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

NCT02391337 | Completed Phase 4 Results DMC

• 1 other identifier: UBCCS_RATEAF
• Study Type: interventional
• Target: 161
• Locations: 1 country
• Sites: 2

Brief Summary

Atrial fibrillation is a common heart rhythm disturbance, causing important discomfort for patients, a high risk of stroke, frequent hospital admissions and a two-fold increase in death. The number of patients with this condition are expected to double in the next 20 years. Medications to control heart-rate are used in the majority of patients, although the choice of agent is often guided by local preference rather than evidence from controlled trials. Despite the fact that patients with atrial fibrillation have high rates of other cardiac conditions such as heart failure, clinicians have insufficient evidence to personalise the use of different therapies. This feasibility study will allow us to develop a range of methods that can characterise patients according to the pumping and relaxing function of the heart, the burden of symptoms and to identify new blood markers. In this way, the investigators hope to improve clinical practice guidelines, allowing doctors to prescribe appropriate treatments for the right patients. The research will be focused around a randomised trial of two medication strategies, providing much-needed data on the comparison of digoxin and beta-blockers (two commonly-used drugs in patients with atrial fibrillation). It will also allow us to identify the best way to record patient-reported quality of life and develop robust techniques to determine heart function using non-invasive imaging, facilitating the conduct of a large-scale clinical trial. The key objectives of the research programme are to define the optimal medications for patients with atrial fibrillation and identify the most valid, reproducible and cost-effective methods to examine patients. The ultimate aim of the project is to improve clinical outcomes in atrial fibrillation, benefiting patients, the National Health Service and the global community.

Conditions

Permanent Atrial Fibrillation

Keywords

Atrial fibrillation; Quality of life; Left ventricular ejection fraction; Diastolic function; Echocardiography; Beta-blockers; Digoxin

Outcome Measures

Primary Outcomes (1)

• Patient Reported Quality of Life (SF-36)

  Patient-reported outcomes as assessed by the SF-36 questionnaire physical component score. The physical component score ranges from 0-100 where higher value indicates better outcome.

  Primary outcome at 6 months timepoint.

Secondary Outcomes (8)

• Left Ventricular Ejection Fraction

  12 months

• Diastolic Function- Measured by the E/e'.

  12 months

• B-type Natriuretic Peptide (BNP) at 6 Months.

  6 months

• Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.

  12 months

• Patient Reported Outcomes- (AFEQT) at 12 Months.

  12 months

Other Outcomes (11)

• Cardiovascular Events

  12 months

• Drug Discontinuation Rate

  12 months

• Drug Discontinuation Rate Within 12 Months.

  12 months

Study Arms (2)

Beta-blocker

ACTIVE COMPARATOR

In Group B, oral bisoprolol will be commenced at either 1.25mg, 2.5mg or 5mg according to the treatment schedule and uptitrated, as required, to 15mg daily. Recommended additional therapy in this arm includes diltiazem. Use of digoxin is explicitly discouraged but will not terminate participation in the study. If intolerance to bisoprolol occurs, investigators will be advised to try an alternate beta-blocker of their choosing (typically carvedilol, nebivolol, or metoprolol) at equivalent dosage.

Drug: Bisoprolol

Digoxin

ACTIVE COMPARATOR

In Group A, the maintenance dose of oral digoxin will be either 62.5mcg or 125mcg according to the pre-defined treatment schedule and uptitrated, as required, to 250mcg daily. A single loading dose of four tablets (250 or 500mcg according to target maintenance dose) will be prescribed in digoxin-naïve participants, where necessary. Recommended additional therapy in this arm includes the calcium-channel blocker diltiazem. Use of beta-blockers is explicitly discouraged but will not terminate participation in the study.

