Digoxin improves systolic cardiac function in patients with AF and HFpEF: the RATE-AF randomised trial

Abstract

Background: The RAte control Therapy Evaluation in permanent AF trial (RATE-AF; NCT02391337) was the first head-to-head controlled trial of beta-blockers versus digoxin in patients with permanent atrial fibrillation (AF) and symptoms of heart failure. Patients randomised to digoxin had similar physical-related quality of life and heart rate, with significantly improved functional class, reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) and substantially less adverse events. The impact of rate control therapy on measures of cardiac function is not currently understood. Purpose(s): To compare the effect of digoxin versus beta-blockers on systolic and diastolic cardiac function according to heart failure sub-type. Method(s): Blinded echocardiograms assessing systolic and diastolic function were performed at baseline and 12 month follow-up, using a robust method to account for rhythm irregularity (average of three index-beats acquired in appropriate cardiac cycles). Outcomes were the change in left-ventricular ejection fraction (LVEF), systolic tissue Doppler velocity (s'), stroke volume, global longitudinal strain (GLS), diastolic tissue Doppler (e'), mitral E wave deceleration time, E/e', pulmonary vein diastolic deceleration time, isovolumic relaxation time and left atrial ejection fraction. Analyses were stratified by baseline LVEF (>=50%, 40-50% and <40%). Result(s): 160 patients were randomised, of which 145 patients survived to 12-month follow-up with median age 75 years (IQR 69-82) and 44% women. Median baseline heart rate was 96 beats/min (IQR 86-112), blood pressure 135/85 mmHg (IQR 124/77-146/91), NTproBNP 1049 pg/mL (744-1463) and mean NYHA class 2.4 (SD 0.6). In 119 patients with LVEF >=50% at baseline, diastolic and systolic parameters improved over time with digoxin therapy. There was a significantly greater improvement in systolic function in 63 patients on digoxin compared to 67 with beta-blockers; Figure 1. Patients randomised to digoxin had a higher LVEF at follow-up (adjusted mean difference [AMD] 2.3%, 95% CI 0.3-4.2; p=0.021), higher s' (1.1cm/s, 1.0-1.2; p=0.003) and higher stroke volume (6.5mL, 0.4-12.6; p=0.037) compared to beta-blockers, without any difference in diastolic parameters (Figure 2). In 16 patients with LVEF 40-50% at baseline, s' significantly increased with digoxin compared to beta-blockers (AMD 1.5 cm/s, 1.2-1.7; p=0.001), with no difference for other systolic or diastolic parameters. 10 patients with LVEF <40% at baseline showed no difference between digoxin and beta-blockers for any echocardiographic measures. Conclusion(s): Patients randomised to digoxin with permanent AF, heart failure symptoms and preserved LVEF have significantly greater improvement in multiple parameters of systolic function compared to conventional treatment with beta-blockers.