Trial Outcomes & Findings for Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) (NCT NCT02391337)

Last Updated: 2021-06-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

161 participants

Primary outcome timeframe

Primary outcome at 6 months timepoint.

Results posted on

2021-06-18

Participant Flow

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.

A total of 390 were screened for the trial, of these screened 161 were randomised.

Participant milestones

Participant milestones
Measure	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
Baseline STARTED	80	81
Baseline COMPLETED	80	81
Baseline NOT COMPLETED	0	0
6 Months Follow-up STARTED	80	81
6 Months Follow-up COMPLETED	74	76
6 Months Follow-up NOT COMPLETED	6	5
12 Months Follow-up STARTED	74	76
12 Months Follow-up COMPLETED	72	73
12 Months Follow-up NOT COMPLETED	2	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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. Bisoprolol: Drug intervention	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. Digoxin: Drug intervention
6 Months Follow-up Death	5	4
6 Months Follow-up Withdrawal by Subject	1	1
12 Months Follow-up Death	2	0
12 Months Follow-up Withdrawal by Subject	0	1
12 Months Follow-up Lost to Follow-up	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Beta-blocker n=80 Participants 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	Digoxin n=81 Participants 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 n=161 Participants Total of all reporting groups
Age, Continuous	76.8 Years STANDARD_DEVIATION 8.1 • n=5 Participants	74.4 Years STANDARD_DEVIATION 8.4 • n=7 Participants	75.6 Years STANDARD_DEVIATION 8.3 • n=5 Participants
Sex: Female, Male Female	38 Participants n=5 Participants	36 Participants n=7 Participants	74 Participants n=5 Participants
Sex: Female, Male Male	42 Participants n=5 Participants	45 Participants n=7 Participants	87 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · White - English / Welsh / Scottish / Northern Iris	66 Participants n=5 Participants	72 Participants n=7 Participants	138 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · White-Irish	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · Asian / Asian British - Indian	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · Asian / Asian British - Pakistani	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · Black / African / Caribbean / Black British- African	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Self declared ethnicity · Black / African / Caribbean / Black British - Caribbean	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United Kingdom	80 participants n=5 Participants	81 participants n=7 Participants	161 participants n=5 Participants
Creatinine	91.4 Micromol/l STANDARD_DEVIATION 23.1 • n=5 Participants	87.9 Micromol/l STANDARD_DEVIATION 25.1 • n=7 Participants	89.6 Micromol/l STANDARD_DEVIATION 24.1 • n=5 Participants
On anticoagulant before randomisation No	17 Participants n=5 Participants	9 Participants n=7 Participants	26 Participants n=5 Participants
On anticoagulant before randomisation Yes	63 Participants n=5 Participants	72 Participants n=7 Participants	135 Participants n=5 Participants
EHRA class EHRA Class 1	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
EHRA class EHRA Class 2a	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
EHRA class EHRA Class 2b	40 Participants n=5 Participants	35 Participants n=7 Participants	75 Participants n=5 Participants
EHRA class EHRA Class 3	27 Participants n=5 Participants	38 Participants n=7 Participants	65 Participants n=5 Participants
EHRA class EHRA Class 4	10 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants
NYHA class Class I	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
NYHA class Class II	53 Participants n=5 Participants	47 Participants n=7 Participants	100 Participants n=5 Participants
NYHA class Class III	24 Participants n=5 Participants	32 Participants n=7 Participants	56 Participants n=5 Participants
NYHA class Class IV	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Previous diagnosis of heart failure? No	56 Participants n=5 Participants	46 Participants n=7 Participants	102 Participants n=5 Participants
Previous diagnosis of heart failure? Yes	24 Participants n=5 Participants	35 Participants n=7 Participants	59 Participants n=5 Participants
Any signs of heart failure at baseline No	45 Participants n=5 Participants	32 Participants n=7 Participants	77 Participants n=5 Participants
Any signs of heart failure at baseline Yes	35 Participants n=5 Participants	49 Participants n=7 Participants	84 Participants n=5 Participants
Type I diabetes No	80 Participants n=5 Participants	81 Participants n=7 Participants	161 Participants n=5 Participants
Type I diabetes Yes	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Type II diabetes No	58 Participants n=5 Participants	65 Participants n=7 Participants	123 Participants n=5 Participants
Type II diabetes Yes	22 Participants n=5 Participants	16 Participants n=7 Participants	38 Participants n=5 Participants
Unplanned admission for AF or HF in last 12 months No	65 Participants n=5 Participants	65 Participants n=7 Participants	130 Participants n=5 Participants
Unplanned admission for AF or HF in last 12 months Yes	15 Participants n=5 Participants	16 Participants n=7 Participants	31 Participants n=5 Participants
Any previous cardioversions No	71 Participants n=5 Participants	74 Participants n=7 Participants	145 Participants n=5 Participants
Any previous cardioversions Yes	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Previously undergone AF ablation No	79 Participants n=5 Participants	79 Participants n=7 Participants	158 Participants n=5 Participants
Previously undergone AF ablation Yes	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Previous history of anti-arrhythmic drugs No	72 Participants n=5 Participants	75 Participants n=7 Participants	147 Participants n=5 Participants
Previous history of anti-arrhythmic drugs Yes	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Baseline NTproBNP	1040.5 pg/mL n=5 Participants	1091 pg/mL n=7 Participants	1057 pg/mL n=5 Participants
Radial artery heart rate	86.9 bpm STANDARD_DEVIATION 10.3 • n=5 Participants	87.8 bpm STANDARD_DEVIATION 12 • n=7 Participants	87.4 bpm STANDARD_DEVIATION 11.2 • n=5 Participants
Apex beat heart rate	99 bpm STANDARD_DEVIATION 16.8 • n=5 Participants	98.3 bpm STANDARD_DEVIATION 15.1 • n=7 Participants	98.7 bpm STANDARD_DEVIATION 15.9 • n=5 Participants
12-Lead ECG Heart Rate	99.2 bpm STANDARD_DEVIATION 19.2 • n=5 Participants	100.3 bpm STANDARD_DEVIATION 16.8 • n=7 Participants	99.7 bpm STANDARD_DEVIATION 18 • n=5 Participants
Systolic BP	137.1 mmHg STANDARD_DEVIATION 17.5 • n=5 Participants	134.5 mmHg STANDARD_DEVIATION 14.9 • n=7 Participants	135.8 mmHg STANDARD_DEVIATION 16.2 • n=5 Participants
Estimated ejection fraction	57.6 Percentage of ejection fraction STANDARD_DEVIATION 10.5 • n=5 Participants	56.2 Percentage of ejection fraction STANDARD_DEVIATION 8.8 • n=7 Participants	56.9 Percentage of ejection fraction STANDARD_DEVIATION 9.7 • n=5 Participants

