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

Permanent Atrial Fibrillation Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02391337
• Other study ID #: UBCCS_RATEAF
• Status: Completed
• Phase: Phase 4
• Start date: December 20, 2016
• Est. completion date: September 16, 2019

Study information

• Verified date: June 2021
• Source: University of Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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 information / eligibility

• Status: Completed
• Enrollment: 161
• Est. completion date: September 16, 2019
• Est. primary completion date: April 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Permanent Atrial Fibrillation

Intervention

Drug:
• Bisoprolol
Drug intervention
• Digoxin
Drug intervention

Locations

Country	Name	City	State
United Kingdom	City Hospital	Birmingham	West Midlands
United Kingdom	Queen Elizabeth Hospital	Birmingham	West Midlands

Sponsors (1)

Lead Sponsor	Collaborator
University of Birmingham

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

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 ß 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cardiovascular Events	Number of Participants with hospital admissions for cardiovascular events.	12 months
Other	Drug Discontinuation Rate	the number and extent to which patients discontinue trial drugs	12 months
Other	Drug Discontinuation Rate Within 12 Months.	Number of participants requiring drug discontinuation due to adverse reactions.	12 months
Other	Hospital Admission Rate	A composite of adverse clinical events	12 months
Other	Retention of Participants	Convenience, compliance and cross-over data	12 months
Other	Preferred Outcome Measures for This Cohort of Patients	Establish which are the best measures for these patients	12 months
Other	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
Other	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
Other	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
Other	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
Other	Number of Participants With Unplanned Hospital Admissions.	Number of Participants with Unplanned Hospital Admissions.	During the 12 month follow-up period.
Primary	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	Left Ventricular Ejection Fraction	The above parameters will be measured using echocardiography and diastolic indices	12 months
Secondary	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
Secondary	B-type Natriuretic Peptide (BNP) at 6 Months.	B-type natriuretic peptide (BNP) at 6 months.	6 months
Secondary	Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.	Composite functional status measures- 6 minute walking distance at 12 months.	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Ambulatory Heart-rate.	24 hour ambulatory heart-rate.	Within 12 months