Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis

BMJ Open. 2015 Oct 26;5(10):e009183. doi: 10.1136/bmjopen-2015-009183.


Objective: To compare the safety and effectiveness of long-acting β-antagonists (LABA), long-acting antimuscarinic agents (LAMA) and inhaled corticosteroids (ICS) for managing chronic obstructive pulmonary disease (COPD).

Setting: Systematic review and network meta-analysis (NMA).

Participants: 208 randomised clinical trials (RCTs) including 134,692 adults with COPD.

Interventions: LABA, LAMA and/or ICS, alone or in combination, versus each other or placebo.

Primary and secondary outcomes: The proportion of patients with moderate-to-severe exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia and cardiovascular-related mortality (CVM) were secondary outcomes.

Results: NMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 26,141 patients with an exacerbation in the past year. 32 treatments were effective versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol and tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% probability of being the most effective according to the Surface Under the Cumulative RAnking (SUCRA) curve). NMA was conducted on mortality (88 RCTs, 97 526 patients); fluticasone/salmeterol was more effective in reducing mortality than placebo, formoterol and fluticasone alone, and was the most effective (SUCRA=71%). NMA was conducted on CVM (37 RCTs, 55,156 patients) and the following were safest: salmeterol versus each OF placebo, tiotropium and tiotropium (Soft Mist Inhaler (SMR)); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful (SUCRA=81%). NMA was conducted on pneumonia occurrence (54 RCTs, 61 551 patients). 24 treatments were more harmful, including 2 that increased risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol (SUCRA=89%). NMA was conducted for arrhythmia; no statistically significant differences between agents were identified.

Conclusions: Many inhaled agents are available for COPD, some are safer and more effective than others. Our results can be used by patients and physicians to tailor administration of these agents.

Protocol registration number: PROSPERO # CRD42013006725.

Keywords: Chronic Obstructive; Network Meta-analysis; Pulmonary Disease; Pulmonary Emphysema; Systematic Review.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / adverse effects*
  • Adrenergic beta-2 Receptor Agonists / adverse effects*
  • Adrenergic beta-2 Receptor Agonists / classification
  • Disease Progression
  • Humans
  • Muscarinic Antagonists / adverse effects*
  • Muscarinic Antagonists / classification
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / mortality
  • Randomized Controlled Trials as Topic


  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Agonists
  • Muscarinic Antagonists