Efficacy and Safety of Bisoprolol in Patients with COPD: A Systematic Review and Meta-Analysis

Authors, Journal, Affiliations, Type, DOI

• Authors: Zhouzhou Feng, Lu Zhang, Yaqin Wang, Hong Guo, Jian Liu
• Journal: International Journal of Chronic Obstructive Pulmonary Disease (Dovepress), December 2023
• Affiliations: First Clinical Medical College of Lanzhou University; Gansu Maternal and Child Health Hospital/Gansu Central Hospital, China
• Type: PRISMA-compliant systematic review and meta-analysis of RCTs; registered at PROSPERO (CRD42023411032)
• DOI: 10.2147/COPD.S438930

Overview

This meta-analysis pooled 35 RCTs (n=3,269) evaluating bisoprolol in COPD patients. Bisoprolol significantly improved lung function (FEV1 +0.46 L, FVC +0.20 L, FEV1% +0.64pp), exercise performance (6MWD MD +1.37), and reduced inflammatory markers (IL-6, IL-8, CRP) compared to controls. Adverse event rates were no higher with bisoprolol (RR 0.83; p=0.38). Crucially, subgroup analyses showed these benefits were present in both COPD+HF and COPD-alone patients, prompting the authors to conclude bisoprolol is safe and effective for COPD independent of cardiac comorbidity. These findings stand in partial contrast to the BLOCK COPD RCT (Dransfield 2019, NEJM), which showed metoprolol caused harm in COPD without cardiac indication — the methodological limitations of this meta-analysis (predominantly unblinded Chinese RCTs, non-placebo controls, high heterogeneity) limit its ability to resolve this tension.

Keywords

Bisoprolol, COPD, beta-blocker, beta1-selective, lung function, FEV1, inflammatory cytokines, meta-analysis, systematic review

Key Takeaways

Study Identification

• Databases: PubMed, Web of Science, Cochrane, CNKI, Wan Fang (to June 2023)
• 299 studies initially identified; 35 RCTs met inclusion criteria
• 32 of 35 studies were in Chinese; 3 in English — significant source of regional/language bias
• Only 2 of 35 studies used placebo controls; 24 used "usual care" (highly variable: cardiotonic, diuretic, vasodilator, mucolytic, bronchodilator, antibiotic combinations)
• Only 2 of 35 studies were blinded; 12 of 35 explicitly reported randomisation method
• Quality assessment by Cochrane risk-of-bias tool

Primary Outcome — Lung Function

FEV1 (22 studies, n=subset):

• MD +0.46 L (95% CI 0.27–0.65; P<0.001); random-effects model (I²=78.2%)
• Subgroup COPD+HF: MD +0.32 L (95% CI 0.07–0.56; P=0.011)
• Subgroup COPD alone: MD +0.57 L (95% CI 0.29–0.85; P<0.001)
• Sensitivity analysis: stable; no publication bias (Begg p=0.430; Egger p=0.264)

FEV1% (14 studies):

• MD +0.64pp (95% CI 0.42–0.86; P<0.001); random-effects (I²=72.6%)
• Subgroup COPD+HF: MD +0.70pp (P<0.001); COPD alone: MD +0.54pp (P<0.001)

FVC (10 studies):

• MD +0.20 L (95% CI 0.05–0.34; P=0.008); random-effects (I²=84.4%)
• Subgroup COPD+HF: MD +0.10 L (P=0.018); COPD alone: MD +0.46 L (P<0.001)

Secondary Outcomes — Exercise Performance

6-Minute Walk Distance (6 studies):

• MD +1.37 (95% CI 1.08–1.66; P<0.001); random-effects (I²=66.0%)
• Subgroup COPD+HF: MD +1.05 (P<0.001); COPD alone: MD +1.65 (P<0.001)
• Note: The small absolute MD values suggest possible unit/scaling inconsistency across included studies; clinical magnitude is uncertain.