PRIMARY outcome

Timeframe: Primary outcome at 6 months timepoint.

Population: ITT Analysis

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.

Outcome measures

Outcome measures
Measure	Beta-blocker n=74 Participants 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	Digoxin n=76 Participants 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
Patient Reported Quality of Life (SF-36)	29.7 score on a scale Standard Deviation 11.4	31.9 score on a scale Standard Deviation 11.7

SECONDARY outcome

Timeframe: 12 months

The above parameters will be measured using echocardiography and diastolic indices

Outcome measures

Outcome measures
Measure	Beta-blocker n=72 Participants 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	Digoxin n=73 Participants 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
Left Ventricular Ejection Fraction	59.8 percentage of ejection fraction Standard Deviation 7.3	59.7 percentage of ejection fraction Standard Deviation 8.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Beta-blocker n=72 Participants 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	Digoxin n=73 Participants 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
Diastolic Function- Measured by the E/e'.	10.8 Ratio of E/e' Standard Deviation 5.5	10.8 Ratio of E/e' Standard Deviation 5.1

SECONDARY outcome

Timeframe: 6 months

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

Outcome measures

Outcome measures
Measure	Beta-blocker n=74 Participants 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	Digoxin n=76 Participants 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
B-type Natriuretic Peptide (BNP) at 6 Months.	1209 ng/L Interval 837.0 to 1531.0	1057.5 ng/L Interval 625.5 to 1531.0

SECONDARY outcome

Timeframe: 12 months

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

Outcome measures

Outcome measures
Measure	Beta-blocker n=69 Participants 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	Digoxin n=71 Participants 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
Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months.	329 metres Interval 120.0 to 429.0	366 metres Interval 233.0 to 435.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Beta-blocker n=72 Participants 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	Digoxin n=73 Participants 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
Patient Reported Outcomes- (AFEQT) at 12 Months.	68.1 score on a scale Standard Deviation 16.1	75.6 score on a scale Standard Deviation 17.1

SECONDARY outcome

Timeframe: 12 months

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

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.

