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

Phase 4

Completed

Conditions: Permanent Atrial Fibrillation

Interventions: Drug: Bisoprolol
Drug: Digoxin

Registration Number: NCT02391337

Lead Sponsor: University of Birmingham

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 161

Inclusion Criteria

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

Exclusion Criteria

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
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Beta-blocker	Bisoprolol	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.
Digoxin	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.

Primary Outcome Measures

Name	Time	Method
Patient Reported Quality of Life (SF-36)	Primary outcome at 6 months timepoint.	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.

Secondary Outcome Measures

Name	Time	Method
Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.	12 months	Composite functional status measures- 6 minute walking distance at 12 months.
Left Ventricular Ejection Fraction	12 months	The above parameters will be measured using echocardiography and diastolic indices
B-type Natriuretic Peptide (BNP) at 6 Months.	6 months	B-type natriuretic peptide (BNP) at 6 months.
Patient Reported Outcomes (EQ-5D-5L)	12 months	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
Ambulatory Heart-rate.	Within 12 months	24 hour ambulatory heart-rate.
Patient Reported Outcomes- (AFEQT) at 12 Months.	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.
Patient Reported Outcomes (SF36) Version 2 at 12 Months.	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.
Diastolic Function- Measured by the E/e'.	12 months	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.