Secondary Outcomes — Safety

Adverse Events (14 studies):

• RR 0.83 (95% CI 0.54–1.26; P=0.382); fixed-effects model (I²=24.9%)
• Subgroup COPD+HF: RR 0.77 (P=0.315); COPD alone: RR 0.97 (P=0.944)
• No significant increase in adverse events with bisoprolol — suggests safety across COPD populations

Secondary Outcomes — Inflammatory Markers

IL-6 (6 studies):

• MD −1.16 (95% CI −1.67 to −0.65; P<0.001); random-effects (I²=90.0%)
• Subgroup COPD+HF: MD −1.93 (P=0.006); COPD alone: MD −0.78 (P<0.001)

IL-8 (6 studies):

• MD −0.94 (95% CI −1.32 to −0.56; P<0.001); random-effects (I²=83.1%)
• Subgroup COPD+HF: MD −1.43 (P<0.001); COPD alone: MD −0.71 (P<0.001)

CRP (10 studies):

• MD −1.74 (95% CI −2.40 to −1.09; P<0.001); random-effects (I²=95.5%)
• Subgroup COPD+HF: MD −1.53 (P<0.001); COPD alone: MD −1.80 (P<0.001)

Proposed Mechanisms

• Bisoprolol β1/β2 selectivity ratio ~14:1 (vs ~2:1 for metoprolol) — high selectivity minimises β2-mediated bronchoconstriction
• HR reduction → decreased myocardial oxygen demand → improved cardiac output → reduced pulmonary congestion
• Anti-inflammatory effects: reduces neutrophil chemotaxis, oxygen free radical production, airway mucin content, cytokine levels, and endothelin-1 release
• Modulates β2-AR upregulation in lungs → may improve bronchodilator efficacy
• Two ongoing RCTs at time of publication: ISRCTN10497306, NCT03917914

Limitations of the Document

1. Predominantly Chinese evidence base: 32/35 studies in Chinese — strong regional bias; results may not generalise internationally
2. Near-universal lack of blinding: Only 2/35 blinded; bisoprolol's HR-lowering effect makes blinding difficult but introduces substantial performance/detection bias
3. Non-placebo comparators dominant: 24/35 studies used "usual care" with heterogeneous co-interventions (diuretics, vasodilators, mucolytics, bronchodilators) — confounds attribution of effect to bisoprolol
4. High heterogeneity: I² 66–95% across most outcomes; random-effects models used but sources of heterogeneity incompletely explored
5. BLOCK COPD not cited or addressed: The Dransfield 2019 NEJM RCT (metoprolol, placebo-controlled, n=532) showing BB harm in COPD without cardiac indication was not discussed — a major omission
6. Patient selection overlap: ~70% of included studies involved COPD+HF patients; the COPD-alone subgroup is smaller and comprises primarily the lower-quality studies
7. Low overall RCT quality: Only 12/35 reported randomisation method; 2/35 blinded; no allocation concealment assessment reported across studies

Key Concepts Mentioned

• concepts/HF-COPD-Comorbidity — bisoprolol effects in COPD with and without HF; β1-selectivity ratio as mechanistic basis
• concepts/Beta-Blocker-Post-MI — bisoprolol as preferred cardioselective BB; COPD safety data

Key Entities Mentioned

• entities/COPD — primary disease; lung function and inflammatory marker outcomes
• entities/Bisoprolol — drug under study; high β1-selectivity (14:1); distinct from metoprolol

Wiki Pages Updated

• wiki/sources/bisoprolol-copd-jcopd-2023.md — created (this file)
• wiki/entities/COPD.md — added bisoprolol meta-analysis findings; new contradiction (bisoprolol MA vs BLOCK COPD); source_count updated
• wiki/concepts/HF-COPD-Comorbidity.md — added bisoprolol data to treatment section; updated β1-selectivity mechanism; new contradiction entry; source_count updated
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated