Abstract
Background and objective
Recent observational data suggest that cardioselective β-blockers like bisoprolol are safe and beneficial for patients with COPD. However, the acute effects of bisoprolol on lung and cardiovascular function in these patients is unclear, a gap that this study aimed to address.
Methods
This was a subanalysis of pre-randomisation screening visit data from the ongoing Preventing Adverse Cardiac Events (PACE) in COPD randomised controlled trial. If all other eligibility criteria were met, participants were orally administered an unblinded 1.25 mg tablet of bisoprolol. Post-bronchodilator spirometry, heart rate and blood pressure were monitored at 0, 30 (cardiovascular parameters only), 60 and 120 min. For this subanalysis, respiratory intolerance was defined as a decrease in forced expiratory volume in 1 s (FEV1) (L) ≥200 mL and ≥12% from the 0-min FEV1 (L) value; and cardiovascular intolerance was defined as systolic blood pressure (SBP) falling below 100 mmHg at 1 or 2 h.
Results
Of 359 consented participants, 292 conducted the test-dose procedure. 13 (4.5%) were respiratory intolerant and six (2.1%) were cardiovascular intolerant at 1 or 2 h. No participant was intolerant for both. There was no significant difference in FEV1 (L) or SBP at baseline At 120 min the intolerant group's mean FEV1 had significantly decreased to 1.05 L (95% CI 0.86–1.25 L; p<0.0001); the tolerant group experienced no change (1.10, 1.05–1.14 L; p=0.33).
Conclusion
The administration of 1.25 mg bisoprolol was acutely well tolerated in >95% of COPD patients.
Shareable abstract
4.5% of 292 COPD patients experienced an acute decrease in lung function at 2 h following an oral 1.25 mg dose of the cardioselective β-blocker bisoprolol. A further 2.1% experienced systolic blood pressure decrease below 100 mmHg. https://bit.ly/4miPS3y
Introduction
COPD continues to be one of the most prevalent causes of global burden and mortality, ranking third in mortality behind cardiovascular diseases (CVD) [1, 2]. Independent of tobacco smoking as a major shared risk factor [3], airflow limitation, characteristic of COPD, is also associated with development of CVD [4]. It is therefore unsurprising that these diseases are often comorbid [5], and that CVD-associated mortality is a significant cause of burden and mortality in COPD patients [6–8]. Despite advancements in the management of CVD and COPD, there is an ongoing need to further improve patient outcomes.
β-blockers remain a cornerstone of pharmacotherapy for CVD, particularly in the management of heart failure with reduced ejection fraction, coronary heart disease and atrial fibrillation [9, 10]. Their strong antagonism of β-adrenergic receptors mediates clinically beneficial reductions in heart rate and stroke volume. However, in clinical practice, the use of this class of drugs in patients with both COPD and CVD has historically been strongly cautioned, potentially discouraging use and leading to under-prescription [11, 12]. This is due to the perceived risks in blocking the β-agonist effects of inhaled bronchodilators on airway smooth muscle β2-receptors. Although a valid concern for the first generation of β-blockers (e.g. propranolol) which nonspecifically targeted all β-receptor subtypes, some of the β-blockers favoured in modern clinical practice, such as bisoprolol and metoprolol, have a significantly higher affinity for β1-receptors that are predominantly located on cardiomyocytes [13–15]. Most available literature evaluated the earlier, less selective β-blockers such as propranolol, often using superseded criteria and procedures for diagnosing COPD and assessing lung function [16–25]. As such, there is a paucity of evidence describing whether a single dose of a β1-cardioselective β-blocker would deleteriously impact COPD patient respiratory and cardiovascular function.
Recently, there has been renewed interest in addressing the gap in literature regarding the long-term safety and efficacy profile of contemporary β1-selective β-blockers in people with COPD defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria [2, 26–30]. Using data from the ongoing Preventing Adverse Cardiac Events (PACE) in COPD trial, we investigated whether a single low dose of bisoprolol, a cardioselective β1-receptor blocker, would acutely impact the lung function and blood pressure in people with stable COPD.
Methods
The PACE in COPD trial (clinicaltrials.gov identifier NCT03917914; https://ctri.nic.in identifier CTRI/2020/08/027322.) protocol has been described previously [31]. It is an ongoing 1:1 randomised, double-blinded trial with a 24-month follow-up in which eligible participants in Australia, India, New Zealand and Sri Lanka orally self-administer 1.25–5 mg bisoprolol or a matched placebo once daily for 2 years.
