Rate control therapy evaluation in atrial fibrillation

Plain English Summary

Background and study aims
Atrial fibrillation (AF) is a common heart condition that around 1 in 4 adults are at risk of developing. It is caused by a fault in the electrical control centre in the heart which is found in the upper right chamber (right atrium), causing it to fire erratically. These uncoordinated signals cause the heart to beat irregularly and often very fast (arrhythmia). Sufferers are typically elderly and often have a number of other medical conditions, including high blood pressure and heart failure. In addition, AF is a common cause of stroke, hospital admissions and early death, and leads to reduced quality of life. An important part of AF treatment is the control of heart rate however evidence as to which medication is the best for rate-control is and whether it can improve quality of life or heart function is currently lacking. The aim of this study is to find out which, of two treatments (digoxin or bisoprolol), improves quality of life and heart function.

Who can participate?
Adults aged 60 and over who have AF, symptoms of breathlessness, and ability to provide written, informed consent.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group are treated with digoxin through a drip once a day for 12 months. Those in the second group are treated with bisoprolol through a drip once a day for 12 months. In both groups, the dosage will vary depending on each participant’s clinical need. At the start of the study and then after 6 and 12 months, participants in both groups complete a number of questionnaires to assess their quality of life, heart monitoring to assess their heart function and blood testing to see how well their bodies are responding to treatment.

What are the possible benefits and risks of participating?
Although there may be no direct benefit to those participating, it is hoped that this study will benefit all future patients with atrial fibrillation. Patient will benefit from being seen more regularly than normal because they are taking part in a study and will have access to the expert study team. There is a small risk that having to take part in the questionnaires, tests and visits to the hospital might be an inconvenience. There is also a small risk of bruising or discomfort during blood tests.

Where is the study run from?
The study is run from Queen Elizabeth Hospital, Sandwell and West Midlands Hospital and Heartlands Hospital and takes place at general practitioners' practices in the Birmingham area (UK)

When is the study starting and how long is it expected to run for?
March 2016 to December 2019

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Dr Dipak Kotecha
d.kotecha@bham.ac.uk

Trial website

www.birmingham.ac.uk/rate-af

Type

Scientific

Primary contact

Dr Dipak Kotecha

ORCID ID

http://orcid.org/0000-0002-2570-9812

Contact details

Institute of Cardiovascular Sciences
University of Birmingham
Medical School
Vincent Drive
Birmingham
B15 2TT
United Kingdom
+44 (0)7974 115676
rate-af@trials.bham.ac.uk

EudraCT number

2015-005043-13

ClinicalTrials.gov number

Protocol/serial number

32563

Scientific title

Evaluating different rate control therapies in permanent atrial fibrillation: a prospective, randomised, open-label, blinded endpoint study comparing digoxin and beta-blockers as initial rate control therapy. RAte control Therapy Evaluation in permanent Atrial Fibrialltion (RATE-AF)

Acronym

RATE-AF

Study hypothesis

The aim of this study is to compare two strategies of rate-control in patients with atrial fibrillation (AF), based either on initial treatment with digoxin or beta-blockers.

Ethics approval

East Midlands - Derby Research Ethics Committee, 18/07/2016, ref: 16/EM/0178

Study design

Randomised; Interventional; Design type: Treatment, Process of Care, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Specialty: Cardiovascular disease, Primary sub-specialty: Other; UKCRC code/ Disease: Cardiovascular/ Other forms of heart disease

Intervention

Participants are be randomised to one of two groups in a 1:1 ratio by a computer generated and stratified minimisation algorithm:
Group 1: Participants receive Digoxin 62.5 – 250 micrograms once daily uptitrated according to response and symptoms.
Group 2: Participants receive Bisoprolol 1.25 – 15 mg once daily uptitrated according to response and symptoms.
Patients in both groups will remain on treatment for 12 months as part of the trial.

The trial is testing the initial randomisation to either a digoxin or beta-blocker strategy. In both groups, additional therapy will likely be needed over the course of the trial.

Follow-up takes place at 6 and 12 months, and involves quality of life measurement, heart ultrasound (echocardiography), blood tests and assessment of function (questionnaires and a walking test).
Most patients will continue their treatment after the trial, according to their needs.