Outcome measures

Outcome measures
Measure	Beta-blocker n=72 Participants 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	Digoxin n=73 Participants 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
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Physical Component Summary	29.4 score on a scale Standard Deviation 12.4	32.5 score on a scale Standard Deviation 13
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Mental Component Summary	51.3 score on a scale Standard Deviation 10.1	53.6 score on a scale Standard Deviation 8.9
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Physical Function Domain Score	27.5 score on a scale Standard Deviation 13	31.5 score on a scale Standard Deviation 14.1
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Role Limitation Due to Physical Domain score	32 score on a scale Standard Deviation 12.4	37 score on a scale Standard Deviation 12.6
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Role Limitation Due to Emotional Problems Domain score	40.7 score on a scale Standard Deviation 15.5	45.2 score on a scale Standard Deviation 12.9
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Social Functioning Domain Score	43.3 score on a scale Standard Deviation 11.6	45.6 score on a scale Standard Deviation 12.3
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Mental Health Domain	51.8 score on a scale Standard Deviation 9.5	51.3 score on a scale Standard Deviation 9.3
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Energy/Vitality Domain Score	42 score on a scale Standard Deviation 10	47.1 score on a scale Standard Deviation 9.9
Patient Reported Outcomes (SF36) Version 2 at 12 Months. Pain Score	41.9 score on a scale Standard Deviation 12.5	40.5 score on a scale Standard Deviation 12.7
Patient Reported Outcomes (SF36) Version 2 at 12 Months. General Health Perception Domain Score	39.6 score on a scale Standard Deviation 10	42.8 score on a scale Standard Deviation 9.9

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Beta-blocker n=78 Participants 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	Digoxin n=77 Participants 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
Patient Reported Outcomes (EQ-5D-5L)	0.62 units on a scale Standard Deviation 0.29	0.66 units on a scale Standard Deviation 0.27

SECONDARY outcome

Timeframe: Within 12 months

24 hour ambulatory heart-rate.

Outcome measures

Outcome measures
Measure	Beta-blocker n=78 Participants 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	Digoxin n=76 Participants 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
Ambulatory Heart-rate.	73.7 bpm Standard Deviation 10.9	78.9 bpm Standard Deviation 11.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

Number of Participants with hospital admissions for cardiovascular events.

Outcome measures

Outcome measures
Measure	Beta-blocker n=80 Participants 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	Digoxin n=81 Participants 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
Cardiovascular Events	12 Participants	2 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

the number and extent to which patients discontinue trial drugs

Outcome measures

Outcome measures
Measure	Beta-blocker n=72 Participants 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	Digoxin n=73 Participants 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
Drug Discontinuation Rate Adherent	65 Participants	70 Participants
Drug Discontinuation Rate Non-Adherent	3 Participants	3 Participants
Drug Discontinuation Rate Missing	4 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

Number of participants requiring drug discontinuation due to adverse reactions.

Outcome measures

Outcome measures
Measure	Beta-blocker n=80 Participants 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	Digoxin n=81 Participants 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
Drug Discontinuation Rate Within 12 Months.	9 Participants	2 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

A composite of adverse clinical events

Outcome measures

Outcome measures
Measure	Beta-blocker n=80 Participants 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	Digoxin n=81 Participants 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
Hospital Admission Rate	19 Participants	11 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

