Beta 2 -adrenoceptor agonists

Combination therapy

Asthma guidelines recommend adding long acting β ₂ -adrenoceptor agonists (LABAs) to inhaled glucocorticoids at step 3 in adults and adolescents before increasing the dose of beclometasone or other glucocorticoids above 400 microgram equivalents and certainly before increasing above 800 micrograms [ , ]. LABAs and combination therapy are licensed for children over 5 years, but have not yet been adequately evaluated below this age. They should not be used in isolation in asthma but as add-on therapy to inhaled glucocorticoids [ ].

Comparative studies

In the multicenter, double-blind, randomized EXCEL study, salmeterol + fluticasone propionate 50/250 micrograms bd was compared with formoterol + budesonide 12/400 micrograms bd in 694 patients with persistent asthma [ ]. The incidences and types of adverse events were similar in the two groups. The most commonly reported treatment-related adverse events were hoarseness/dysphonia (2% in each group), candidiasis of the mouth or throat (2% with salmeterol + fluticasone propionate, 1% with formoterol + budesonide), and headache (1% with salmeterol + fluticasone propionate, 2% with formoterol + budesonide). There were no deaths and only a few patients reported serious adverse events.

Cardiovascular

In the heart β ₁ - and β ₂ -adrenoceptors co-exist in a ratio of 3:1 [ ], and β ₂ -adrenoceptor agonists have direct effects on the heart. Cardiovascular adverse effects, such as heart failure and dysrhythmias, are more frequent in patients with COPD than in the general population, and such patients have a higher risk of hospitalization and death because of these conditions [ , ].

Eight men with mild asthma underwent measurement of forearm blood flow, a surrogate marker for peripheral vasodilatation [ ]. All received in sequential order the following: normoxia plus placebo, normoxia plus inhaled salbutamol 800 micrograms, hypoxia (S _p O ₂ 82%) plus placebo, and hypoxia plus inhaled salbutamol 800 micrograms. The period of mask breathing was 60 minutes and inhalation of salbutamol/placebo started after 30 minutes. While there were non-significant differences in blood pressure and potassium concentrations between the different treatments, forearm blood flow increased significantly by 45% in hypoxic patients inhaling salbutamol versus normoxic patients inhaling placebo. The authors concluded that the combination of hypoxia and inhalation of β ₂ agonists has serious systemic vascular adverse effects, potentially leading to pulmonary shunting and reduced venous return, which may be associated with sudden death. Furthermore, asthmatic patients in respiratory distress should be given β ₂ agonists and oxygen concomitantly whenever possible.

Intravenous and intracoronary salbutamol (10–30 micrograms/minute and 1–10 micrograms/minute respectively), and intravenous isoprenaline (1–5 micrograms/minute), a mixed β ₁ /β ₂ -adrenoceptor agonist, were infused in 85 patients with coronary artery disease and 22 healthy controls during fixed atrial pacing [ ]. Both salbutamol and isoprenaline produced large increases in QT dispersion (QT _onset , QT _peak , and QT _end ), more pronouncedly in patients with coronary artery disease. Dispersion of the QT interval is thought to be a surrogate marker for cardiac dysrhythmia [ ]. The authors concluded that β ₂ -adrenoceptors mediate important electrophysiological effects in human ventricular myocardium and can trigger dysrhythmias in susceptible patients.

In a blind, randomized study, 29 children aged under 2 years, with moderate to severe acute exacerbations of hyper-reactive airways disease, were treated with either a standard dose of nebulized salbutamol (0.15 mg/kg) or a low dose of nebulized salbutamol (0.075 mg/kg) plus nebulized ipratropium bromide 250 micrograms [ ]. Standard and low-dose nebulized salbutamol was given three times at intervals of 20 minutes and nebulized ipratropium bromide was given once. Clinical improvement, measured as O ₂ saturation and relief of respiratory distress, was similar in both groups. QT dispersion was measured at baseline and after treatment and was significantly increased only by the standard dose of nebulized salbutamol.

In a randomized, placebo-controlled study of the cardiac safety of formoterol 12 micrograms bd for 8 weeks in 204 patients with COPD, 24-hour continuous electrocardiography (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment [ ]. Only six patients (four taking formoterol and two taking placebo) had a predefined, prodysrhythmic event. Holter monitoring showed no significant differences between formoterol and placebo, for variables such as heart rate, number and rate of ventricular extra beats, ventricular tachycardia events, and supraventricular extra beats. Corrected QT intervals were similar. Cardiovascular adverse events were recorded in one patient taking formoterol (atrial flutter) and four taking placebo (atrioventricular block, palpitation, sinus bradycardia, supraventricular tachycardia). Hypertension was reported in one patient taking placebo. There were no important differences between the groups in overall adverse events. Although the results of this study are reassuring, larger studies providing more robust statistical power are required to assess the full benefit to harm balance of formoterol in this patient population.

Concerns have been raised about the long-term safety of long-acting β ₂ -adrenoceptor agonists; their overall adverse effects were reviewed in SEDA-30 (p. 198) and their respiratory adverse effects in SEDA-31 (p. 309). Subsequently, death from any cause was examined in the 3-year, multicenter, randomized, placebo-controlled TORCH trial in COPD, in which salmeterol + fluticasone (50 and 500 micrograms bd) was compared with salmeterol alone, fluticasone alone, or placebo (n = 6184; 1542 in the salmeterol arm; mean age 65 years) [ ]. All-cause mortality rates were 13% with the combination, 14% with salmeterol, 16% with fluticasone, and 15% with placebo. Although there was an 18% reduction in the risk of death with combination therapy compared with placebo, this did not quite reach statistical significance (HR = 0.825; 95% CI = 0.681, 1.002). There was no significant difference in the cardiovascular causes of death (3% of patients) or in all-cause mortality between salmeterol and placebo. The incidence of cardiac disorders was not significantly increased by salmeterol (reported event rates per study year, 0.087 with combination therapy, 0.114 with salmeterol alone, 0.102 with fluticasone, and 0.113 with placebo). Some have linked the use of β ₂ -adrenoceptor agonists to an increased risk of fractures, but the incidence of fractures was comparable across the groups.

The risk of acute myocardial infarction in patients using β ₂ -adrenoceptor agonists has been assessed in a nested case–control study (n = 2476) within a cohort of antihypertensive drug users in the Dutch PHARMO RLS database [ ]. Current users had an increased risk of acute myocardial infarction (crude OR = 1.36; 95% CI = 1.15, 1.61), but this risk was reduced after adjustment for the severity of asthma and COPD (adjusted OR = 1.18; 95% CI = 0.93, 1.49). Thus, only patients with ischemic heart disease with low cumulative exposure to β ₂ -adrenoceptor agonists had an increased risk of acute myocardial infarction (adjusted OR = 2.47; 95% CI = 1.60, 3.82). This excess risk was attributed to latent cardiovascular disease rather than to the direct effects of β ₂ -adrenoceptor agonists.