The PACE in COPD study was approved by the Sydney Local Health District human research ethics committee at The Concord Repatriation General Hospital (2019/ETH08709). In New Zealand, the study was approved by the health and disability ethics committee at the Ministry of Health, Wellington (2022 AM 9124). In India, each clinical site's institutional ethics committee individually approved the study. In Sri Lanka, the study was approved by the ethics review committee, Faculty of Medicine, University of Kelaniya (P/127/09/2021) and the National Medicines Regulatory Authority (NMRA/CTRD/P60/12-4/2022).
To be eligible for the PACE study, participants had a diagnosis of COPD, per the GOLD 2019 criteria [32] with a post-bronchodilator forced expiratory volume in 1 s (FEV1) of ≥30% and ≤70% predicted and a 24-month history of at least one exacerbation that required treatment with antibiotics and/or oral corticosteroids.
If all other eligibility criteria were met, participants performed an unblinded test-dose procedure. This involved administration of a 1.25 mg oral dose of bisoprolol (0 min) followed by regular spirometry (0, 60 and 120 min) and cardiovascular (0, 30, 60 and 120 min) measurements (systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate) under study staff supervision. Participants withheld smoking tobacco for 1 h prior to the test and were bronchodilated before the start of the test-dose procedure, either:
1) by 400 mg of inhaled salbutamol for the pre–post spirometry, if all screening procedures were conducted in a single visit; or
2) by taking their regular bronchodilator maintenance medication if the test-dose procedure was conducted in a second, split-screening visit.
This analysis defined respiratory intolerance as a decrease in a participant's 0-min post-bronchodilator FEV1 values of ≥200 mL and ≥12% of absolute FEV1 at 1 or 2 h. These thresholds were selected to align with the clinical definition of bronchodilator reversibility provided by the 2019 Global Initiative for Asthma report [33]. A secondary definition which aligned with the PACE in COPD trial eligibility criteria for respiratory intolerance was also investigated, with the same thresholds but only applied to the 2-h lung function measurements. Cardiovascular intolerance was defined as a reduction in SBP <100 mmHg at the 1 or 2 h time interval; this conservative threshold was selected to minimise the risk of a participant experiencing hypotension.
The primary outcome was the change in absolute FEV1 (L), with a secondary outcome investigating the change in FEV1 expressed as the percentage of predicted value after 120 min. Other secondary outcomes included the change in forced vital capacity (FVC) (absolute), SBP, DBP and heart rate; as well as the change between successive measurements of FEV1 and cardiovascular vital signs within each group. The authors and all study personnel of this study remained blinded to subsequent participant randomisation and could access blinded data from the screening and baseline visits only.
Analysis was performed in STATA Basic Edition (version 18; StataCorp, TX, USA). Participants were grouped by their tolerance status and differences between the groups for each outcome variable at each time point were analysed using generalised linear regression adjusted for age, sex and antihypertensive use (SBP and DBP analysis only). Least-square (adjusted) means were generated for each time point and compared to determine significant changes within, and between, tolerance groups. Univariable analysis of demographic and medical history (table 1 presents a complete list of variables included) for predictors of respiratory intolerance was performed using binary logistic regression. For the analysis of difference in pre- and post-bronchodilator FEV1 values, the pre-bronchodilator FEV1 was included as a covariate in a multivariable binary logistic analysis. A p-value of <0.05 was used to indicate statistical significance (hereafter referred to as “significant”).
TABLE 1.
