The impact of regular bisoprolol on the response to salbutamol in asthma: A double‐blind randomized placebo‐controlled crossover trial

Abstract

Background and objective: Non-selective beta-blockers impair the bronchodilator response to beta 2-agonists. Cardio-selective beta 1-blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta 1blocker treatment in people with asthma. Methods: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV 1). Immediately after mannitol challenge, salbutamol (100, 100 and 200 μg) was administered via spacer at 5-min intervals with repeated FEV 1 measures. The FEV 1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. Results: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV 1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the openlabel extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. Conclusion: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardioselective beta 1-blocker, bisoprolol, compared to placebo.

The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports

“…A randomised placebo-controlled cross-over trial of 19 adults with mild or moderate asthma given bisoprolol daily for a minimum of 2 weeks found no difference in exacerbations between the groups. 37 Rescue beta-agonist therapy after a controlled bronchoconstriction was also non-inferior with bisoprolol treatment.…”

“…24 However, the bronchodilator response to beta-agonist therapy is maintained during continuous treatment with cardio-selective beta 1blockers. [35][36][37]…”

Therapeutic Properties of Highly Selective β-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease

“…Less blockade of peripheral β 2 -adrenoceptors with a selective agent reduces the likelihood feelings of cold in the extremities [16][17][18] Controlled clinical trials of bisoprolol (vs. lisinopril [19]) and nebivolol (vs. metoprolol [20]) have demonstrated effective BP lowering, and no cause for concern regarding worsening of limb ischaemia Glycaemic control Many reports have described a worsening of glycaemic control during treatment with a β-blocker and use of a cardioselective agent helps to minimise these effects [17,18] The clinical significance of this phenomenon may have been overrated, however, worsened glycaemia may be unrelated to β-blockade [21],,and use of a β-blocker in a large diabetes prevention trial was not associated with increased risk of diabetes [22] Bisoprolol or nebivolol has not been associated with worsening of glycaemia [7,[23][24][25][26][27][28][29] Asthma and COPD Bronchospasm in patients with COPD or asthma may be exacerbated by blockade of β 2 -adrenoceptors in the smooth muscle of the airways [30] Non-selective β 1 -blockers, but not β 1 -selective agents, increase the risk of asthma exacerbations [31] A recent (2020) randomised, double-blind, crossover study confirmed that the bronchodilatory effects of bisoprolol were non-inferior during treatment with bisoprolol vs. placebo [32] Such findings have led to a reappraisal of the use of selective β 1 -blockers in patients with asthma or COPD [30,33]; β 1selective agents are no contraindicated in Europe only for "severe bronchial asthma" Erectile function β-blockers, have been associated with new or exacerbated erectile dysfunction [34], although neither bisoprolol nor nebivolol were associated with sexual dysfunction [35][36][37] Nebivolol improved erectile function vs. metoprolol [38,39], or atenolol (± chlorthalidone) [40] Another study demonstrated fewer patients reporting vs. not reporting sexual dysfunction on nebivolol vs. other β-blockers…”

“…A recent (2020) randomised, double-blind, crossover study confirmed that the bronchodilatory effects of bisoprolol were non-inferior during treatment with bisoprolol vs. placebo [ 32 ]…”

Cardiac‐specific beta‐blockers and asthma: An end to fear?

“…2 The recent publication in Respirology by Bennet et al and the Waikato research team has used a randomorder, double-blinded, placebo-controlled, non-inferiority, crossover study of 19 adults with mild to moderate asthma to demonstrate the safety of bisoprolol. 5 Bisoprolol is a β 1 -selective adrenoreceptor beta-blocker that is widely used for stable, chronic, moderate to severe heart failure. The study participants were adults with mild to moderate asthma as defined by Global Initiative for Asthma (GINA) 2018 Steps 1-2.…”