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Permanent Atrial FibrillationPhase 4RATE-AFNCT02391337

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

A Phase 4 study testing Bisoprolol and Digoxin in people with Permanent Atrial Fibrillation, run by University of Birmingham at 2 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 60 years and older
Conditions the study is for
Permanent Atrial Fibrillation
What is being tested?
Bisoprolol and Digoxin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
161 participants
Where
2 sitesUnited Kingdom
Study dates
20 Dec 2016to 16 Sep 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 19Show fewer
  • 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
  • Received or on waiting list for heart transplantation
  • Receiving renal replacement therapy
  • Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
  • Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy

Trial locations and contacts

2 sites in 1 country.

United Kingdom2 sites
  • City Hospital

    Birmingham, West Midlands

  • Queen Elizabeth Hospital

    Birmingham, West Midlands

Other trials in United Kingdom

About this study

Official title: Evaluating Different Rate Control Therapies in Permanent Atrial Fibrillation: A Prospective, Randomised, Open-label, Blinded Endpoint Feasibility Pilot Comparing Digoxin and Beta-blockers as Initial Rate Control Therapy

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.

Read the detailed description

Atrial fibrillation (AF) is an increasingly common cardiac condition that leads to a substantial burden on quality-of-life (QoL), an increased risk of cardiovascular events, hospitalisation and death, and significant healthcare costs for the NHS. In addition to anti-coagulation and considerations for rhythm control therapy, most patients with AF are in need of pharmacological control of heart rate. This aspect of care has not received stringent investigation, with treatment guidelines based on small crossover studies and observational data rather than robust controlled trials. Beta-blocker monotherapy remains the first-line option in the current NICE AF guidelines consultation document, with digoxin only for sedentary patients, although this recommendation is based on 'very low-quality evidence'. The benefit of different rate-control therapies on symptoms and other intermediate outcomes (such as left-ventricular ejection fraction [LVEF] and diastolic function) are unknown, as are their effects on clinical events such as hospitalisation. This situation is unacceptable in light of the potential benefits and risk of different rate-control options in AF. It also limits our ability to personalise treatment according to patient characteristics.

The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial is informed by a number of in-depth systematic reviews of management and clinical outcomes in AF patients. Taken together, this information provides a sound basis to plan a major randomised controlled trial (RCT). However as trials of rate-control in AF have typically been small or uncontrolled, further information is needed before designing a trial that can assess clinical outcomes. The RATE-AF trial will allow us to define appropriate primary and secondary outcome measures and their standard deviation in a contemporary population of patients with permanent AF. This information will allow us to estimate sample size, determination of recruitment, retention and adherence policies, and to ascertain the best methods of obtaining adverse event data and reliable economic costs for a larger trial assessing cardiovascular outcomes and hospitalization. The RATE-AF trial will also be the largest RCT of its kind, allowing us to compare the effect of beta-blockers and digoxin on QoL as initial rate-control therapy in patients with permanent AF. The long-term aim of the research is to answer key questions about how to initiate therapy, stratified by relevant patient characteristics such as systolic and diastolic cardiac function, baseline symptoms and concurrent medication. The research will also define the patho-physiological mechanisms underlying AF-related symptoms, left-ventricular function and their association with adverse clinical outcomes, and to identify clinical markers for the response to different rate control therapy.

Being tested
Bisoprolol, Digoxin
Keywords
Atrial fibrillation, Quality of life, Left ventricular ejection fraction, Diastolic function, Echocardiography, Beta-blockers, Digoxin
Medical subject headings
Atrial Fibrillation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BisoprololDrug

    Drug intervention

  • DigoxinDrug

    Drug intervention

Study groups in NCT02391337
Study groupRoleWhat they receive
Beta-blockerActive comparatorIn 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.
Receives: Drug: Bisoprolol
DigoxinActive comparatorIn 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.
Receives: Drug: Digoxin

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Primary outcome at 6 months timepoint.

Secondary outcomes (8)
  1. Left Ventricular Ejection Fraction

    The above parameters will be measured using echocardiography and diastolic indices

    Measured: 12 months

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

    The above parameters will be measured using echocardiography and diastolic indices.

    E/e' - the ratio between early mitral inflow velocity and mitral annular early diastolic velocity.

    Measured: 12 months

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

    B-type natriuretic peptide (BNP) at 6 months.

    Measured: 6 months

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

    Composite functional status measures- 6 minute walking distance at 12 months.

    Measured: 12 months

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

    As assessed using the AFEQT overall score at 12 months. The range for AFEQT overall score is from 0= complete disability to 100=no disability.

    Measured: 12 months

  6. Patient Reported Outcomes (SF36) Version 2 at 12 Months.

    As assessed using the SF-36 version 2 global and specific scores at 12 months. All domains presented are between 0 to 100 scale where the higher score indicates better outcomes.

    Measured: 12 months

  7. Patient Reported Outcomes (EQ-5D-5L)

    As assessed using the EQ-5D-5L summary index questionnaires at both 6 and 12 months.

    The range for summary index is from -0.594=worst score to 1=best score

    Measured: 12 months

  8. Ambulatory Heart-rate.

    24 hour ambulatory heart-rate.

    Measured: Within 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Mar 2015 (estimated)
  2. Study start20 Dec 2016
  3. Primary completion15 Apr 2019
  4. Study completion16 Sep 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
161 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02391337
Sponsor's protocol ID
UBCCS_RATEAF
Acronym
RATE-AF
Status last verified
Jun 2021
First submitted
27 Feb 2015
Last updated
18 Jun 2021
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 25193873
  • 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.

    PubMed 41462450
  • 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.

    PubMed 39819610
  • 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.

    PubMed 39009776
  • 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.

    PubMed 33351042
  • 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.

    PubMed 28729311

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Bisoprolol and Digoxin in people with Permanent Atrial Fibrillation, run by University of Birmingham at 2 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Patient Reported Quality of Life (SF-36) (time frame: Primary outcome at 6 months timepoint.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02391337, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2021.

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