Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial

Abstract

Importance: There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure.

Objective: To compare low-dose digoxin with bisoprolol (a β-blocker).

Design, setting, and participants: Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019.

Interventions: Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d).

Main outcomes and measures: The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting.

Results: Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group.

Conclusions and relevance: Among patients 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 potentially basing decisions about treatment on other end points.

Trial registration: ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kotecha reported receiving grants from the National Institute for Health Research, the British Heart Foundation, the European Union-European Federation of Pharma Industries and Associations Innovative Medicines Initiative BigData@Heart, the European Society of Cardiology (in collaboration with Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, Bayer, Daiichi-Sankyo, and Boston Scientific), and the IRCCS San Raffaele/Menarini Research; and receiving personal fees from Bayer, AtriCure, Amomed, and Myokardia. Dr Gill reported receiving grants from BigData@Heart. Dr Calvert reported receiving grants from the National Institute for Health Research, Health Data Research UK, Macmillan Cancer Support, UCB Pharma, and Innovate UK; and receiving personal fees from Astellas, Takeda, Merck, GlaxoSmithKline, Daiichi-Sankyo, Glaukos, and the Patient-Centered Outcomes Research Institute. Dr Strauss reported receiving grants from Amgen and the Research for Patient Benefit program of the National Institute for Health Research. Dr Rahimi reported receiving grants from the British Heart Foundation, the National Institute for Health Research, the Oxford Biomedical Research Centre, the Oxford Martin School, and the UK Research and Innovation Global Challenge Research Fund; and receiving personal fees from BMJ Heart and PLOS Medicine. Dr Camm reported receiving grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, and Daiichi-Sankyo; and receiving personal fees from Boston Scientific and Abbott. Dr Lip reported receiving personal fees paid to his institution from Bayer/Janssen, Bristol-Myers Squibb-Pfizer Alliance, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo; and receiving speaker’s fees from Bayer, Bristol-Myers Squibb-Pfizer Alliance, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. Dr Kirchhof reported receiving grants and nonfinancial support from the European Union BigData@Heart, the British Heart Foundation, the German Ministry of Education and Research, the Leducq Foundation, the UK Medical Research Council, and the German Centre for Cardiovascular Research; and being the inventor on 2 patents held by University of Birmingham for atrial fibrillation therapy and markers for atrial fibrillation. No other disclosures were reported.

Figures

Figure 1.. Study Enrollment and Analysis in the RATE-AF Trial of Digoxin vs Bisoprolol for Atrial Fibrillation

aNew York Heart Association class I indicates no limitation of physical activity, with ordinary physical activity not causing undue fatigue, palpitation, or dyspnea; class II, slight limitation of physical activity, comfortable at rest, but ordinary physical activity resulting in fatigue, palpitation, or dyspnea; class III, marked limitation of physical activity, comfortable at rest, but less than ordinary activity causing fatigue, palpitation, or dyspnea; and class IV, unable to carry out any physical activity without discomfort, symptoms of heart failure at rest, and if any physical activity is undertaken, discomfort increases. bRandomization included minimization to balance sex and modified European Heart Rhythm Association class at baseline. One person withdrew after randomization before receiving any therapy. cOr another β-blocker if patient had an intolerance to bisoprolol. dOne patient completed only 35 of 36 elements of the 36-Item Short Form Health Survey at 12 months.

Figure 2.. Change in Symptom Classification

The modified European Heart Rhythm Association (EHRA) score ranks atrial fibrillation (AF)–related symptoms and the effect these have on the patient’s daily life into 5 classes, ranging from asymptomatic (class 1) to disabling (class 4). The modified score subdivides class 2 into “a” (not troubling) and “b” (troubling) to identify patients in need of further intervention. The Sankey plots for participants that attended the 6-month follow-up are displayed with bars proportional to the number of patients in each modified EHRA class at that time point. There were no patients with a modified EHRA class 1 score at baseline in either randomized group. Comparisons of modified EHRA class were made using ordinal logistic regression across all categories for digoxin vs bisoprolol. The adjusted odds ratio at 6 months was 0.12 (95% CI, 0.06-0.25; P < .001) and at 12 months was 0.16 (95% CI, 0.08-0.33; P < .001). An odds ratio of less than 1 indicates superiority of digoxin at both time points. Data on the change in New York Heart Association class during the study appear in eFigure 5 in Supplement 3.