information. This project received support from the NIHR Clinical Research Network.