Abstract
Background
Observational studies of people with chronic obstructive pulmonary disease using beta-blockers for cardiovascular disease indicate that beta-blocker use is associated with reduced risk of chronic obstructive pulmonary disease exacerbation. However, at the time this study was initiated, there had been no randomised controlled trials confirming or refuting this.
Objective(s)
To determine the clinical and cost-effectiveness of adding bisoprolol (maximal dose 5 mg once daily) to usual chronic obstructive pulmonary disease therapies in patients with chronic obstructive pulmonary disease at high risk of exacerbation.
Design
A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial.
Setting
Seventy-six United Kingdom primary and secondary care sites.
Participants
People aged ≥ 40 years with a diagnosis of at least moderately severe chronic obstructive pulmonary disease with a history of at least two exacerbations in the previous year.
Interventions
Participants were randomised (1 : 1) to receive either bisoprolol or placebo for 1 year. During a 4- to 7-week titration period, the maximum tolerated dose was established (1.25 mg, 2.5 mg, 3.75 mg, 5 mg once daily).
Primary outcome
A number of participant-reported exacerbations during the 1-year treatment period.
Results
In total, 519 participants were recruited and randomised. Four post-randomisation exclusions left 259 in the bisoprolol group and 256 in the placebo group. Treatment groups were balanced at baseline: mean (standard deviation) age 68 (7.9) years; 53% men; mean (standard deviation) pack year smoking history 45 (25.2); mean (standard deviation) 3.5 (1.9) exacerbations in previous year. Primary outcome data were available for 99.8% of participants (bisoprolol 259, placebo 255). The mean (standard deviation) number of exacerbations was 2.03 (1.91) in the bisoprolol group and 2.01 (1.75) in the placebo group (adjusted incidence rate ratio 0.97, 95% confidence interval 0.84 to 1.13), p = 0.72. The number of participants with serious adverse events was similar between the two groups (bisoprolol 37, placebo 36). The total number of adverse reactions was also similar between the two groups. As expected, bisoprolol was associated with a higher proportion of vascular adverse reactions (e.g. hypotension, cold peripheries) than placebo, but was not associated with an excess of other adverse reactions, including those classified as respiratory. Adding bisoprolol resulted in a statistically insignificant trend towards higher costs (£636, 95% confidence interval £118 to £1391) and fewer quality-adjusted life-years (0.035, 95% confidence interval 0.059 to 0.010) compared to placebo.
Limitations
The study findings should be interpreted with caution as the target sample size of 1574 was not achieved because the funder considered the study to be unviable in the COVID-19 pandemic clinical research environment. Although 28% of participants did not initiate bisoprolol/placebo (1.6%) or ceased during the treatment period (26.2%), this is consistent with similar trials in the United Kingdom.
Conclusions
In this underpowered study, the addition of bisoprolol to usual chronic obstructive pulmonary disease treatment did not reduce the likelihood of exacerbations, and bisoprolol cannot be recommended as a treatment for chronic obstructive pulmonary disease.
Future work
To incorporate definitive statements into appropriate clinical guidelines about the safety of bisoprolol for cardiovascular indications in people with chronic obstructive pulmonary disease.
Observational studies of people with chronic obstructive pulmonary disease using beta-blockers for cardiovascular disease indicate that beta-blocker use is associated with reduced risk of chronic obstructive pulmonary disease exacerbation. However, at the time this study was initiated, there had been no randomised controlled trials confirming or refuting this.
Objective(s)
To determine the clinical and cost-effectiveness of adding bisoprolol (maximal dose 5 mg once daily) to usual chronic obstructive pulmonary disease therapies in patients with chronic obstructive pulmonary disease at high risk of exacerbation.
Design
A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial.
Setting
Seventy-six United Kingdom primary and secondary care sites.
Participants
People aged ≥ 40 years with a diagnosis of at least moderately severe chronic obstructive pulmonary disease with a history of at least two exacerbations in the previous year.
Interventions
Participants were randomised (1 : 1) to receive either bisoprolol or placebo for 1 year. During a 4- to 7-week titration period, the maximum tolerated dose was established (1.25 mg, 2.5 mg, 3.75 mg, 5 mg once daily).
Primary outcome
A number of participant-reported exacerbations during the 1-year treatment period.
Results
In total, 519 participants were recruited and randomised. Four post-randomisation exclusions left 259 in the bisoprolol group and 256 in the placebo group. Treatment groups were balanced at baseline: mean (standard deviation) age 68 (7.9) years; 53% men; mean (standard deviation) pack year smoking history 45 (25.2); mean (standard deviation) 3.5 (1.9) exacerbations in previous year. Primary outcome data were available for 99.8% of participants (bisoprolol 259, placebo 255). The mean (standard deviation) number of exacerbations was 2.03 (1.91) in the bisoprolol group and 2.01 (1.75) in the placebo group (adjusted incidence rate ratio 0.97, 95% confidence interval 0.84 to 1.13), p = 0.72. The number of participants with serious adverse events was similar between the two groups (bisoprolol 37, placebo 36). The total number of adverse reactions was also similar between the two groups. As expected, bisoprolol was associated with a higher proportion of vascular adverse reactions (e.g. hypotension, cold peripheries) than placebo, but was not associated with an excess of other adverse reactions, including those classified as respiratory. Adding bisoprolol resulted in a statistically insignificant trend towards higher costs (£636, 95% confidence interval £118 to £1391) and fewer quality-adjusted life-years (0.035, 95% confidence interval 0.059 to 0.010) compared to placebo.
