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

• Sponsor: University of Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT02391337
• Collaborator: (none)
• Enrollment: 161
• Locations: 2
• Arms: 2
• Actual Duration (Months): 32.9
• Patients Per Site: 80.5
• Patients Per Site Per Month: 2.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Permanent Atrial Fibrillation	Drug: Bisoprolol; Drug: Digoxin	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 161 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Dec 20, 2016
• Actual Primary Completion Date: Apr 15, 2019
• Actual Study Completion Date: Sep 16, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. Left Ventricular Ejection Fraction [12 months]

   The above parameters will be measured using echocardiography and diastolic indices

2. 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.

3. B-type Natriuretic Peptide (BNP) at 6 Months. [6 months]

   B-type natriuretic peptide (BNP) at 6 months.

4. Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months. [12 months]

   Composite functional status measures- 6 minute walking distance at 12 months.

5. 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.

6. 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.

7. 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

8. Ambulatory Heart-rate. [Within 12 months]

   24 hour ambulatory heart-rate.

Other Outcome Measures

1. Cardiovascular Events [12 months]

   Number of Participants with hospital admissions for cardiovascular events.

2. Drug Discontinuation Rate [12 months]

   the number and extent to which patients discontinue trial drugs

3. Drug Discontinuation Rate Within 12 Months. [12 months]

   Number of participants requiring drug discontinuation due to adverse reactions.

4. Hospital Admission Rate [12 months]

   A composite of adverse clinical events

5. Retention of Participants [12 months]

   Convenience, compliance and cross-over data

6. Preferred Outcome Measures for This Cohort of Patients [12 months]

   Establish which are the best measures for these patients

7. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [12 months]

   SF-36 physical function score at 6 and 12 months

8. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [12 months]

   SF-36 overall score at 6 and 12 months

9. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [12 months]

   AFEQT overall score at 6 and 12 months

10. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [12 months]

    LVEF and E/e scores at 6 and 12 months

11. Number of Participants With Unplanned Hospital Admissions. [During the 12 month follow-up period.]

    Number of Participants with Unplanned Hospital Admissions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City Hospital	Birmingham	West Midlands	United Kingdom
2	Queen Elizabeth Hospital	Birmingham	West Midlands	United Kingdom

Sponsors and Collaborators

• University of Birmingham

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jul 25, 2019
• Statistical Analysis Plan - Dec 17, 2019

More Information

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 β 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.

• Responsible Party: University of Birmingham
• ClinicalTrials.gov Identifier: NCT02391337
• Other Study ID Numbers: UBCCS_RATEAF
• First Posted: Mar 18, 2015
• Last Update Posted: Jun 18, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Birmingham: Atrial fibrillation; Quality of life; Left ventricular ejection fraction; Diastolic function; Echocardiography; Beta-blockers; Digoxin
• Additional relevant MeSH terms: Atrial Fibrillation; Digoxin; Bisoprolol

Study Results

Participant Flow

Recruitment Details	The trial opened for recruitment in December 2016 and the first participant was randomised on the 20th December 2016 and the last participant was randomised on the 1st October 2018. A total of 161 participants were randomised into the trial with 1 centre recruiting patients into the trial.
Pre-assignment Detail	A total of 390 were screened for the trial, of these screened 161 were randomised.

