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

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.

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