Long-acting inhaled bronchodilators for cystic fibrosis

Cystic fibrosis is a life-limiting inherited condition which affects one in 2500 newborns in the UK and 70,000 children and adults worldwide. The condition is multifaceted and affects many systems in the body. The respiratory system is particularly affected due to a build up of thickened secretions and a predisposition to infection. Inhaled bronchodilators are prescribed for 80% of people with cystic fibrosis in order to widen the airways and alleviate symptoms. Both short- and long-acting inhaled bronchodilators are used to improve respiratory symptoms. Short-acting inhaled bronchodilators take effect in minutes and typically last for four to eight hours (muscarinic antagonists). Long-acting inhaled bronchodilators also take effect within minutes but typically last for around 12 hours and sometimes longer. This review is one of two which are replacing a previously published review of both long- and short-acting inhaled bronchodilators.

This review aims to evaluate long-acting inhaled bronchodilators in children and adults with cystic fibrosis in terms of clinical outcomes and safety. If possible, we aimed to assess the optimal drug and dosage regimen.

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search: 10 October 2017.We also carried out a separate search of Embase and the reference lists of included trials. We searched clinical trials registries for any ongoing trials and made contact with pharmaceutical companies for any further trials.Date of Embase search: 11 October 2017.

Randomised or quasi-randomised parallel trials comparing long-acting inhaled bronchodilators (beta-2 agonists and muscarinic antagonists) with placebo, no treatment or a different long-acting inhaled bronchodilator in adults and children with cystic fibrosis.

Both authors independently assessed trials for inclusion (based on title, abstract and full text). The authors independently assessed the included trials for quality and risk of bias and extracted data. Discrepancies were resolved by a third party.

The searches identified 195 unique references, of which 155 were excluded on title and abstract. We assessed the full texts of the remaining references, excluded 16 trials (28 references) and included four trials (12 references) in the review with 1082 participants.One trial (n = 16) measuring the effect of beta-2 agonists reported an improvement in forced expiratory volume at one second (FEV₁) after treatment (at one month), but the trial was small with an unclear risk of bias so we judged the evidence to be very low quality. The trial did not report on participant-reported outcomes, quality of life or adverse events.Three trials (n = 1066) looked at the effects of the muscarinic antagonist tiotropium at doses of 2.5 µg and 5.0 µg in both the short term (up to 28 days) and the longer term (up to three months). Only one of the trials reported the change in FEV₁ (L) after 28 days treatment and showed no significant difference between groups; with 2.5 µg tiotropium, mean difference (MD) -0.02 (95% confidence interval (CI) -0.13 to 0.09), or 5.0 µg tiotropium, MD 0.00 (95% CI -0.10 to 0.10) (moderate-quality evidence). All three trials of muscarinic antagonists provided data on adverse events which were found to differ little from placebo at doses of 2.5 µg, risk ratio (RR) 1.01 (95% CI 0.92 to 1.11) or 5.0 µg, RR 0.98 (95% CI 0.90 to 1.06). Very little participant-reported outcome data or quality of life data were available for analysis. Two of the trials were at low risk of bias overall whilst the remaining trial was at an unclear risk overall.

Neither long-acting beta-2 agonists nor long-acting muscarinic antagonist bronchodilators demonstrate improvement in our primary outcome of FEV₁. No difference was observed between intervention and placebo in terms of quality of life or adverse events. The quality of evidence for the use of beta-2 agonists was very low. The use of a long-acting inhaled bronchodilator may help to reduce the burden of treatment for people with cystic fibrosis as it is taken less often than a short-acting inhaled bronchodilator, but future trials would benefit from looking at the effects on our primary outcomes (spirometric changes from baseline, quality of life and adverse effects) in the longer term.