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Period Title: Baseline
STARTED	80	81
COMPLETED	80	81
NOT COMPLETED	0	0
Period Title: Baseline
STARTED	80	81
COMPLETED	74	76
NOT COMPLETED	6	5
Period Title: Baseline
STARTED	74	76
COMPLETED	72	73
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Beta-blocker	Digoxin	Total
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention	Total of all reporting groups
Overall Participants	80	81	161
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	76.8 (8.1)	74.4 (8.4)	75.6 (8.3)
Sex: Female, Male (Count of Participants)
Female	38 47.5%	36 44.4%	74 46%
Male	42 52.5%	45 55.6%	87 54%
Race/Ethnicity, Customized (Count of Participants)
White - English / Welsh / Scottish / Northern Iris	66 82.5%	72 88.9%	138 85.7%
White-Irish	8 10%	4 4.9%	12 7.5%
Asian / Asian British - Indian	2 2.5%	3 3.7%	5 3.1%
Asian / Asian British - Pakistani	3 3.8%	0 0%	3 1.9%
Black / African / Caribbean / Black British- African	1 1.3%	0 0%	1 0.6%
Black / African / Caribbean / Black British - Caribbean	0 0%	2 2.5%	2 1.2%
Region of Enrollment (participants) [Number]
United Kingdom	80 100%	81 100%	161 100%
Creatinine (Micromol/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Micromol/l]	91.4 (23.1)	87.9 (25.1)	89.6 (24.1)
On anticoagulant before randomisation (Count of Participants)
No	17 21.3%	9 11.1%	26 16.1%
Yes	63 78.8%	72 88.9%	135 83.9%
EHRA class (Count of Participants)
EHRA Class 1	0 0%	0 0%	0 0%
EHRA Class 2a	3 3.8%	3 3.7%	6 3.7%
EHRA Class 2b	40 50%	35 43.2%	75 46.6%
EHRA Class 3	27 33.8%	38 46.9%	65 40.4%
EHRA Class 4	10 12.5%	5 6.2%	15 9.3%
NYHA class (Count of Participants)
Class I	0 0%	0 0%	0 0%
Class II	53 66.3%	47 58%	100 62.1%
Class III	24 30%	32 39.5%	56 34.8%
Class IV	3 3.8%	2 2.5%	5 3.1%
Previous diagnosis of heart failure? (Count of Participants)
No	56 70%	46 56.8%	102 63.4%
Yes	24 30%	35 43.2%	59 36.6%
Any signs of heart failure at baseline (Count of Participants)
No	45 56.3%	32 39.5%	77 47.8%
Yes	35 43.8%	49 60.5%	84 52.2%
Type I diabetes (Count of Participants)
No	80 100%	81 100%	161 100%
Yes	0 0%	0 0%	0 0%
Type II diabetes (Count of Participants)
No	58 72.5%	65 80.2%	123 76.4%
Yes	22 27.5%	16 19.8%	38 23.6%
Unplanned admission for AF or HF in last 12 months (Count of Participants)
No	65 81.3%	65 80.2%	130 80.7%
Yes	15 18.8%	16 19.8%	31 19.3%
Any previous cardioversions (Count of Participants)
No	71 88.8%	74 91.4%	145 90.1%
Yes	9 11.3%	7 8.6%	16 9.9%
Previously undergone AF ablation (Count of Participants)
No	79 98.8%	79 97.5%	158 98.1%
Yes	1 1.3%	2 2.5%	3 1.9%
Previous history of anti-arrhythmic drugs (Count of Participants)
No	72 90%	75 92.6%	147 91.3%
Yes	8 10%	6 7.4%	14 8.7%
Baseline NTproBNP (pg/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pg/mL]	1040.5	1091	1057
Radial artery heart rate (bpm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [bpm]	86.9 (10.3)	87.8 (12)	87.4 (11.2)
Apex beat heart rate (bpm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [bpm]	99 (16.8)	98.3 (15.1)	98.7 (15.9)
12-Lead ECG Heart Rate (bpm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [bpm]	99.2 (19.2)	100.3 (16.8)	99.7 (18)
Systolic BP (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	137.1 (17.5)	134.5 (14.9)	135.8 (16.2)
Estimated ejection fraction (Percentage of ejection fraction) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of ejection fraction]	57.6 (10.5)	56.2 (8.8)	56.9 (9.7)

Outcome Measures

1. Primary Outcome

Title	Patient Reported Quality of Life (SF-36)
Description	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.
Time Frame	Primary outcome at 6 months timepoint.

