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

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.

Study Overview

• Status: Completed
• Conditions: Permanent Atrial Fibrillation
• Intervention / Treatment: Drug: Bisoprolol; Drug: Digoxin

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.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom
      • Queen Elizabeth Hospital
    • Birmingham, West Midlands, United Kingdom
      • City Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients aged 60 years or older, able to provide informed written consent
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

Exclusion Criteria:

1. Established indication for beta-blocker therapy, e.g. survived 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 <60 bpm
4. Known intolerance of beta-blockers or digoxin
5. A history of severe bronchospasm (e.g. due to asthma) that would preclude use of beta-blockers
6. Baseline heart rate <60 bpm
7. History of second or third-degree heart block
8. Supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation
9. Planned pacemaker implantation, pacemaker-dependent rhythm or history of atrioventricular node ablation
10. Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
11. A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
12. Received or on waiting list for heart transplantation
13. Initiation of cardiac resynchronization therapy (with/without defibrillator) within 6 months prior to randomisation
14. Intravenous infusions for heart failure (inotropes, vasodilators or diuretics) within 7 days prior to randomisation
15. A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
16. Received or on waiting list for heart transplantation
17. Receiving renal replacement therapy
18. Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
19. Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Beta-blocker; 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; Drug intervention
Active Comparator: Digoxin; 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; Drug intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Ejection Fraction	The above parameters will be measured using echocardiography and diastolic indices	12 months
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.	12 months
B-type Natriuretic Peptide (BNP) at 6 Months.	B-type natriuretic peptide (BNP) at 6 months.	6 months
Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.	Composite functional status measures- 6 minute walking distance at 12 months.	12 months
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.	12 months
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.	12 months
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	12 months
Ambulatory Heart-rate.	24 hour ambulatory heart-rate.	Within 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular Events	Number of Participants with hospital admissions for cardiovascular events.	12 months
Drug Discontinuation Rate	the number and extent to which patients discontinue trial drugs	12 months
Drug Discontinuation Rate Within 12 Months.	Number of participants requiring drug discontinuation due to adverse reactions.	12 months
Hospital Admission Rate	A composite of adverse clinical events	12 months
Retention of Participants	Convenience, compliance and cross-over data	12 months
Preferred Outcome Measures for This Cohort of Patients	Establish which are the best measures for these patients	12 months
Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.	SF-36 physical function score at 6 and 12 months	12 months
Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.	SF-36 overall score at 6 and 12 months	12 months
Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.	AFEQT overall score at 6 and 12 months	12 months
Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.	LVEF and E/e scores at 6 and 12 months	12 months
Number of Participants With Unplanned Hospital Admissions.	Number of Participants with Unplanned Hospital Admissions.	During the 12 month follow-up period.

Collaborators and Investigators

• Sponsor: University of Birmingham
• Investigators: Principal Investigator: Dipak Kotecha, MBChB PhD MRCP, University of Birmingham

Publications and helpful links

General 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2016
• Primary Completion (Actual): April 15, 2019
• Study Completion (Actual): September 16, 2019

Study Registration Dates

• First Submitted: February 27, 2015
• First Submitted That Met QC Criteria: March 12, 2015
• First Posted (Estimate): March 18, 2015

Study Record Updates

• Last Update Posted (Actual): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Quality of life; Beta-blockers; Echocardiography; Digoxin; Left ventricular ejection fraction; Diastolic function
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Digoxin; Bisoprolol
• Other Study ID Numbers: UBCCS_RATEAF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No