Proof of Concept Study to Assess the Differential Effects of Chronic Beta-blockade (Celiprolol Versus Bisoprolol) on Cardiopulmonary Outcomes at Rest and During Exercise in Chronic Obstructive Pulmonary Disease
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in Inspiratory Capacity (IC) from rest to isotime peak.
研究概览
简要总结
What are the differential effects of beta-blockers on lung and heart function during exercise in chronic obstructive pulmonary disease (COPD)? COPD is a major cause of illness and death. Not only do these individuals suffer from lung disease, but COPD often leads to other illnesses, particularly heart disease. Beta-blockers very successfully treat heart disease. It is therefore logical that one would want to use this treatment in COPD patients with heart disease too. However, there has always been concern that beta-blockers could cause significant problems in COPD by worsening lung function, as these can have the opposite effect to inhalers used to treat COPD that open up airways. Pointedly, there is increasing evidence that despite this problem, COPD patients who have been prescribed beta-blockers have been shown to gain benefit particularly in terms of preventing death.
In this study, the investigators therefore want to examine which beta-blocker might be the safest for COPD patients, as each work slightly differently. Some beta-blockers may have a more beneficial effect on airways than others, whilst still benefitting the heart. The investigators will study two different beta-blockers; one that potentially narrows airways and one that potentially opens airways. The investigators will be using cardiopulmonary exercise testing (an exercise bike that measures both heart and lung function during exercise) to look for differences between both beta-blockers primarily in terms of lung function but also with information about the heart. The investigators will recruit people with moderate to severe COPD who are able to complete a cycle exercise test through their respiratory research department. The study will last for 10-12 weeks with 5 main visits to the department for serial exercise tests, breathing tests, simple heart function tests and simple blood tests that will tell the investigators what other effects these beta-blockers are having on the heart and lungs.
详细描述
Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death. In fact, by 2020, the World Health Organization predicts that COPD will become the third leading cause of death (currently fourth), and the fifth leading cause of disability (currently twelfth) worldwide. COPD and cardiovascular (heart) disease are intertwined due to the associated risk of smoking related atherosclerosis. Beta-blockers are generally avoided in COPD patients due to the associated risk of worsening lung function and acute bronchospasm (airway narrowing) due to beta-2-receptor blockade. Despite these concerns a recent Cochrane review has shown that chronic beta-blockade with "cardioselective" beta-blockers (for example bisoprolol) that preferentially block beta-1 (mostly heart) over beta-2 (mostly airway) receptors are well tolerated with less beta-2-blockade and subsequently less bronchospasm.
Furthermore, observational studies evaluating the impact of beta-blocker use in COPD patients have shown benefits on survival with beta-blockers. We have published retrospective data from 5,977 patients with COPD with a mean follow up of 4.35 years, showing that patients using beta-blockers (88% cardio-selective) produced a 22% overall reduction in death as well as significant reductions in respiratory hospital admissions and oral steroid use.
Beta-blockers are pharmacologically different and there now needs to be an assessment of the clinical consequences of different beta-blockers in COPD. Despite being "cardioselective", bisoprolol still shows significant beta-2-receptor blockade at usual treatment doses, which results in a significant worsening in Forced Expiratory Volume in 1second - FEV1 (a major marker of lung function) following chronic use. Celiprolol however is a unique beta-blocker which in addition to its beta-1-receptor blockade has partial beta-2-agonist activity and therefore it does not cause bronchoconstriction or interact with short and long acting beta-agonist inhalers which are the mainstay of COPD treatment. Thus celiprolol might confer an ideal profile for use in COPD (i.e. good for heart and not detrimental to lungs), especially in more severe patients where even a small fall in FEV1 might have significant consequences on their breathing and exercise capacity.
Poor exercise tolerance is associated with worsening quality of life and increased risk of death and thus provides a valuable surrogate marker of death. Worsening respiratory symptoms in COPD patients are more commonly seen on exertion than at rest, and associated with abnormal increases in lung volumes where air that is breathed in becomes trapped and cannot completely escape when breathing out (dynamic hyperinflation).
Cardiopulmonary exercise testing provides a global assessment of both respiratory (lung) and cardiovascular (heart) response to exercise. Whilst studies have shown a worsening of dynamic hyperinflation with bisoprolol, due to their differing pharmacological properties it might be that celiprolol will not result in worsening dynamic hyperinflation, whilst also demonstrating improvement in cardiovascular outcomes such as stroke volume (the pump function of the heart) and heart rate recovery following exercise. Whether these effects result in an improved exercise tolerance is unknown. Another interesting property of celiprolol is reduced cholesterol and increased High Density Lipoprotein (HDL) fraction conferred by partial beta-2-agonist activity. We will also measure serum markers of cardiac dysfunction (B-type Natriuretic Peptide (BNP) and Galectin-3) and their response to beta-blockade which to the investigators' knowledge has never been performed in a COPD study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female volunteers aged 40-80 years
- •Stable moderate to severe COPD (Global initiative on Obstructive Lung Disease [GOLD] stage 2/3)
- •Post-bronchodilator FEV1 30-80% predicted
- •FEV1/FVC ratio <70%
- •Stable defined as no exacerbation in previous 1 month
- •Smoking history ≥10 pack-years
- •Oxygen saturations ≥92% on room air at rest
- •Electrocardiogram demonstrating sinus rhythm.
