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

Abstract

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 To compare the effect of digoxin versus beta-blockers on systolic and diastolic cardiac function according to heart failure sub-type. Methods 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%). Results 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 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. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research