Long-acting inhaled treatment to open up the airways in cystic fibrosis

Review question

We reviewed the evidence for the benefit of long-acting inhaled bronchodilators (treatment which opens up the airways often called "relievers") in people with cystic fibrosis.

Background

Cystic fibrosis affects many systems in the body, in particular how well the lungs work. There is a build-up of thickened, sticky mucus which makes breathing more difficult and makes people with cystic fibrosis more likely to get infections in their lungs. Short- and long-acting bronchodilators are prescribed for most people with cystic fibrosis to widen the airways and improve symptoms. This review partly replaces an earlier review of both short-acting and long-acting inhaled bronchodilators.

Search date

The evidence is current to: 10 October 2017.

Trial characteristics

We included four trials in our review, with a total of 1082 people whose ages ranged from five months to 70 years. The trials included in the review looked at the effects of two different types of long-acting inhaled bronchodilator (beta-2 agonists e.g. salmeterol, and muscarinic antagonists e.g. tiotropium). The trials lasted between 28 days and 12 weeks.

Key results

The small trial of beta-2 agonists compared to placebo (no active medication) reported some improvement in lung function (forced expiratory volume at one second (FEV1)) after treatment, but did not provide data we could analyse. They did not report on any side effects.

Only one of the three trials comparing tiotropium to a placebo reported on FEV1 (measured in litres) and found little difference between treatment and placebo. Two of these trials reported on quality of life, but there was not enough evidence to comment on whether this improved or not. Three trials noted side effects, some of which were seen after treatment with tiotropium, but these symptoms were also seen in the group of people who were given placebo. Future trials would improve our knowledge if they measure side effects and quality of life in a more meaningful way.

Quality of the evidence

Only 16 people took part in the trial of the beta-2 agonist which only lasted for 28 days, which makes the results less reliable. The trials of muscarinic antagonists included 1066 people and the trials appeared to be well run. We don't think any design factors will have influenced the results in a negative way.

None of the trials ran for more than 12 weeks which makes it difficult to comment on the effects over a longer time period.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

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.

Objectives: 

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.

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

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.

Main results: 

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.

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