Intervention type

Other

Phase

Phase IV

Drug names

Primary outcome measure

Patient-reported quality of life is measured using the SF-36 physical component summary score at baseline and 6 months

Secondary outcome measures

1. Patient-reported quality of life is measured using SF-36 global and domain-specific scores, EQ-5D-5L summary index and visual analogue scale and AFEQT overall score at baseline, 6 and 12 months
2. Cardiac function is assessed by measuring echocardiographic left ventricular ejection fraction and diastolic function (E/e’ and composite of diastolic indices) at baseline and 12 months
3. Six-minute walking distance is measured at baseline, 6 and 12 months
4. European Heart Rhythm Association (EHRA) functional class information is checked at baseline, 6 and 12 months
5. B-type natriuretic peptide (BNP) levels and other biomarkers of treatment response are measured using blood testing at baseline, 6 and 12 months
6. Heart rate control is measured using 24-hour ambulatory ECG at approximately 3 months

Overall trial start date

23/03/2016

Overall trial end date

31/12/2019

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Adult patients aged 60 years or older
2. 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
3. Symptoms of breathlessness (New York Heart Association Class II or more)
4. Able to provide written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 160; UK Sample Size: 160

Participant exclusion criteria

Current exclusion criteria as of 22/06/2018:
1. Established clinical indication for beta-blocker therapy, e.g. myocardial infarction in the last 6 months
2. 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
3. Baseline heart rate history of atrioventricular node ablation
4. History of second or third-degree heart block
5. Supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation
6. Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
7. A current diagnosis of obstructive hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
8. Received or on waiting list for heart transplantation
9. Receiving renal replacement therapy
10. Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
11. Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy

Previous exclusion criteria:
1. Established clinical indication for beta-blocker therapy, e.g. myocardial infarction in the last 6 months
2. 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
3. Baseline heart rate history of atrioventricular node ablation
4. Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
5. A current diagnosis of obstructive hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
6. Received or on waiting list for heart transplantation
7. Receiving renal replacement therapy
8. Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
9. Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy

Recruitment start date

05/12/2016

Recruitment end date

02/10/2018

Countries of recruitment

United Kingdom

Trial participating centre

Queen Elizabeth Hospital
University Hospital Birmingham NHS Trust Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Trial participating centre

City Hospital
Sandwell and West Birmingham Hospitals NHS Trust Dudley Road
Birmingham
B18 7QH
United Kingdom

Trial participating centre

Sandwell General Hospital
Sandwell and West Birmingham Hospitals Lyndon
West Bromwich
B71 4HJ
United Kingdom

Trial participating centre

Birmingham Heartlands Hospital
Bordesley Green East
Birmingham
B9 5SS
United Kingdom

Organisation

University of Birmingham

Sponsor details

Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 8165
researchgovernance@contacts.bham.ac.uk

Sponsor type

Hospital/treatment centre

Website

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Publication and dissemination plan

The Chief Investigator will coordinate dissemination of data from this trial (likely publication mid-2019). All publications and presentations, including abstracts, relating to the main trial will be authorised by the RATE-AF Trial Management Group. The results of the analysis will be published in the name of the RATE-AF Collaborative Group in a peer reviewed journal (provided that this does not conflict with the journal’s policy). Named authors must satisfy the International Committee of Medical Journal Editors (ICMJE) criteria for authorship (contribute to drafting of the article or revision for important intellectual content), provide timely approval of the final version to be published and supply detailed statements on any potential conflict of interest or financial relationship (http://www.icmje.org/). Members of the group who do not fulfil ICMJE criteria for authorship will be listed in the article appendix. Trial participants will be sent a lay summary of the final results of the trial, which will contain a reference to the full paper.

IPD Sharing plan:
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/01/2020

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

2017 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/28729311

Publication citations

11/10/2018: The recruitment end date has been changed from 31/07/2018 to 02/10/2018. 22/06/2018: The following changes have been made: 1. The recruitment end date has been changed from 31/03/2018 to 31/07/2018. 2. Birmingham Heartlands Hospital has been added as a trial centre. 3. The intention to publish date has been changed from 31/07/2019 to 31/01/2020. 4. The overall trial end date has been changed from 31/08/2019 to 31/12/2019. 5. The participant exclusion criteria have been changed. 6. The plain English summary has been updated to reflect the above changes. 25/07/2017: Publication reference added.