Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE-AF randomized clinical trial

Rate Control Therapy Evaluation in Permanent 13 Atrial Fibrillation (RATE-AF) team, Dipak Kotecha, Karina Bunting, Simrat Gill, Samir Mehta, Mary Stanbury, Jackie Jones, Sandra Haynes , Melanie Calvert, Jon Deeks, Richard P Steeds, Victoria Y Strauss , Kazem Rahimi, A John Camm, Michael Griffith, Gregory Lip, Jonathan N Townend, Paulus Kirchhof

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Importance: There is little evidence to support selection of rate-control therapy in the growing population with permanent atrial fibrillation (AF), in particular those with coexisting heart failure.

Objective: To compare low-dose digoxin with beta-blockers.

Design, Setting, and Participants: Randomized, open-label, blinded end-point trial of 160 patients aged ≥60 years with permanent AF, defined as no plans to restore sinus rhythm, and at least NYHA class II dyspnea; recruitment from 3 hospitals and primary care in England 2016-2018, with last follow-up October 2019.

Interventions: 1:1 randomization to digoxin (n=80; 62.5-250mcg daily; mean 161mcg) or bisoprolol (n=80; 1.25-15mg daily; mean 3.2mg).

Main Outcomes and Measures: The primary endpoint was patient-reported quality of life using the SF36 Physical Component Summary (PCS) at 6-months (higher better; range 0-100), with a minimal clinically-important difference of 0.5 SD. There were 17 and 20 secondary endpoints at 6 and 12-months respectively, including other QoL outcomes, heart rate, modified European Heart Rhythm Association (mEHRA) symptom classification and NTpro-B-type natriuretic peptide (BNP); in addition to adverse event reporting.

Results: Among 160 patients (mean age, 75.6 years; 74 (46%) women; mean baseline heart rate, 100 [18] beats/min), 145 (91%) completed the trial and 150 (94%) completed were included in the analysis for the primary endpointoutcome. Baseline heart rate was 100±18 beats/min, with no significant difference between groups at any time-point. There was no significant difference in the primary outcome: normalized SF36-PCS at 6-months 31.9±11.7 for digoxin and 29.7±11.4 for beta-blockers; adjusted mean difference 1.4, -1.1 to 3.8; p=0.28. Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (76.9 [12.1] with digoxin vs 74.8 [11.6] with bisoprolol; difference 1.5 beats/min, 95% CI -2.0 to 5.1; p=0.40). Of the 17 secondary comparisons at 6-months, only mEHRA class was significantly different between groups, with 53% reporting a two-class improvement with digoxin, versus 9% for beta-blockers (adjusted OR 10.3, 4.0-26.6; p<0.001). By 12-months, 8 of 20 outcomes were significantly different (all favoring digoxin), with median NTproBNP 960 pg/mL (626-1531) with digoxin and 1250 pg/mL (847-1890) with beta-blockers; ratio 0.77, 0.64-0.92; p=0.005. Twelve outcomes were not significantly different between groups, including resting heart rate (75.4 [9.9] with digoxin vs 74.3 [11.2] with bisoprolol; difference, 0.3 beats/min, 95% CI -3.0 to 3.5; p=0.87).By 12-months, 8/20 outcomes were significantly different (all favoring digoxin) and 12 null. Median NTproBNP was 960 pg/mL in the digoxin group (626-1531) and 1250 pg/mL for beta-blockers (847-1890); ratio 0.77, 0.64-0.92; p=0.005. Adverse events were less common with digoxin, with 20 patients (25%) having at least one event versus 51 (64%) for beta-blockers (p<0.001). The total number of adverse and serious adverse events was 29 and 16 for digoxin, versus 142 and 37 for beta-blockers.

Conclusion and relevance: Among patients aged 60 and older with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support basing decisions about treatment on other endpoints.

Trial registration: clinicaltrials.gov NCT02391337; ISRCTN 95259705; EudraCT 2015-005043-13.
Original languageEnglish
Pages (from-to)2497-2508
Number of pages12
JournalJAMA The Journal of the American Medical Association
Issue number24
Publication statusPublished - 22 Dec 2020


  • Adrenergic beta-1 Receptor Antagonists/therapeutic use
  • Aged
  • Aged, 80 and over
  • Anti-Arrhythmia Agents/adverse effects
  • Atrial Fibrillation/complications
  • Bisoprolol/adverse effects
  • Digoxin/adverse effects
  • Female
  • Heart Failure/complications
  • Heart Rate/drug effects
  • Humans
  • Male
  • Middle Aged
  • Quality of Life
  • Single-Blind Method
  • Stroke Volume


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