Long-acting beta-2 agonists (LABAs) are widely used.
The BTS/SIGN guidelines on asthma suggest commencing LABAs after a trial of low-dose inhaled corticosteroids and before the dose of inhaled corticosteroids is increased.
However, trials and studies have repeatedly suggested that LABAs may be associated with exacerbations and asthma-related deaths.
Concerns about LABAs were first raised following case reports of deaths among patients who misused the drug for acute relief of symptoms. The reports were followed by a phase-IV clinical trial of salmeterol that found a three-fold increase in the risk of death when compared with salbutamol used regularly.
The results of the Salmeterol Multicentre Asthma Research Trial (SMART) revealed that patients using salmeterol had a four-fold increased risk of asthma-related deaths, and warnings were then placed on labels.
Further concern has been caused by a recent meta-analysis by Saltpeter et al showing that LABAs increased severe and life-threatening asthma exacerbations, as well as asthma-related deaths.
The conclusions of this meta-analysis have been criticised, however, and in general it is difficult to draw clear conclusions on the issue of LABA treatment, as the evidence is muddied by confounding factors.
LABAs are used to treat patients whose asthma is so severe that treatment with short-acting beta agonists and inhaled corticosteroids is not sufficient.
In these patients it is difficult to distinguish cause and effect: does LABA treatment cause exacerbations, or are the associations seen in studies due the greater severity of asthma in patients in whom LABA treatments are prescribed? Some studies have given ‘confounding by indication’ as the explanation for the apparent risk.
Several studies have suggested that LABAs do not pose a risk when taken within the recommended dosage. Indeed, some have found that they produce good symptom control, that the lung function benefit is maintained and that the long-term effect is equivalent to doubling the dose of inhaled corticosteroids.
Difficulties in designing effective trials, the large numbers required to demonstrate an event as rare as asthma-related mortality and the frequency of inaccurate coding of asthma on death certificates have contributed to the lack of consensus on the safety of LABAs.
A common-sense approach to monitoring patients taking LABAs and to stopping treatment if there is no response is described in the current BTS/ SIGN guidelines. This should pick up potential LABA-related exacerbations early and prevent unnecessary exposure to LABAs.
Other possible explanations for contradictory results may lie in genetic differences between patients.
Beta-2 agonists have been shown to be associated with a loss of bronchoprotection to non-specific bronchoconstrictors, and a possible augmented response of the airways to allergens. Asthmatic patients with the Arg/Arg genotype for the beta-2 adrenergic receptor may also experience a deterioration in air flow and a worsening in asthma control when using beta-2 agonists.
It has been reported that a high proportion of ethnic minorities, particularly black patients, have this genotype. A recent study in Scotland found that 13 per cent of the children and young adults studied had this genotype, and that it was associated with exacerbations, particularly in those exposed to regular salmeterol.
The evidence on whether steroids reduce risk is conflicting. In a study looking at salmeterol versus corticosteroids patients controlled on inhaled corticosteroids were randomised to continuing treatment, a placebo or salmeterol. Researchers found evidence of increasing airway inflammation at tissue level in the salmeterol group.
Synergistic interactions have been identified at the molecular level, and clinical trials have also shown that combination therapy is more effective than monotherapy.
However, a recent meta-analysis found that concomitent use of inhaled steroids did not guard against the adverse effects of LABAs.
It is reasonable to conclude that they should not be prescribed in isolation according to current guidelines.
Further research is needed to identify the effect of corticosteroids on airway inflammation caused by LABAs, at molecular and disease levels.
In future, a better understanding of the genes involved is likely to dictate the way doctors prescribe, but for now GPs should regularly review patients on LABAs. If the medication does work, it is important that is stopped and the dosage of inhaled corticosteroids increased to 800µg/24 hours. It would be wise to follow the principle of using the lowest dose that controls the disease.
Overall, with the present body of knowledge there is no need for GPs to change current prescribing habits.
Dr Upadhyay is clinical research fellow at the department of primary care and social medicine, Imperial College London