Baseline demographics and medical history of consented participants who undertook the baseline bisoprolol test-dose procedure
| Respiratory# | Cardiovascular¶ | Total | |||
|---|---|---|---|---|---|
| Tolerant | Intolerant | Tolerant | Intolerant | ||
| Participants | 279 | 13 | 286 | 6 | 292 |
| Age years | 67.7±7.5 | 65.1±8.5 | 67.6±7.6 | 70.2±5.4 | 67.6±7.6 |
| Male | 230 (82.4) | 12 (92.3) | 237 (82.9) | 5 (83.3) | 242 (82.9) |
| BMI kg·m−2 | 22.7±6.8 | 22.2±3.7 | 22.8±6.7 | 19.9±2.5 | 22.7±6.7 |
| Smoking status | |||||
| Never | 21 (7.5) | 3 (23.1) | 24 (8.9) | 0 (0.0) | 24 (8.2) |
| Former | 223 (79.9) | 9 (69.2) | 226 (79.0) | 6 (100.0) | 232 (79.5) |
| Current | 35 (12.5) | 1 (7.7) | 36 (12.6) | 0 (0.0) | 36 (12.3) |
| Current smoker pack-years | 33.0±22.2 | 40 | 32.2±22.3 | 0±0.0 | 32.2±22.3 |
| LAMA | 106 (38.0) | 7 (53.8) | 112 (39.2) | 1 (16.7) | 113 (38.7) |
| LAMA/LABA | 22 (7.9) | 2 (15.4) | 24 (8.4) | 0 (0.0) | 24 (8.2) |
| Current LAMA/LABA/ICS | 30 (10.8) | 0 (0.0) | 29 (10.1) | 1 (16.7) | 30 (10.3) |
| Current antihypertensives | 88 (31.5) | 5 (38.5) | 92 (32.2) | 1 (16.7) | 93 (31.8) |
| Spirometry+ | |||||
| Pre-BD FEV1 L | 1.02±0.34 | 1.15±0.42 | 1.03±0.34 | 0.83±0.09 | 1.03±0.34 |
| Pre-BD FEV1 % pred | 42.1±11.5 | 46.2±12.4 | 42.3±11.6 | 38.7±5.9 | 42.3±11.5 |
| Post-BD FEV1 L | 1.10±0.35 | 1.28±0.40 | 1.11±0.36 | 0.89±0.13 | 1.11±0.36 |
| Post-BD FEV1 % pred | 45.3±11.9 | 51.9±10.4 | 45.6±12.0 | 43.3±8.0 | 45.6±11.9 |
| Pre-Post FEV1 change % | 8.3±10.0 | 14.2±10.8 | 8.6±10.2 | 6.7±5.7 | 8.6±10.1 |
| Post-BD FVC L | 2.22±0.71 | 2.52±1.01 | 2.24±0.7 | 1.64±0.43 | 2.23±0.73 |
| FEV1/FVC ratio | 0.51±0.11 | 0.53±0.09 | 0.51±0.11 | 0.57±0.11 | 0.51±0.11 |
| Cardiovascular parameters§ | |||||
| Heart rate beats·min−1 | 82.2±10.1 | 84.8±16.8 | 82.3±10.4 | 80.7±12.0 | 80.7±9.7 |
| SBP mmHg | 131.0±15.3 | 127.6±14.8 | 131.3±15.0 | 111±13.7 | 130.9±15.2 |
| DBP mmHg | 80.7±9.7 | 84.8±16.8 | 80.9±9.6 | 71.5±10.2 | 82.3±10.4 |
| Country of residence | |||||
| Australia | 47 (16.8) | 0 (0.00) | 46 (16.1) | 1 (16.7) | 47 (16.1) |
| New Zealand | 25 (9.0) | 1 (7.7) | 26 (9.1) | 0 (0.0) | 26 (8.9) |
| India | 65 (23.3) | 8 (61.5) | 73 (25.5) | 0 (0.0) | 73 (25.0) |
| Sri Lanka | 142 (50.9) | 4 (30.8) | 141 (49.3) | 5 (83.3) | 146 (50.0) |
Data are presented as n, mean±sd or n (%). Intolerance was defined using this analysis’ primary definition. n=292. LAMA: long-acting muscarinic antagonist; LABA: long-acting β-agonist; ICS: inhaled corticosteroid; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; SBP: systolic blood pressure; DBP: diastolic blood pressure. #: defined as a decrease in FEV1 ≥200 mL and ≥12% from the 0-min FEV1 value; ¶: defined as SBP falling below 100 mmHg at 1 or 2 h; +: post-bronchodilator spirometry values set as time 0 for the test dose; §: cardiovascular parameters set as time 0 for the test dose.
Results
From the 359 participants who consented to the study, 292 passed initial screening procedures and were administered the test-dose of bisoprolol (figure 1). The baseline demographics and medical history are shown in table 1. In brief, the mean±sd age was 67.6±7.6 years; 242 (82.9%) were male; and 91.8% had a history of tobacco smoking.
FIGURE 1.
Assessment for eligibility of participants who consented to participate in the Preventing Adverse Cardiac Events (PACE) in COPD trial, and bisoprolol test-dose outcome using the primary exploratory definition of respiratory intolerance. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; OCS: oral corticosteroids. #: participants could be excluded for not meeting multiple eligibility criteria.