Outcome Measure Data

Analysis Population Description

ITT Analysis

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	74	76
Mean (Standard Deviation) [score on a scale]	29.7 (11.4)	31.9 (11.7)

2. Secondary Outcome

Title	Left Ventricular Ejection Fraction
Description	The above parameters will be measured using echocardiography and diastolic indices
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	72	73
Mean (Standard Deviation) [percentage of ejection fraction]	59.8 (7.3)	59.7 (8.7)

3. Secondary Outcome

Title	Diastolic Function- Measured by the E/e'.
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	72	73
Mean (Standard Deviation) [Ratio of E/e']	10.8 (5.5)	10.8 (5.1)

4. Secondary Outcome

Title	B-type Natriuretic Peptide (BNP) at 6 Months.
Description	B-type natriuretic peptide (BNP) at 6 months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	74	76
Median (Inter-Quartile Range) [ng/L]	1209	1057.5

5. Secondary Outcome

Title	Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.
Description	Composite functional status measures- 6 minute walking distance at 12 months.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	69	71
Median (Inter-Quartile Range) [metres]	329	366

6. Secondary Outcome

Title	Patient Reported Outcomes- (AFEQT) at 12 Months.
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	72	73
Mean (Standard Deviation) [score on a scale]	68.1 (16.1)	75.6 (17.1)

7. Secondary Outcome

Title	Patient Reported Outcomes (SF36) Version 2 at 12 Months.
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Some domains of the SFF36 version 2 were not possible to be computed due to missing data in the questionnaire.

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	72	73
Physical Component Summary	29.4 (12.4)	32.5 (13)
Mental Component Summary	51.3 (10.1)	53.6 (8.9)
Physical Function Domain Score	27.5 (13)	31.5 (14.1)
Role Limitation Due to Physical Domain score	32 (12.4)	37 (12.6)
Role Limitation Due to Emotional Problems Domain score	40.7 (15.5)	45.2 (12.9)
Social Functioning Domain Score	43.3 (11.6)	45.6 (12.3)
Mental Health Domain	51.8 (9.5)	51.3 (9.3)
Energy/Vitality Domain Score	42 (10)	47.1 (9.9)
Pain Score	41.9 (12.5)	40.5 (12.7)
General Health Perception Domain Score	39.6 (10)	42.8 (9.9)

8. Secondary Outcome

Title	Patient Reported Outcomes (EQ-5D-5L)
Description	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
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	78	77
Mean (Standard Deviation) [units on a scale]	0.62 (0.29)	0.66 (0.27)

9. Secondary Outcome

Title	Ambulatory Heart-rate.
Description	24 hour ambulatory heart-rate.
Time Frame	Within 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	78	76
Mean (Standard Deviation) [bpm]	73.7 (10.9)	78.9 (11.3)

10. Other Pre-specified Outcome

Title	Cardiovascular Events
Description	Number of Participants with hospital admissions for cardiovascular events.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	80	81
Count of Participants [Participants]	12 15%	2 2.5%

11. Other Pre-specified Outcome

Title	Drug Discontinuation Rate
Description	the number and extent to which patients discontinue trial drugs
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	72	73
Adherent	65 81.3%	70 86.4%
Non-Adherent	3 3.8%	3 3.7%
Missing	4 5%	0 0%

12. Other Pre-specified Outcome

Title	Drug Discontinuation Rate Within 12 Months.
Description	Number of participants requiring drug discontinuation due to adverse reactions.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	80	81
Count of Participants [Participants]	9 11.3%	2 2.5%

13. Other Pre-specified Outcome

Title	Hospital Admission Rate
Description	A composite of adverse clinical events
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	80	81
Count of Participants [Participants]	19 23.8%	11 13.6%

14. Other Pre-specified Outcome

Title	Retention of Participants
Description	Convenience, compliance and cross-over data
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	80	81
yes	7 8.8%	4 4.9%
No	73 91.3%	77 95.1%
yes	0 0%	2 2.5%
No	80 100%	79 97.5%
yes	1 1.3%	2 2.5%
No	79 98.8%	79 97.5%

15. Other Pre-specified Outcome

Title	Preferred Outcome Measures for This Cohort of Patients
Description	Establish which are the best measures for these patients
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
Description	SF-36 physical function score at 6 and 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Other Pre-specified Outcome

Title	Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
Description	SF-36 overall score at 6 and 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Other Pre-specified Outcome

Title	Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
Description	AFEQT overall score at 6 and 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