排除标准
- •Use of domiciliary oxygen
- •History of other primary obstructive lung disease including asthma or bronchiectasis
- •Hospitalisation with exacerbation of COPD within past 3 months
- •History of unstable angina, uncontrolled hypertension or heart failure (New York Heart Association class 3-4)
- •Overt clinical signs of right heart failure
- •Average resting systolic BP<110mmHg or average resting HR<55bpm
- •Pregnancy or lactation
- •Known or suspected sensitivity to/intolerance of investigational medicinal product
- •Inability to comply with compulsory aspects of protocol
- •Any degree (first, second or third) of heart block
- •Sino-atrial block
- •Sick sinus syndrome
- •Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome
- •Untreated phaeochromocytoma
- •Severe renal impairment (eGFR<15ml/min)
- •Concomitant prescription of beta-blockers, rate-limiting calcium channel blockers, digoxin, amiodarone
- •Any clinically significant medical condition that may endanger the health or safety of the participant, or jeopardise the protocol
- •Participation in another trial within the previous 30 days
研究组 & 干预措施
Bisoprolol
2.5mg once daily for 2 weeks then 5mg once daily for 2 weeks.
干预措施: Bisoprolol (Drug)
Celiprolol
200mg once daily for 2 weeks then 400mg once daily for 2 weeks.
干预措施: Celiprolol (Drug)
结局指标
主要结局
Change in Inspiratory Capacity (IC) from rest to isotime peak.
时间窗: Baseline to 4 weeks
The primary outcome for this study will be the difference from baseline in the change in Inspiratory Capacity (IC) from rest to isotime peak (i.e. same time point during endurance exercise test) between beta-blocker treatments at 4 weeks. This will evaluate any differences in dynamic hyperinflation during exercise between treatments.
次要结局
- Non-invasive cardiac output measure: Cardiac Index(Baseline to 4 weeks)
- Spirometry: FEV1/FVC ratio(Baseline to 4 weeks)
- Exercise outcome: Anaerobic threshold (AT)(Baseline to 4 weeks.)
- Exercise outcome: Oxygen uptake at peak exercise (VO2peak)(Baseline to 4 weeks.)
- Exercise outcome: Heart rate(Baseline to 4 weeks.)
- Exercise outcome: Heart rate reserve (HRR)(Baseline to 4 weeks.)
- Exercise outcome: Heart rate recovery (HRrec)(Baseline to 4 weeks.)
- Exercise outcome: Breathing reserve(Baseline to 4 weeks.)
- Exercise outcome: Respiratory rate(Baseline to 4 weeks.)
- Exercise outcome: Ventilatory equivalent for oxygen at anaerobic threshold(Baseline to 4 weeks.)
- Exercise outcome: Ventilatory equivalent for carbon dioxide at anaerobic threshold(Baseline to 4 weeks.)
- Exercise outcome: Pulse oximetry at peak exercise(Baseline to 4 weeks.)
- Exercise outcome: Oxygen pulse (O2P)(Baseline to 4 weeks.)
- Exercise outcome: Total exercise time(Baseline to 4 weeks.)
- Non-invasive cardiac output measure: Stroke volume(Baseline to 4 weeks)
- Non-invasive cardiac output measure: Cardiac output(Baseline to 4 weeks)
- Impulse oscillometry: Resistance at 20 Hertz (R20)(Baseline to 4 weeks)
- Impulse oscillometry: Reactance at 5 Hertz (X5)(Baseline to 4 weeks)
- Change in blood Cholesterol/HDL levels(Baseline to 4 weeks)
- Spirometry: Forced expiratory volume in 1s (FEV1)(Baseline to 4 weeks)
- Spirometry: Forced Vital Capacity (FVC)(Baseline to 4 weeks)
- Spirometry: Forced expiratory flow between 25-75% of FVC(Baseline to 4 weeks)
- Impulse oscillometry: Resistance at 5 Hertz (R5)(Baseline to 4 weeks)
- Change in blood potassium levels(Baseline to 4 weeks)
- Impulse oscillometry: Area under the curve(Baseline to 4 weeks)
- Whole body plethysmography: Total lung capacity(Baseline to 4 weeks)
- Change in blood creatine kinase levels(Baseline to 4 weeks)
- Impulse oscillometry: Frequency of resonance(Baseline to 4 weeks)
- Whole body plethysmography: Residual volume(Baseline to 4 weeks)
- Supine blood pressure(Baseline to 4 weeks)
- Erect blood pressure(Baseline to 4 weeks)
- Change in blood B-natriuretic peptide levels(Baseline to 4 weeks)
- Change in blood Galectin levels(Baseline to 4 weeks)
研究者
William J Anderson
Consultant Respiratory Physician and Honorary Senior Lecturer
University of Dundee