Two adverse events were reported as being associated with the test-dose procedure: a rapid decrease in SBP in a participant who self-administered oral opioids during the monitoring period without alerting investigators, and a participant reporting chest pain due to the number of spirometry manoeuvres performed. No acute emergence or worsening of respiratory symptoms were reported by participants.
Of the 292 participants, 13 (4.5%) were identified as respiratory intolerant at the 1- or 2-h lung function measurements, with nine (3.1%) participants intolerant at 2 h only and deemed ineligible using the PACE in COPD eligibility criteria. A further six (2.1%) participants were identified as having cardiovascular intolerance. No participant was both respiratory and cardiovascular intolerant.
Respiratory intolerant at 1 or 2 h (n=13)
The change in FEV1 (L) during the monitoring interval is shown in figure 2 for the respiratory-intolerant group. At 0 min the adjusted mean FEV1 (L) of the tolerant group was 1.10 L (95% CI 1.06–1.14 L), and 1.24 L (95% CI 1.05–1.44 L) in the intolerant group. The difference in these values was not significant (p=0.164). At 60 min, the tolerant group's mean adjusted FEV1 was 1.11 L (95% CI 1.06–1.15 L), which was not a statistically significant change from the 0-min value (p=0.460). The intolerant group's 60-min value of 1.03 L (95% CI 0.83–1.22 L) was a significant decrease from its 0-min value (p<0.0001). The difference between the tolerant and intolerant group values was not significantly different (p=0.441). At 120 min, the tolerant group mean adjusted FEV1 (L) was 1.10 L (95% CI 1.05–1.14 L), and 1.05 L (95% CI 0.86–1.25 L) in the intolerant group. The tolerant group FEV1 (L) at 120 min was not significantly different from the 0-min value (p=0.329), but the intolerant group mean FEV1 was significantly lower (p<0.0001) than baseline. Neither group's 120-min values were significantly different from the 60-min values. The difference between the adjusted mean 120-min FEV1 (L) values was not significant (p=0.674). There were no significant differences in FEV1 (L) in the cardiovascular-intolerant group (table 2).
FIGURE 2.
Adjusted mean post-bronchodilator forced expiratory volume in 1 s (FEV1) (L) values at 0, 60 and 120 min following oral administration of 1.25 mg bisoprolol, for the respiratory-tolerant (n=279) and -intolerant (n=13) groups. ****: p<0.0001 between successive measurements within a tolerance group; ####: p<0.0001 between 0-min and 120-min measurements.
TABLE 2.
Adjusted mean secondary cardiovascular and spirometry outcomes at 0, 30, 60 and 120 min following oral administration of 1.25 mg bisoprolol in the respiratory-tolerant and -intolerant groups and the cardiovascular-tolerant and -intolerant groups
| Respiratory tolerance | Cardiovascular tolerance | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| SBP mmHg | DBP mmHg | Heart rate beats·min−1 | FVC L | DBP mmHg | Heart rate beats·min−1 | FEV1 L | FEV1 % pred | FVC L | |
| 0 min | |||||||||
| Tolerant | 131 (129–133) | 81 (80–82) | 82 (81–83) | 2.22 (2.14–2.30) | 81 (80–82) | 82 (81–83) | 1.11 (1.07–1.15) | 45.63 (44.21–47.05) | 2.24 (2.16–2.32) |
| Intolerant | 127 (119–135) | 81 (76–86) | 84 (79–90) | 2.46 (2.08–2.85) | 72 (64–79) | 81 (73–89) | 0.92 (0.64–1.20) | 43.07 (33.23–52.90) | 1.67 (1.11–2.24) |
| 30 min | |||||||||
| Tolerant | 128**** (126–129) | 79**** (77–80) | 79**** (78–81) | Not performed at 30 min | 79**** (78–80) | 80**** (78–81) | Not performed at 30 min | ||
| Intolerant | 124 (116–132) | 81 (75–86) | 79* (74–85) | 62* (55–69) | 77 (69–85) | ||||
| 60 min | |||||||||
| Tolerant | 126* (124–127) | 77* (76–78) | 77**** (76–78) | 2.23 (2.15–2.32) | 78* (77–79) | 77**** (76–78) | 1.11 (1.07–1.15) | 45.44 (44.01–46.86) | 2.24 (2.16–2.32) |
| Intolerant | 122 (113–130) | 79 (74–85) | 76* (70–81) | 2.15 (1.76–2.53) | 62 (55–70) | 72* (64–80) | 0.91 (0.63–1.20) | 42.57 (32.73–52.40) | 1.75 (1.18–2.32) |
| 120 min | |||||||||
| Tolerant | 125#### (123–127) | 77#### (76–78) | 75****, #### (73–76) | 2.21* (2.12–2.29) | 77#### (76–79) | 75****, #### (73–76) | 1.10 (1.06–1.14) | 43.66 (42.24–45.08) | 2.21* (2.13–2.29) |
| Intolerant | 124 (115–132) | 80 (75–86) | 74#### (69–80) | 2.04 (1.66–2.43) | 59#### (51–66) | 72* (64–80) | 0.93 (0.64–1.22) | 43.66 (33.72–53.60) | 1.69 (1.12–2.26) |
| Between-group comparison | p=0.771 | p=0.192 | p=0.979 | p=0.423 | p<0.0001 | p=0.489 | p=0.258 | p=0.796 | p=0.077 |
Data are presented as mean (95% CI). SBP: systolic blood pressure; DBP: diastolic blood pressure; FVC: forced vital capacity; FEV1, forced expiratory volume in 1 s. *: p<0.05, ****: p<0.0001 between the adjusted mean and previous adjusted mean within a tolerance group; #: p<0.05, ####: p<0.0001 between the 0-min and 12-min measurements.