Title	Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions.
Description	LVEF and E/e scores at 6 and 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Other Pre-specified Outcome

Title	Number of Participants With Unplanned Hospital Admissions.
Description	Number of Participants with Unplanned Hospital Admissions.
Time Frame	During the 12 month follow-up period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Beta-blocker	Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Measure Participants	80	81
Count of Participants [Participants]	19 23.8%	11 13.6%

Adverse Events

Time Frame	During the 12 month follow-up period.
Adverse Event Reporting Description	Adverse events (AEs) were recorded in the medical records and CRFs. Most AE/ARs that occurred in the trial, whether they are serious or not, were 'expected' treatment-related toxicities due to the drugs used in this trial.
Arm/Group Title	Beta-blocker		Digoxin
Arm/Group Description	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. Bisoprolol: Drug intervention		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. Digoxin: Drug intervention
All Cause Mortality
	Beta-blocker		Digoxin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/80 (8.8%)		4/81 (4.9%)
Serious Adverse Events
	Beta-blocker		Digoxin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/80 (26.3%)		13/81 (16%)
Blood and lymphatic system disorders
Lymphatics	1/80 (1.3%)	1	0/81 (0%)	0
Cardiac disorders
Cardiac Arrhythmia	3/80 (3.8%)	3	1/81 (1.2%)	1
Cardiac General	4/80 (5%)	5	1/81 (1.2%)	2
Death	2/80 (2.5%)	2	1/81 (1.2%)	1
Gastrointestinal disorders
Gastrointestinal	3/80 (3.8%)	5	1/81 (1.2%)	1
Death	1/80 (1.3%)	1	0/81 (0%)	0
General disorders
Constitutional Symptoms	1/80 (1.3%)	1	1/81 (1.2%)	1
Death	1/80 (1.3%)	1	0/81 (0%)	0
Hepatobiliary disorders
Hepatobiliary/Pancreas	0/80 (0%)	0	1/81 (1.2%)	1
Death	0/80 (0%)	0	1/81 (1.2%)	1
Infections and infestations
Infection	4/80 (5%)	4	0/81 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal/Soft Tissue	1/80 (1.3%)	1	2/81 (2.5%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy	1/80 (1.3%)	2	0/81 (0%)	0
Death	2/80 (2.5%)	2	2/81 (2.5%)	2
Nervous system disorders
Pain	0/80 (0%)	0	1/81 (1.2%)	1
Neurology	1/80 (1.3%)	1	0/81 (0%)	0
Renal and urinary disorders
Renal/Genitourinary	1/80 (1.3%)	1	0/81 (0%)	0
Death	1/80 (1.3%)	1	0/81 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper Respiratory	4/80 (5%)	4	1/81 (1.2%)	1
Skin and subcutaneous tissue disorders
Dermatology/Skin	0/80 (0%)	0	1/81 (1.2%)	1
Vascular disorders
Haemorrhage/Bleeding	0/80 (0%)	0	1/81 (1.2%)	1
Vascular	2/80 (2.5%)	2	0/81 (0%)	0
Other (Not Including Serious) Adverse Events
	Beta-blocker		Digoxin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/80 (63.8%)		20/81 (24.7%)
Cardiac disorders
Symptomatic bradycardia	5/80 (6.3%)	5	0/81 (0%)	0
Symptomatic hypotension	6/80 (7.5%)	7	0/81 (0%)	0
Eye disorders
Blurred vision	1/80 (1.3%)	1	2/81 (2.5%)	2
Gastrointestinal disorders
Gastrointestinal upset	8/80 (10%)	8	5/81 (6.2%)	5
General disorders
Peripheral oedema	11/80 (13.8%)	12	1/81 (1.2%)	1
Dizziness	24/80 (30%)	28	4/81 (4.9%)	4
Headache	9/80 (11.3%)	11	5/81 (6.2%)	5
Lethargy	30/80 (37.5%)	37	7/81 (8.6%)	7
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract symptoms	13/80 (16.3%)	15	1/81 (1.2%)	1
Skin and subcutaneous tissue disorders
Rash	0/80 (0%)	0	1/81 (1.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.