Convenience, compliance and cross-over data

Outcome measures

Outcome measures
Measure	Beta-blocker n=80 Participants 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	Digoxin n=81 Participants 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
Retention of Participants Death · yes	7 Participants	4 Participants
Retention of Participants Death · No	73 Participants	77 Participants
Retention of Participants Lost to follow-up · yes	0 Participants	2 Participants
Retention of Participants Lost to follow-up · No	80 Participants	79 Participants
Retention of Participants Withdrawn consent · yes	1 Participants	2 Participants
Retention of Participants Withdrawn consent · No	79 Participants	79 Participants

Adverse Events

Beta-blocker

Serious events: 21 serious events

Other events: 51 other events

Deaths: 7 deaths

Digoxin

Serious events: 13 serious events

Other events: 20 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Beta-blocker n=80 participants at risk 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	Digoxin n=81 participants at risk 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
Gastrointestinal disorders Gastrointestinal upset	10.0% 8/80 • Number of events 8 • During the 12 month follow-up period. 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.	6.2% 5/81 • Number of events 5 • During the 12 month follow-up period. 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.
Eye disorders Blurred vision	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	2.5% 2/81 • Number of events 2 • During the 12 month follow-up period. 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.
Skin and subcutaneous tissue disorders Rash	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
General disorders Peripheral oedema	13.8% 11/80 • Number of events 12 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Cardiac disorders Symptomatic bradycardia	6.2% 5/80 • Number of events 5 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
General disorders Dizziness	30.0% 24/80 • Number of events 28 • During the 12 month follow-up period. 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.	4.9% 4/81 • Number of events 4 • During the 12 month follow-up period. 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.
General disorders Headache	11.2% 9/80 • Number of events 11 • During the 12 month follow-up period. 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.	6.2% 5/81 • Number of events 5 • During the 12 month follow-up period. 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.
General disorders Lethargy	37.5% 30/80 • Number of events 37 • During the 12 month follow-up period. 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.	8.6% 7/81 • Number of events 7 • During the 12 month follow-up period. 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.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract symptoms	16.2% 13/80 • Number of events 15 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Cardiac disorders Symptomatic hypotension	7.5% 6/80 • Number of events 7 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.

Additional Information

Prof. Dipak Kotecha

University of Birmingham

Phone: +44 (0) 7974 115676

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Beta-blocker n=80 participants at risk 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	Digoxin n=81 participants at risk 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
Cardiac disorders Cardiac Arrhythmia	3.8% 3/80 • Number of events 3 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Cardiac disorders Cardiac General	5.0% 4/80 • Number of events 5 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 2 • During the 12 month follow-up period. 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.
Vascular disorders Haemorrhage/Bleeding	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Gastrointestinal disorders Gastrointestinal	3.8% 3/80 • Number of events 5 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Respiratory, thoracic and mediastinal disorders Pulmonary/Upper Respiratory	5.0% 4/80 • Number of events 4 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
General disorders Constitutional Symptoms	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Skin and subcutaneous tissue disorders Dermatology/Skin	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Nervous system disorders Pain	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Musculoskeletal and connective tissue disorders Musculoskeletal/Soft Tissue	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	2.5% 2/81 • Number of events 2 • During the 12 month follow-up period. 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.
Hepatobiliary disorders Hepatobiliary/Pancreas	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Nervous system disorders Neurology	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Infections and infestations Infection	5.0% 4/80 • Number of events 4 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secondary Malignancy	1.2% 1/80 • Number of events 2 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Renal and urinary disorders Renal/Genitourinary	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Vascular disorders Vascular	2.5% 2/80 • Number of events 2 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Blood and lymphatic system disorders Lymphatics	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Cardiac disorders Death	2.5% 2/80 • Number of events 2 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Death	2.5% 2/80 • Number of events 2 • During the 12 month follow-up period. 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.	2.5% 2/81 • Number of events 2 • During the 12 month follow-up period. 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.
Hepatobiliary disorders Death	0.00% 0/80 • During the 12 month follow-up period. 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.	1.2% 1/81 • Number of events 1 • During the 12 month follow-up period. 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.
General disorders Death	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Renal and urinary disorders Death	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.
Gastrointestinal disorders Death	1.2% 1/80 • Number of events 1 • During the 12 month follow-up period. 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.	0.00% 0/81 • During the 12 month follow-up period. 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.