As shown in figure 3, the FEV1 expressed as percent predicted was significantly different between the tolerant (45.25%, 95% CI 43.82–46.69%) and intolerant (52.54%, 95% CI 45.86–59.23%) respiratory groups at 0 min (p=0.037). At 60 min, the tolerant group's mean adjusted value was 45.47% (95% CI 44.03–46.90%), which was not significantly different from the 0-min value. The intolerant group's decrease to 43.47% (95% CI 36.78–50.15%) was significant (p<0.0001). At this time point, the difference between the groups was not significant (p=0.567). At 120 min, each group's adjusted mean percent predicted FEV1 value had decreased; 45.00% (95% CI 43.56–46.44%) for tolerant, and 43.93% (95% CI 37.24–50.62%) for intolerant. The tolerant group FEV1 % predicted at 120 min was not significantly different from the 0-min value (p=0.350), but the intolerant group mean FEV1 was significantly lower (p<0.0001) than baseline. Neither group's 120-min values were significantly different from the 60-min values. The difference between the two groups was not significant at 120 min (p=0.759). There were no significant differences in FEV1 % predicted in the cardiovascular intolerant group (table 2).
FIGURE 3.
Adjusted mean post-bronchodilator forced expiratory volume in 1 s (FEV1) (percentage predicted) values at 0, 60 and 120 min following oral administration of 1.25 mg bisoprolol for the respiratory-tolerant (n=279) and -intolerant (n=13) groups. ****: p<0.0001 between successive measurements within a tolerance group; ####: p<0.0001 between 0-min and 120-min measurements.
The FVC was not significantly different between or within the tolerance groups in either the respiratory or cardiovascular outcomes (table 2).
Respiratory intolerant at 2 h (n=9)
Participants identified as respiratory intolerant using the PACE in COPD eligibility criteria definition had an adjusted 0-min mean FEV1 (L) of 1.25 L (95% CI 1.02–1.48 L); that of the tolerant group was 1.10 L (95% CI 1.06–1.14 L), with no statistically significant difference between the groups (p=0.219). At 120 min, the intolerant, ineligible group's mean adjusted FEV1 had significantly decreased from the 0-min value (p<0.0001) to 0.96 L (95% CI 0.72–1.19 L). The adjusted 0-min mean FEV1 (L) of the tolerant, eligible group had not changed (1.10 L, 95% CI 1.06–1.14 L; p=0.219). The difference between the adjusted mean 120-min FEV1 (L) values was not significant (p=0.239).
Expressed as FEV % predicted, the PACE protocol-defined intolerant participants had a mean, adjusted 0-min value of 51.97% (95% CI 43.96–59.98%) that significantly (p<0.0001) decreased to 38.97% (95% CI 30.96–46.98%) at 120 min. The tolerant, eligible participants had a 0-min mean adjusted value of 45.38% (95% CI 43.95–46.80%) and a 120-min value of 45.14% (95% CI 43.72–46.57%; p=0.387). The difference between the two groups was not significant at 0 (p=0.112) or 120 min (p=0.137). Further analysis of cardiovascular values and FVC can be found in the supplementary material.
