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Randomized Controlled Trial
. 2024 Aug 13;332(6):462-470.
doi: 10.1001/jama.2024.8771.

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial

Graham Devereux  1   2   3 , Seonaidh Cotton  2 , Mintu Nath  4 , Nicola McMeekin  5 , Karen Campbell  2 , Rekha Chaudhuri  6 , Gourab Choudhury  7 , Anthony De Soyza  8 , Shona Fielding  4 , Simon Gompertz  9 , John Haughney  10 , Amanda J Lee  4 , Graeme MacLennan  2 , Alyn Morice  11 , John Norrie  12 , David Price  10 , Philip Short  13 , Jorgen Vestbo  14 , Paul Walker  3 , Jadwiga Wedzicha  15 , Andrew Wilson  16 , Olivia Wu  5 , Brian J Lipworth  17
Affiliations
Randomized Controlled Trial

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial

Graham Devereux et al. JAMA. .

Abstract

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission.

Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations.

Design, setting, and participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023.

Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol.

Main outcomes and measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions.

Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96).

Conclusions and relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both.

Trial registration: isrctn.org Identifier: ISRCTN10497306.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cotton reported receiving grants from the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) Programme (to her institution) during the conduct of the study. Dr Nath reported receiving grants from the University of Aberdeen during the conduct of the study. Dr Campbell reported receiving grants from the NIHR HTA Programme during the conduct of the study. Dr Chaudhuri reported receiving grants from AstraZeneca for an asthma study; meeting and lecture fees from AstraZeneca and GSK; lecture fees from Sanofi, Chiesi, and Teva Pharmaceuticals; advisory board meeting fees from Celltrion; and conference attendance support from Sanofi, Chiesi, and GSK outside the submitted work. Dr Choudhury reported receiving grants from GSK and AstraZeneca; receiving fees for lectures from AstraZeneca, GSK, and Chiesi during the conduct of the study; chairing the Lothian Respiratory Managed Clinical Network for respiratory medicine; being the Scottish Government lead for COPD Respiratory Care Action Plan planning; and chairing the Act on COPD group for AstraZeneca in Scotland. Dr De Soyza reported receiving grants from AstraZeneca, Bayer, GSK, Teva Pharmaceuticals, and Pfizer; and speaker fees and travel support fees from AstraZeneca, Bayer, GSK, Teva Pharmaceuticals, and Pfizer to attend congress outside the submitted work. Dr Fielding reported receiving grants from NIHR during the conduct of the study. Dr Gompertz reported receiving grants from NIHR and per-patient payments for recruited patients from the UK funding body, NIHR, during the conduct of the study. Dr Haughney reported receiving consulting fees from AstraZeneca and speaker fees from Chiesi outside the submitted work. Dr MacLennan reported receiving grants from NIHR to deliver the project to his institution during the conduct of the study. Dr Morice reported receiving grants from NIHR HTA during the conduct of the study; consulting fees from Merck; and grants from GSK, Trevi, and Nocion outside the submitted work. Dr Norrie reported receiving grants from the University of Aberdeen NIHR during the conduct of the study; receiving grants from GSK to the University of Edinburgh; receiving grants from RESPIRE to the University of Edinburgh; and chairing the MRC/NIHR Efficacy and Mechanism Evaluation Board, 2019 to present, outside the submitted work. Dr Price reported having advisory board membership and consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Viatris, and Teva Pharmaceuticals; receiving grants and unrestricted funding for investigator-initiated studies (conducted through the Observational and Pragmatic Research Institute) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and the UK National Health Service; receiving payment for lectures and speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; receiving payment for travel, accommodation, and meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, and Teva Pharmaceuticals; having stock and stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owning 74% of the social enterprise Optimum Patient Care Ltd (Australia and United Kingdom) and 92.61% of Observational and Pragmatic Research Institute (Singapore); having 5% shareholding in Timestamp, which develops adherence monitoring technology; being a peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation program and for HTA; and having been an expert witness for GSK. Dr Vestbo reported receiving advising fees from ALK-Abelló; advising and presentation fees from AstraZeneca and Chiesi; presentation fees from Boehringer Ingelheim; and advising fees from Teva Pharmaceuticals outside the submitted work. Dr Walker reported chairing the British Thoracic Society. Dr Wedzicha reported receiving grants from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, and 37 Clinical; and consulting fees for serving on advisory boards for GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Roche, Sanofi, Gilead, Empirico, Recipharm, EpiEndo, Bristol Myers Squibb, Pulmatrix, and Pieris outside the submitted work. Dr Wilson reported receiving institutional research funding from Aseptika, Brainomix, Celgene Corporation, GSK, and Insmed; speaker fees from Boehringer Ingelheim and Trevi Therapeutics; and support to attend conferences from Chiesi. Dr Wu reported receiving grants from NIHR during the conduct of the study. Dr Lipworth reported receiving grants from AstraZeneca, Sanofi, and Chiesi; and consulting fees from Glenmark and Lupin outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment, Randomization, and Follow-Up of Patients
BP indicates blood pressure; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in the first second of expiration; and IC, inclusion criteria.
Figure 2.
Figure 2.. Primary and Secondary Outcomes Expressed as Adjusted Incidence Rate Ratios (IRRs) or Hazard Ratios (HRs)
Estimates of IRR and HR and corresponding 95% CIs were obtained from models adjusted for center (as a random effect), recruitment setting (primary or secondary care), age centered on the mean, sex, smoking status (current vs former), forced expiratory volume in the first second of expiration percentage predicted, number of COPD exacerbations in the previous year, baseline COPD treatment, and treatment with long-term antibiotics. COPD indicates chronic obstructive pulmonary disease; PY, person-years.
Figure 3.
Figure 3.. Freedom From Exacerbation of Chronic Obstructive Pulmonary Disease in the 2 Trial Groups
The curves include median time to first exacerbation for the bisoprolol and placebo groups.
See this image and copyright information in PMC

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