Adding a LAMA to ICS/LABA Therapy

A Meta-analysis of Triple Combination Therapy in COPD
Published:January 17, 2019DOI:


      Inhaled corticosteroid (ICS)/long-acting β 2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (LAMA) to ICS/LABA combination in COPD.


      Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/LAMA combination in COPD. The primary end points were the effect of triple therapy on trough FEV 1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence.


      Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/LAMA combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/LAMA combination improved trough FEV 1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV 1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/LAMA combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a LAMA to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence).


      Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a LAMA is added to the combination.

      Trial Registry; No.: CRD42018095300; URL:

      Key Words


      AECOPD ( risk of acute exacerbation of COPD), GRADE ( Grading of Recommendations Assessment, Development, and Evaluation), HRQoL ( health-related quality of life), ICS ( inhaled corticosteroid), LABA ( long-acting β2-agonist), LAMA ( long-acting muscarinic receptor antagonist), MCID ( minimal clinically important difference), MD ( mean difference), NNT ( number needed to treat), PICO ( patient problem, intervention, comparison, and outcome), RCT ( randomized controlled trial), RR ( relative risk), SAE ( serious adverse event), SGRQ ( St. George’s Respiratory Questionnaire), TDI ( transitional dyspnea index)
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      Linked Article

      • Single Triple vs Dual Inhaler Therapy
        CHESTVol. 155Issue 5
        • In Brief
          We read with interest the well-conducted meta-analysis of triple therapy by Calzetta et al1 in a recent issue of CHEST comprising randomized controlled trials evaluating adding long-acting muscarinic antagonist (LAMA) to inhaled corticosteroid and long-acting beta agonist (ICS/LABA) in COPD. Their results showed that 2 long-acting bronchodilators (LAMA and LABA) are better than 1 (LABA) in terms of improving lung function, symptoms, and health status as well as reducing exacerbations.
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      • Response
        CHESTVol. 155Issue 5
        • In Brief
          We thank Drs Lipworth and Kuo for their comments on our meta-analysis1 published in CHEST. First, we must highlight that, in our recent meta-analysis focused on triple therapy vs single and dual long-acting bronchodilator therapy in COPD,2 we found that the overall values of surface under the cumulative ranking curve, a method that we used to systematically rank order inhaled corticosteroid (ICS) and non-ICS based therapies, taking into consideration their benefits as well as their risks, favored long-acting bronchodilator/long-acting muscarinic antagonist (LABA/LAMA) combination over ICS/LABA/LAMA and LABA or LAMA alone.
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