Limitations
The study findings should be interpreted with caution as the target sample size of 1574 was not achieved because the funder considered the study to be unviable in the COVID-19 pandemic clinical research environment. Although 28% of participants did not initiate bisoprolol/placebo (1.6%) or ceased during the treatment period (26.2%), this is consistent with similar trials in the United Kingdom.
Conclusions
In this underpowered study, the addition of bisoprolol to usual chronic obstructive pulmonary disease treatment did not reduce the likelihood of exacerbations, and bisoprolol cannot be recommended as a treatment for chronic obstructive pulmonary disease.
Future work
To incorporate definitive statements into appropriate clinical guidelines about the safety of bisoprolol for cardiovascular indications in people with chronic obstructive pulmonary disease.
| Original language | English |
|---|---|
| Journal | Health Technology Assessment |
| Volume | 29 |
| Issue number | 17 |
| Early online date | 15 May 2025 |
| DOIs | |
| Publication status | Published - May 2025 |
Bibliographical note
We would like to thank all the participants who took part in the trial. We are grateful to all the staff at recruitment sites who facilitated identification, recruitment and follow-up of study participants (listed below). We are also grateful to other general practices and organisations that acted as PICs for the trial. We could not have completed the trial without the ongoing support of local and primary care research networks:NHS Research Scotland Primary Care Network – Amanda Cardy, Samantha Holden, Tracy Ibbotson, Catriona Loots, Yvonne McIlvenna, Kim Stringer.
NIHR CRN North East and North Cumbria – Jill Ducker, Laura Gebbie, Clare Graham, Gillian Johnson, Fiona McIntosh, Rachel Nixon, Beth Pickering, Norah Phipps, Laura Renwick, Cheryl Rigg, Bertie Rowell, Rebecca Russell, Nicky Todd, Lauren Tough, Jacqui Vicars, Lisa Westwood, Alicja Yilmaz.
NIHR CRN North West – Margaret Brunton, Lisa Cheng, Debbie Dickerson, Jacqui Dooley, Grace Hull, Kate Maitland, Julie Mugarza, Gail Timcke, Sara Yearsley.
NIHR CRN South West Peninsula – Lynsey Beall, Tania Crabb, Samantha Hayward, Sara McNamara, Lauren Merrin.
NIHR CRN East of England – Anneka Bicknell, Siobhan Campbell, Donna Clements, Kate Ellerby, Zenzi Fernandes, Julia Fromings Hill, Rachel Hollis, Bonnie Jackson, Emma Jameson, Jenny Johnson, Helen Jung, Heather Leishman, Philippa Lincoln, Suzanne Lockwood, Gosia Majsak-Newman, Kate McCloskey, Ruth Osborne, Julie Selley, Susanne Skinner, Karen Tibbenham, Nicola Ward, Gilda Watson.
NIHR CRN East Midlands – Kylie Bate, Craig Beecroft, Michelle Chalke, John Cvancara, Kate Ellis, Fenglin Guo, Juliet Jones, Valentina Lazarevic, Hayley Simpson, Johanna Williams.
NIHR CRN Kent, Surrey and Sussex – Natalie Billington, Claire Cox, Christina Gibbon, Louise Phillips.
We are grateful to Janice Cruden for her secretarial and data co-ordination support and to other members of the CHaRT trial management and data co-ordination team for their help with discrete tasks. We are grateful to Kirsty McCormack for her help and advice in developing the grant proposal. We thank Mark Forrest and the programming team in CHaRT for developing and maintaining the trial website. We also thank Juliette Snow and Rachel West for their help with contracting, and Blair Annandale and Anne Buckle for their help in managing the budget.
We are grateful for the guidance and support of the TSC (chairperson: Professor Edwin Chilvers; independent members: Matt Sydes, Rod Lawson, Dave Bertin and Alister Laird) and the DMC (chairperson: Mike Thomas; independent members: Michael Steiner, Stephen Gerry).
The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate.
Data Availability Statement
Individual de-identified participant data that underlie the results reported in this article, along with data dictionary and study protocol are available upon reasonable request. Please contact the corresponding author.Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/130/20)
| Funders | Funder number |
|---|---|
| National Institute for Health and Care Research | 15/130/20 |
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- Devereux_etal_HTA_Bisoprolol_for_Patients_VOR
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