• All-cause mortality [ Time Frame: Baseline to 24 months ]
• Hospitalisation for COPD exacerbation [ Time Frame: Baseline to 24 months ]
• Hospitalisation for primary cardiac cause (ischaemia, arrhythmia or heart failure) [ Time Frame: Baseline to 24 months ]
• Major Adverse Cardiovascular Event (MACE) [ Time Frame: Baseline to 24 months ]
  Major Adverse Cardiovascular Event (MACE) includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke.

• COPD exacerbation rate (annualised) [ Time Frame: Baseline to 24 months ]
  Exacerbations will be defined as worsening respiratory symptoms resulting in treatment with antibiotics or systemic glucocorticoids. Exacerbation severity will be graded (secondary outcome) according to the following scale: i. moderate (requiring oral corticosteroids, antibiotics or both without hospital admission) ii. severe (requiring above treatment and hospital admission)
• Time to first moderate-severe COPD Exacerbation [ Time Frame: Baseline to 24 months ]
• Severe (hospital admission) COPD exacerbation rate (annualised) [ Time Frame: Baseline to 24 months ]
• Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE [ Time Frame: Baseline to 24 months ]
• Quality of life assessed by St George's Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline to 24 months ]
  The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction. Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has been demonstrated in clinical trials. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The SGRQ has been used in a range of disease groups including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis, and in a range of settings such as randomised controlled therapy trials and population surveys.
• EuroQoL Group 5-5 Dimension self-report questionnaire (EQ-5D-5L) to assess health state utilities [ Time Frame: Baseline to 24 months ]
  EQ-5D-5L consists of 2pg: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). Five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. Patient indicates their health state by ticking most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. EQ VAS records patient's self-rated health on a vertical visual analogue scale. Endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.
• Healthcare utilisation costs and Quality Adjusted Life Years (QALYs) evaluation of the treatment intervention [ Time Frame: Baseline to 24 months ]
  Mean differences in healthcare utilisation costs and Quality Adjusted Life Years between both treatment groups will be estimated. Costs will be ascertained from participants and study records. Health care utilisation will be on the basis of self-reported GP and hospital attendances and changes in concomitant medication. Health state utilities will be estimated via the EQ-5D-5L and will be used to weight survival up to 24 months to determine Quality Adjusted Life Years.
• Health status assessed by COPD Assessment Test (CAT) [ Time Frame: Baseline to 24 months ]
• Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L) [ Time Frame: Baseline to 24 months ]
• Clinic spirometry: % predicted post-bronchodilator [ Time Frame: Baseline to 24 months ]
• Hospital admissions for all respiratory causes [ Time Frame: Baseline to 24 months ]
• Hospital admissions for all cardiac causes [ Time Frame: Baseline to 24 months ]
  All cardiac causes includes ischaemia, arrhythmia, heart failure, acute arrhythmia, non-ST-elevation myocardial infarction, urgent revascularisation (stent/angioplasty/coronary artery bypass grafting), and MACE events (includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke).
• Total Number of cardiac events: MACE plus acute arrhythmia, Non-ST-elevation myocardial infarction (NSTEMI), urgent revascularisation (stent/angioplasty/Coronary artery bypass grafting [CABGs]) and clinically diagnosed heart failure episodes. [ Time Frame: Baseline to 24 months ]

• COPD exacerbation rate (annualised) [ Time Frame: Baseline to 24 months ]
  Exacerbations will be defined as worsening respiratory symptoms resulting in treatment with antibiotics or systemic glucocorticoids. Exacerbation severity will be graded (secondary outcome) according to the following scale: i. moderate (requiring oral corticosteroids, antibiotics or both without hospitalization) ii. severe (requiring above treatment and hospitalization)
• Time to first moderate-severe COPD Exacerbation [ Time Frame: Baseline to 24 months ]
• Severe (hospital admission) COPD exacerbation rate (annualised) [ Time Frame: Baseline to 24 months ]
• Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE [ Time Frame: Baseline to 24 months ]
• Quality of life assessed by St George's Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline to 24 months ]
  The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction. Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has been demonstrated in clinical trials. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The SGRQ has been used in a range of disease groups including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis, and in a range of settings such as randomised controlled therapy trials and population surveys.
• Quality of life assessed by EuroQoL Group 5-Dimension self-report questionnaire (EQ-5D-5L) [ Time Frame: Baseline to 24 months ]
  EQ-5D-5L consists of 2pg: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). Five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. Patient indicates their health state by ticking most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. EQ VAS records patient's self-rated health on a vertical visual analogue scale. Endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.
• Health status assessed by COPD Assessment Test (CAT) [ Time Frame: Baseline to 24 months ]
• Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L) [ Time Frame: Baseline to 24 months ]
• Hospital admissions for all respiratory causes [ Time Frame: Baseline to 24 months ]
• Total Number of cardiac events: MACE plus acute arrhythmia, Non-ST-elevation myocardial infarction (NSTEMI), urgent revascularisation (stent/angioplasty/Coronary artery bypass grafting [CABGs]) and clinically diagnosed heart failure (HF) episodes. [ Time Frame: Baseline to 24 months ]

