Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies

Eur Respir J. 2021 Sep 2;58(3):2004233. doi: 10.1183/13993003.04233-2020. Print 2021 Sep.


Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC).Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma.Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium-dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk 0.61-0.80) and increasing trough forced expiratory volume in 1 s (from +33 to +114 mL). Triple combination therapies including HD ICS were superior (p<0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns.This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

Publication types

  • Meta-Analysis

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / therapeutic use
  • Adrenergic beta-2 Receptor Agonists / therapeutic use
  • Asthma* / drug therapy
  • Bronchodilator Agents / therapeutic use
  • Clinical Trials, Phase III as Topic
  • Drug Therapy, Combination
  • Humans
  • Muscarinic Antagonists / therapeutic use
  • Network Meta-Analysis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy


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