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

Educational Objective
To learn the effects of low-dose digoxin vs bisoprolol or an alternate β-blocker with respect to quality-of-life outcomes in patients with permanent atrial fibrillation and symptoms of heart failure.

1 Credit CME

JAMA

Published Online: December 22/29, 2020

Original Investigation

Article Information and Disclosures

Dipak Kotecha, MD, PhD, MSc^1,2,3;

Karina V. Bunting, PhD, MSc^1,2;

Simrat K. Gill, MD, MPharm^1,2;

et al

Samir Mehta, MSc⁴;

Mary Stanbury⁵;

Jacqueline C. Jones⁵;

Sandra Haynes, MBE, MBA⁵;

Melanie J. Calvert, PhD^3,6,7;

Jonathan J. Deeks, PhD, MSc, CStat^4,6;

Richard P. Steeds, MD, MA^1,2;

Victoria Y. Strauss, PhD, MSc⁸;

Kazem Rahimi, DM, MSc⁹;

A. John Camm, MD¹⁰;

Michael Griffith, MD^1,2;

Gregory Y. H. Lip, MD^11,12;

Jonathan N. Townend, MD^1,2;

Paulus Kirchhof, MD^1,13,14;

for the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Team

Author Affiliations

¹Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, England
²University Hospitals Birmingham NHS Foundation Trust, Birmingham, England
³Centre for Patient Reported Outcomes Research, University of Birmingham, Birmingham, England
⁴Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England
⁵Patient and Public Involvement Team, RATE-AF Trial, West Midlands, England
⁶NIHR Biomedical Research Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, England
⁷Birmingham Health Partners Centre for Regulatory Science and Innovation, Birmingham, England
⁸Medical Sciences Division, University of Oxford, Oxford, England
⁹Deep Medicine, Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, England
¹⁰Cardiology Clinical Academic Group Molecular and Clinical Sciences Institute, St George's University of London, London, England
¹¹Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, England
¹²Thrombosis Research Unit, Aalborg University, Aalborg, Denmark
¹³University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
¹⁴Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, England

Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Teamfor the

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Key Points

Question 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?

Findings 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.

Meaning There was no statistically significant difference in patient-reported quality of life; the findings support potentially basing decisions about treatment on other end points.

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

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Article Information

Corresponding Author: Dipak Kotecha, MD, PhD, MSc, Institute of Cardiovascular Sciences, University of Birmingham Medical School, Vincent Drive, Birmingham B15 2TT, England (d.kotecha@bham.ac.uk).

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.

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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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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

Digitalis Glycosides for Heart Rate Control in Atrial Fibrillation

Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation—Reply

Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation

AMA CME Accreditation Information

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

Digitalis Glycosides for Heart Rate Control in Atrial Fibrillation

Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation—Reply

Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation

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