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global health-related morbidity and mortality. Heart disease in COPD is a known but neglected comorbidity and cardiovascular disease (CVD) accounts for 30-50% of deaths in COPD participants. Studies repeatedly show that CVD in COPD participants is under-recognised and under-treated yet participants with COPD are frequently excluded from clinical trials of drugs which reduce cardiac morbidity and mortality. This has led to under-treatment of CVD in COPD participants. A particular concern is low use of β-blockers. These have previously been considered to be contra-indicated in COPD and no RCTs have been conducted in this population. There is now observational evidence that cardioselective β-blockers are safe and may improve mortality, but this data is limited to retrospective analyses of cohorts of COPD participants. Contrary to previous concerns, retrospective analyses also suggest that cardioselective β-blockers may reduce the risk of COPD exacerbations. The proposed study will focus on treating CVD in COPD participants to reduce mortality and morbidity.

The study will be conducted in approximately 20 sites in Australia and New Zealand, and possibly 1-2 international sites. Participants with COPD will be randomised to one of two treatment arms in addition to receiving usual care for their COPD over the study duration of 24 months.

• Chronic Obstructive Pulmonary Disease
• Cardiovascular Diseases

• Drug: Bisoprolol
  As in arm description
• Drug: Placebo Oral Tablet
  As in arm description

• Active Comparator: Bisoprolol
  1.25, 2.5 or 5mg of bisoprolol daily
  Intervention: Drug: Bisoprolol
• Placebo Comparator: Placebo
  1.25, 2.5 or 5mg of matched placebo daily
  Intervention: Drug: Placebo Oral Tablet

Inclusion Criteria:

Participants will be eligible for this study if they qualify on all of the following:

1. Have provided written informed consent
2. Have COPD defined by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria
3. Aged 40-85 years
4. FEV1 ≥30% and ≤70% predicted post-bronchodilator
5. FEV1/FVC <0.7 post-bronchodilator
6. Have had a COPD exacerbation in the previous 12 months requiring oral corticosteroid, antibiotics, or both
7. If taking maintenance OCS, dosage is stable and ≤10mg daily for 4 weeks prior to randomisation
8. Resting SBP ≥100mmHg
9. SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg
10. (New Zealand only) A history of cardiovascular disease, including heart failure, ischaemic heart disease, tachyarrhythmias, and hypertension

Exclusion Criteria:

Participants will be ineligible for the study if they have any of the following:

1. Concurrent therapy with any other β-blocker
2. Resting HR <60bpm
3. Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in clinicians' opinion)
4. Clinically significant pulmonary hypertension, which in the investigator's opinion would be a contraindication for β-blocker therapy
5. Severe end-stage peripheral vascular disease
6. 2nd or 3rd degree heart block
7. Currently using or have been prescribed LTOT or resting saturated oxygen level <90% when stable
8. Expected survival is less than 12 months, or in the investigator's opinion, the person has such unstable disease (of any type) that maintaining 12 months' participation would be unlikely
9. Clinical instability since a MACE in the previous 12 weeks
10. Lower respiratory tract infection or AECOPD within the last 8 weeks
11. COPD not clinically stable as determined by the investigator
12. In the clinician's view, have asthma-COPD overlap or co-existent asthma are present; or an improvement in FEV1 ≥400mL post-bronchodilator is observed on two occasions
13. Females of child-bearing age and capability who are pregnant or breastfeeding or those in this group not using adequate birth control
14. Coexistent illness which precludes participation in the study (poorly controlled diabetes, active malignancy)
15. Severe end-stage liver disease defined by INR>1.3 and albumin<30g/L or portal hypertension/ascites
16. High chance in the view of the treating physician that the potential participant will not adhere to study requirements