Cardiovascular intolerant at 1 or 2 h (n=6)
The cardiovascular-tolerant group (n=286) had a mean adjusted SBP of 131 mmHg (95% CI 129–133 mmHg) at 0 min, while the intolerant group (n=6) mean SBP was 111 mmHg (95% CI 100–123 mmHg), which was significantly different (p=0.0013) (figure 4). By 120 min, the tolerant group mean SBP had decreased to 125 mmHg (95% CI 125–127 mmHg), which was significantly different from baseline (p<0.0001). The intolerant group mean SBP at 120 min was 91 mmHg (95% CI 80–103 mmHg), which was a significant decrease from baseline (p<0.0001). The difference between the tolerant and intolerant group SBP values at 120 min was significantly different (p<0.0001). There was no significant difference in SBP in the respiratory-intolerant group (table 2).
FIGURE 4.
Adjusted mean systolic blood pressure values at 0, 30, 60 and 120 min following oral administration of 1.25 mg bisoprolol for the cardiovascular-tolerant (n=279) and -intolerant (n=13) groups. *: p<0.05, ****: p<0.0001 between successive measurements within a tolerance group; ####: p<0.0001 between 0-min and 120-min measurements.
The mean adjusted DBP was similarly significantly different at 0 min between the cardiovascular-tolerant (81 mmHg, 95% CI 80–82 mmHg) and -intolerant groups (72 mmHg, 95% CI 64–79 mmHg; p<0.0001). At 120 min, both the tolerant (77 mmHg, 95% CI 76–66 mmHg; <0.0001) and intolerant (59 mmHg, 95% CI 51–66 mmHg; p<0.0001) groups had DBP values significantly lower than their 0-min values (table 2).
Within each group for both cardiovascular and respiratory tolerance/intolerance, the adjusted mean heart rate values at 120 min were significantly decreased from the baseline 0-min values (table 2), but were not significantly different between tolerant/intolerant groups.
Analysis of predictors of respiratory intolerance
Respiratory intolerance at 1 or 2 h was significantly associated with percentage difference between pre- and post-bronchodilator FEV1 (L): OR 1.07 (95% CI 1.01–1.105; p=0.015), followed by the participant residing in Sri Lanka with OR 4.37 (95% CI 1.27–15.03; p=0.019); and percentage-predicted post-bronchodilator FVC (OR 1.03, 95% CI 1.00–1.06; p=0.043).
When using the PACE in COPD trial eligibility definition of respiratory intolerance (decrease in a participant's 0-min post-bronchodilator FEV1 values of ≥200 mL and ≥12% of absolute FEV1 at 2 h only), the percentage difference in pre- and post-bronchodilator FEV1 prior to test-dose administration was the strongest predictor of respiratory intolerance with OR 1.10 (95% CI 1.03–1.17; p=0.005), followed by the absolute difference (p=0.018). No other variables reached statistical significance.
Discussion
This analysis used data collected from the ongoing PACE in COPD trial and aimed to determine if oral administration of 1.25 mg of the β1-receptor selective drug bisoprolol would cause an acute decrease in lung function or blood pressure. The results suggest that while there was a potentially clinically significant decrease in FEV1 in 4.5% of participants, lung function was preserved in the majority (>96.9%) over a 2-h period. When using the PACE in COPD protocol eligibility definition, this group decreased to 3.1%, with four participants from this analysis’ intolerance criteria demonstrating an improvement in lung function between 60 min and 120 min that re-classified them as tolerant. For both groups the strongest predictor was the percentage difference between pre- and post-bronchodilator FEV1 (L), even when adjusted for baseline pre-bronchodilator values. When investigating cardiovascular intolerance, only 2.1% experienced a decrease in SBP below 100 mmHg. All participants regardless of respiratory intolerance experienced a pharmacologically predictable and statistically significant decrease in blood pressure and heart rate during the procedure. The results in this study suggest that low-dose bisoprolol does not have significant acute effects on lung function or blood pressure in a large majority of COPD patients, and should be safe to be prescribed for treatment of comorbid CVD.
Although there is some recent literature documenting the short-term impact of β-blockers on the lung function of COPD patients [34–36], there is scant literature describing the acute effects of a single dose of β1-selective β-blockers such as bisoprolol. In addition, the studies with other β-blockers that were conducted were reported between 1966 and 2002 [16–25]. As such, they lack the standardised definition and diagnostic criteria currently used to identify COPD, and their methodologies are no longer aligned with current clinical or respiratory research practice. Given the comorbidity of COPD and heart failure, such a gap in the literature is significant, particularly when the prevailing clinical sentiment was that this class of drugs should be avoided due to perceived safety risks despite their potential benefits in the management of CVD. The results of this analysis provide contemporary evidence indicating that the risk of experiencing acute effects of highly selective β1-blockers may be marginal, while still providing cardiovascular benefit.