Drug: Digoxin

Interventions

Bisoprolol DRUG

Drug intervention

Beta-blocker

Digoxin DRUG

Drug intervention

Digoxin

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients aged 60 years or older, able to provide informed written consent
• Permanent AF, characterised (at time of randomisation) as a physician decision for rate-control with no plans for cardioversion, anti-arrhythmic medication, or ablation therapy
• Symptoms of breathlessness (New York Heart Association Class II or more)
• Able to provide written, informed consent

You may not qualify if:

• Established indication for beta-blocker therapy, e.g. survived myocardial infarction in the last 6 months
• Known contraindications for therapy with beta-blockers or digoxin, e.g. a history of severe bronchospasm that would preclude use of beta-blockers, or known intolerance to these medications
• Baseline heart rate \<60 bpm
• Known intolerance of beta-blockers or digoxin
• A history of severe bronchospasm (e.g. due to asthma) that would preclude use of beta-blockers
• Baseline heart rate \<60 bpm
• History of second or third-degree heart block
• Supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation
• Planned pacemaker implantation, pacemaker-dependent rhythm or history of atrioventricular node ablation
• Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
• A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
• Received or on waiting list for heart transplantation
• Initiation of cardiac resynchronization therapy (with/without defibrillator) within 6 months prior to randomisation
• Intravenous infusions for heart failure (inotropes, vasodilators or diuretics) within 7 days prior to randomisation
• A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis

Sponsors & Collaborators

• University of Birmingham: lead

Study Sites (2)

City Hospital

Birmingham, West Midlands, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, West Midlands, United Kingdom

Location

Related Publications (6)

• Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014 Dec 20;384(9961):2235-43. doi: 10.1016/S0140-6736(14)61373-8. Epub 2014 Sep 2.

  PMID: 25193873 BACKGROUND

• Akoumianakis I, Gilligan LC, Bunting KV, Fobian D, Kirchhof P, Arlt W, Taylor AE, Pavlovic D, Kotecha D; Rate control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial team. Quantification and impact of circulating cardiotonic steroids in the RATE-AF randomised trial of patients with atrial fibrillation and heart failure. BMC Med. 2025 Dec 29;23(1):694. doi: 10.1186/s12916-025-04476-2.

  PMID: 41462450 DERIVED

• Abdali Z, Bunting KV, Mehta S, Camm J, Rahimi K, Stanbury M, Haynes S, Kotecha D, Jowett S. Cost-effectiveness of digoxin versus beta blockers in permanent atrial fibrillation: the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) randomised trial. Heart. 2025 Mar 26;111(8):362-369. doi: 10.1136/heartjnl-2024-324761.

  PMID: 39819610 DERIVED

• Gill SK, Barsky A, Guan X, Bunting KV, Karwath A, Tica O, Stanbury M, Haynes S, Folarin A, Dobson R, Kurps J, Asselbergs FW, Grobbee DE, Camm AJ, Eijkemans MJC, Gkoutos GV, Kotecha D; BigData@Heart Consortium; cardAIc group; RATE-AF trial team. Consumer wearable devices for evaluation of heart rate control using digoxin versus beta-blockers: the RATE-AF randomized trial. Nat Med. 2024 Jul;30(7):2030-2036. doi: 10.1038/s41591-024-03094-4. Epub 2024 Jul 15.

  PMID: 39009776 DERIVED

• Kotecha D, Bunting KV, Gill SK, Mehta S, Stanbury M, Jones JC, Haynes S, Calvert MJ, Deeks JJ, Steeds RP, Strauss VY, Rahimi K, Camm AJ, Griffith M, Lip GYH, Townend JN, Kirchhof P; Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Team. Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial. JAMA. 2020 Dec 22;324(24):2497-2508. doi: 10.1001/jama.2020.23138.

  PMID: 33351042 DERIVED

• Kotecha D, Calvert M, Deeks JJ, Griffith M, Kirchhof P, Lip GY, Mehta S, Slinn G, Stanbury M, Steeds RP, Townend JN. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial. BMJ Open. 2017 Jul 20;7(7):e015099. doi: 10.1136/bmjopen-2016-015099.

  PMID: 28729311 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Bisoprolol; Digoxin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Results Point of Contact

• Title: Prof. Dipak Kotecha
• Organization: University of Birmingham

d.kotecha@bham.ac.uk

+44 (0) 7974 115676

Study Officials

• Dipak Kotecha, MBChB PhD MRCP

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2015
• First Posted: March 18, 2015
• Study Start: December 20, 2016
• Primary Completion: April 15, 2019
• Study Completion: September 16, 2019
• Last Updated: June 18, 2021
• Results First Posted: June 16, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)