Is there a difference in patient-reported quality of life among patients with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and symptoms of heart failure treated with digoxin or bisoprolol (a β-blocker) for heart rate control?
This randomized clinical trial included 160 adults aged 60 years or older with atrial fibrillation and symptoms of heart failure randomized to digoxin (mean attained dose, 161 μg/d) vs bisoprolol (mean attained dose, 3.2 mg/d). At 6 months, the mean 36-Item Short Form Health Survey physical component summary scores (higher scores are better) were 31.5 for the digoxin group vs 29.3 for the bisoprolol group, a difference that was not statistically significant.
There was no statistically significant difference in patient-reported quality of life; the findings support potentially basing decisions about treatment on other end points.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Dipak Kotecha, MD, PhD, MSc, Institute of Cardiovascular Sciences, University of Birmingham Medical School, Vincent Drive, Birmingham B15 2TT, England (firstname.lastname@example.org).
Accepted for Publication: November 6, 2020.
Author Contributions: Dr Kotecha and Mr Mehta had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Kotecha, Mehta, Stanbury, Jones, Haynes, Calvert, Deeks, Steeds, Strauss, Griffith, Lip, Kirchhof.
Acquisition, analysis, or interpretation of data: Kotecha, Bunting, Gill, Mehta, Calvert, Deeks, Steeds, Strauss, Rahimi, Camm, Griffith, Townend, Kirchhof.
Drafting of the manuscript: Kotecha, Bunting, Gill, Mehta, Steeds.
Critical revision of the manuscript for important intellectual content: Kotecha, Bunting, Gill, Stanbury, Jones, Haynes, Calvert, Deeks, Steeds, Strauss, Rahimi, Camm, Griffith, Lip, Townend, Kirchhof.
Statistical analysis: Mehta, Deeks, Strauss.
Obtained funding: Kotecha, Calvert, Griffith, Lip.
Administrative, technical, or material support: Kotecha, Bunting, Gill, Stanbury, Jones, Haynes, Rahimi, Griffith.
Supervision: Kotecha, Deeks, Steeds, Camm, Lip, Townend, Kirchhof.
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.
Funding/Support: The RATE-AF trial was funded by the National Institute for Health Research as part of a career development fellowship (CDF-2015-08-074) awarded to Dr Kotecha. The study was also supported by a British Heart Foundation accelerator award (AA/18/2/34218) given to the University of Birmingham Institute of Cardiovascular Sciences.
Role of the Funder/Sponsor: The National Institute for Health Research and the British Heart Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
The Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Team: In addition to the named authors, the team included: Patience Domingos, RN (Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, England); Margaret Grant, PhD, Emma Hayes, Hannah Watson, Sukhi Sehmi, Rebekah Wale, and Gemma Slinn, MPhil (Birmingham Clinical Trials Unit, Birmingham, England); Susan Jowett, PhD, and Jonathan Mathers (Institute of Applied Health Research, University of Birmingham, England); Victoria Stoll (University Hospitals Birmingham NHS Foundation Trust, Birmingham, England); and the research nursing staff at the Birmingham National Institute for Health Research/Wellcome Trust Clinical Research Facility (Birmingham Health Partnership).
Disclaimer: The opinions expressed in this article are those of the authors and do not represent the British Heart Foundation, the National Institute for Health Research, or the UK Department of Health and Social Care.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We are indebted to the patients and their families who dedicated their time to take part in National Health Service research. We thank the independent members of the trial oversight committees and the patient and public involvement team.
Additional Information: A summary of the results for patients (written by the patient and public involvement team) appears on the trial website at https://www.birmingham.ac.uk/rate-af.
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