Bisoprolol and other cardioselective β-blockers have been administered safely by clinicians for decades based on evidence in many observational studies conducted using different patient populations and designs [26, 37–48]. More recently, the Bisoprolol in COPD Study (BICS) trial found no increased long-term risk of any kind in COPD patients administered bisoprolol versus placebo [2]. This contrasts with the results of the BLOCK COPD trial, which terminated early, due to an increased rate of severe exacerbations in the group that received metoprolol [27]. The reason for this disparity is unclear, but could be due to metoprolol's inferior cardioselectivity [13, 15], potentially leading to off-target antagonism of the β2-receptor in airway tissue. The results of the primary PACE analysis and the ongoing BRONCHIOLE trial investing metoprolol [49] may provide further evidence to inform future clinical decisions in this patient population.
This study has several strengths. Primarily it studied a large number of consented trial participants who underwent prior eligibility screening before the test dose procedure to ensure a representative sample of COPD patients. The study population was drawn from diverse settings including Australasia and South Asia. Furthermore, it uses a robust statistical model to minimise the potential influence of confounding variables in the analysis. One limitation could be the use of multiple spirometry measurements in a single visit. As each time interval required at least three concordant manoeuvres to produce a reliable dataset, participants were required to perform a minimum of nine manoeuvres over 2 h in a single screening visit. This may have led to a decline in measured values in some patients due to fatigue, potentially leading to submaximal exhalation and thus overestimation of the deleterious effects of bisoprolol.
In conclusion, these findings suggest that a low dose of a cardioselective β-blocker such as bisoprolol may only adversely affect a small proportion of COPD patients, with most demonstrating the predictable clinical effect of safe reductions in heart rate and blood pressure.
Acknowledgements
The authors would like to thank The George Institute Australian research team (Barangaroo, Australia): Ayesha Mallik, Brittany Aldridge, Chris Gianacas, Manuela Armenis and Junya Eguchi; the New Zealand Waikato coordinating centre team (Hamilton, New Zealand): Christine Tuffery and Anneke Marais; the George Institute Indian coordinating centre team (New Delhi, India): Shani Thankachen and Sachin Rana; the Sri Lankan RemediumOne coordinating centre team (Colombo, Sri Lanka): Poornima Ellawalla, Anne Vithushi and Niran Perera; as well as all the study participants involved in the PACE in COPD trial.
Footnotes
Provenance: Submitted article, peer reviewed.
PACE in COPD principal investigators: John Wheatley (Westmead Hospital, Sydney, Australia), Christopher Kosky (Sir Charles Gairdner Hospital, Perth, Australia), Siva Sivakumaran (Gold Coast University Hospital, Southport, Australia), John Upham (Princess Alexandra Hospital, Brisbane, Australia), Peter Bremner (TrialsWest Pty Ltd, Spearwood, Australia), Jack Drummer (Dunedin Hospital, Dunedin, New Zealand), Conroy Wong (Middlemore Hospital, Auckland, New Zealand), Lutz Beckert (University of Otago, Christchurch, New Zealand), Christopher Lewis (Greenlane Clinical Centre, Auckland, New Zealand), Uma Maheswari Krishnaswamy (St John's Medical College Hospital, Bangalore, India), D.J. Christopher (Christian Medical College, Vellore, India), Anant Mohan (All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India), Dhruva Chaudhry (Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India), Alok Nath (Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India), Amitha Fernando (Central Chest Clinic, Colombo, Sri Lanka), Dushantha Madegedara (Kandy National Hospital, Kandy, Sri Lanka), Eshanth Perera (National Institute of Respiratory Diseases, Wellisara, Sri Lanka), Ravini Karunattilake (Central Chest Clinic – Borella, Colombo, Sri Lanka), Vanessa McDonald (Hunter Medical Research Institute, Newcastle, Australia), Claudia Dobler (Liverpool Hospital, Sydney, Australia), Claude Farah (Concord and Repatriation Hospital, Sydney, Australia), Belinda Cochrane (Campbelltown Hospital, Sydney, Australia), Jeremy Wrobel (Fiona Stanley Hospital, Perth, Australia), Ian Yang (The Prince Charles Hospital, Chermside, Australia), Robert Hancox (Dunedin Hospital, Dunedin, New Zealand), Adjunct Richard Beasley (Medical Research Institute of New Zealand, Wellington, New Zealand), Caterina Chang (Waikato Hospital, Hamilton, New Zealand), Ashutosh Aggarwal (Postgraduate Institute of Medical Education and Research, Chandigarh, India) and Graham Hillis (Royal Perth Hospital, Perth, Australia).
