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Which long-acting inhaled drugs, used alone or in combination, are the most effective for people with COPD?

Kew KM, Dias S, Cates CJ
Published Online: 
26 March 2014

Why is this question important?

Inhaled drugs for COPD have been shown to relieve symptoms, improve quality of life and prevent or treat flare-ups. Treatment with these inhaled drugs tends to begin with one inhaler, and additional therapies are introduced as necessary. For persistent or worsening symptoms, long-acting inhaled drugs taken once or twice daily are preferred over short-acting ones. Several Cochrane reviews have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments. However for patients and clinicians, it is important to understand the benefits of these treatments relative to each other, and whether a particular type of inhaled therapy is more beneficial than the others.

How did we answer the question?
We looked for studies in existing Cochrane reviews and performed detailed electronic searches up to September 2013. Studies were included if they lasted at least six months and compared any of the following treatments versus any other for people with COPD: long-acting beta2-agonists (LABAs—formoterol, indacaterol, salmeterol); long-acting muscarinic antagonists (LAMAs—aclidinium, glycopyrronium, tiotropium); inhaled corticosteroids (ICSs—budesonide, fluticasone, mometasone); combination long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS—formoterol/budesonide, formoterol/mometasone, salmeterol/fluticasone); and placebo.

We conducted a network meta-analysis to assess the benefits of each type of treatment (e.g. long-acting beta2-agonists) relative to the others for quality of life and lung function. We also looked at how much individual treatments varied (e.g. How different were the three inhaled steroids from one other?) and whether particular treatments were more effective than others. We assessed the data for six months and 12 months separately and reported six months as the primary findings.

What did we find?
We found 71 relevant studies, but not all measured the outcomes we were interested in. Forty-two studies were included in the quality of life analyses (measured on St George's Respiratory Questionnaire), and 46 were included in the lung function analyses.

Evidence from good quality and similar trials supported LABA/ICS combinations as the most likely treatment strategy to bring the greatest improvement to quality of life and lung function. Combination therapy gave an average benefit of 3.9 units over placebo at six months. LAMAs and LABAs were ranked second and third at six months (-2.63 and -2.29 units, respectively), especially when unreliable trials were not included, but a large degree of overlap in the estimates was noted.

Combination LABA/ICS was the highest ranked class for trough forced expiratory volume in one second (FEV1), with mean improvement over placebo of 133 mL at six months (95% credible Interval (CrI) 101 to 164). As was the case for SGRQ, LAMAs (mean difference (MD) 104, 95% CrI 82 to 125) were ranked just ahead of LABAs (MD 99, 95% CrI 72 to 128) at six months, and ICSs were the lowest ranked class (MD 65, 95% CrI 33 to 97).

For both outcomes, the effects of LABA and ICS used alone appeared to increase when used together for six months, but initial differences between the treatment classes were less obvious after a year of treatment.

Conclusion
Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1 that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been shown by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines.