Clinical trial NCT02391337: Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Permanent Atrial Fibrillation
Keywords: Atrial fibrillation
Quality of life
Left ventricular ejection fraction
Diastolic function
Echocardiography
Beta-blockers
Digoxin
Lead sponsor: University of Birmingham
Sponsor class: OTHER
First posted: 2015-03-18
Enrollment: 161
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Patient Reported Quality of Life (SF-36)
timeFrame: Primary outcome at 6 months timepoint.
Secondary outcomes:
measure: Left Ventricular Ejection Fraction
timeFrame: 12 months
measure: Diastolic Function- Measured by the E/e'.
timeFrame: 12 months
measure: B-type Natriuretic Peptide (BNP) at 6 Months.
timeFrame: 6 months
measure: Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.
timeFrame: 12 months
measure: Patient Reported Outcomes- (AFEQT) at 12 Months.
timeFrame: 12 months
measure: Patient Reported Outcomes (SF36) Version 2 at 12 Months.
timeFrame: 12 months
measure: Patient Reported Outcomes (EQ-5D-5L)
timeFrame: 12 months
measure: Ambulatory Heart-rate.
timeFrame: Within 12 months
Other outcomes:
measure: Cardiovascular Events
timeFrame: 12 months
measure: Drug Discontinuation Rate
timeFrame: 12 months
measure: Drug Discontinuation Rate Within 12 Months.
timeFrame: 12 months
measure: Hospital Admission Rate
timeFrame: 12 months
measure: Retention of Participants
timeFrame: 12 months
measure: Preferred Outcome Measures for This Cohort of Patients
timeFrame: 12 months
measure: Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
timeFrame: 12 months
measure: Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
timeFrame: 12 months
measure: Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
timeFrame: 12 months
measure: Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
timeFrame: 12 months
measure: Number of Participants With Unplanned Hospital Admissions.
timeFrame: During the 12 month follow-up period.
Locations:
city: Birmingham
country: United Kingdom
facility: City Hospital
state: West Midlands
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
Study officials:
affiliation: University of Birmingham
name: Dipak Kotecha, MBChB PhD MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.