Ethics statement: Per the main text, this publication's data is derived from the PACE in COPD study, which is registered at clinicaltrials.gov (NCT03917914) and the Clinical Trials Registry – India (CTRI/2020/08/027322). The PACE in COPD study was approved by the Sydney Local Health District Human Research Ethics Committee at The Concord Repatriation General Hospital (2019/ETH08709). In New Zealand, the study was approved by the Health and Disability Ethics Committee at the Ministry of Health, Wellington (2022 AM 9124). In India, each clinical site’s Institutional Ethics committee individually approved the study. In Sri Lanka the study was approved by the ERC, Faculty of Medicine, University of Kelaniya (P/127/09/2021) and the National Medicines Regulatory Authority (NMRA/CTRD/P60/12-4/2022).
Conflicts of Interest: Thomas F. Bradbury received a PhD top-up stipend funded by GSK for a portion of their candidature, during which time some work on this study was undertaken. A. Martin, C.C. Dobler, I.A. Yang, C.S. Farah, G.S. Hillis, C. Polak Scoowcroft, A. Aggarwal and S. Galgey have nothing to declare in relation to this work. R.J. Hancox declares that they are a staff member of the University of Otago, which received a grant from the Health Research Council of New Zealand; have received honoraria from GSK; and received honoraria and travel funding from AstraZeneca. C.L. Chang declares that the Health Research Council of New Zealand provided a grant for study, which was paid to the University of Otago then subcontracted out to their employer, Waikato Hospital. R. Beasley declares that he has previously received project grant from the Health Research Council of New Zealand; has received institutional research funding from AstraZeneca, Teva, and Fisher and Paykel Healthcare; received payment for personal fees from AstraZeneca and Cipla; received support from AstraZenca to attend meetings; has received medication and equipment from AstraZeneca to support clinical trials; was previously on the board of the Global Initiative for Obstructive Lung disease, and chaired the Asthma Guidelines group within the New Zealand Asthma and Respiratory Foundation. J.P. Wrobel has received honoraria from Boehringer Ingelheim for lectures; has received support to attend the “Airways” conference in Sydney, Australia, and the 2023 American Thoracic Society Annual Scientific Meeting in Washington, DC, USA. V.M. McDonald declares that they have received a grant from the National Health and Medical Research Council of Australia. B. Cochrane declares that they have received institutional grant funding from GSK for an investigator-sponsored study; have received personal consultancy fees from GSK and Sanofi; have received personal speaker's fees from AstraZeneca, Moderna and RX Global; and are a member of the COPD coordinating committee and the COPDX Guidelines, which are both associated with the Lung Foundation of Australia. C. Ranasinha declares that they have received payment from AstraZeneca for delivering lectures and received support for attending APSR 2024; received honorarium from The George Institute for Global Health via Remedium One. C.R. Jenkins declares that she has received personal and institutional grants from GSK and AstraZeneca; institutional grants from Chiesi, Sanofi and Menarini; consulting fees and payments for other activities from GSK, AstraZeneca, Chiesi, Sanofi and Menar; payment for expert testimony from AstraZeneca and Chiesi; travel bookings and accommodation paid for by GSK and AstraZeneca; is a director of the Lung Foundation Australia and the Asbestos and Dust Disease Research Institute Board; was a member of the data safety monitoring board without payment for the LAMA by Night, COPERNICUS and VCAPS4 studies; was a member of the CICERO – Catalina steering committee without payment; and has received payment for participating on advisory boards for GSK, AstraZeneca, Chiesi, Sanofi and Menarini.
Support statement: This study was funded by the National Health and Medical Research Council of Australia project grant APP1163143 and the Health Research Council of New Zealand project grant 19/487. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00591-2025.SUPPLEMENT
Data availability
The data that support the findings of this study are available from the corresponding author and the PACE in COPD steering committee upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00591-2025.SUPPLEMENT
Data Availability Statement
The data that support the findings of this study are available from the corresponding author and the PACE in COPD steering committee upon reasonable request.