Comparative Effects of LAMA-LABA-ICS vs LAMA-LABA for COPD

Cohort Study in Real-World Clinical Practice
  • Samy Suissa
    Correspondence
    CORRESPONDENCE TO: Samy Suissa, PhD, Centre for Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste-Catherine, H-461, Montreal, QC, Canada H3T 1E2
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute - Jewish General Hospital; and the Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada
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  • Sophie Dell’Aniello
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute - Jewish General Hospital; and the Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada
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  • Pierre Ernst
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute - Jewish General Hospital; and the Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada
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Published:November 21, 2019DOI:https://doi.org/10.1016/j.chest.2019.11.007

      Background

      Triple therapy combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta 2-agonist (LABA), and an inhaled corticosteroid (ICS) for COPD were studied in randomized trials and observational studies, with variable results. We compared the effectiveness and safety of triple therapy with a LAMA-LABA combination in a real-world clinical practice setting.

      Methods

      We identified a cohort of patients with COPD during 2002 through 2015, ≥ 55 years of age, from the UK’s Clinical Practice Research Datalink. Patients initiating LAMA-LABA-ICS were matched 4:1 on time-conditional propensity scores with patients initiating LAMA-LABA, and followed for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia.

      Results

      The cohort included 6,921 initiators of LAMA-LABA-ICS matched to 1,932 initiators of LAMA-LABA. The adjusted hazard ratio (HR) of a COPD exacerbation associated with LAMA-LABA-ICS initiation compared with LAMA-LABA initiation was 0.97 (95% CI, 0.87-1.08). For patients with blood eosinophil counts > 6%, the HR was 0.66 (95% CI, 0.46-0.94). For patients with two or more prior exacerbations, it was 0.83 (95% CI, 0.70-0.98). The incidence of severe pneumonia requiring hospitalization was increased with LAMA-LABA-ICS initiation (HR, 1.46; 95% CI, 1.03-2.06).

      Conclusions

      In a real-world setting of COPD treatment, the triple combination of LAMA, LABA, and ICS inhalers is generally as effective as combining LAMA and LABA inhalers in preventing COPD exacerbations. However, with the possible exception of patients with significant eosinophilia or frequent exacerbators, a LAMA-LABA combination without ICS may be preferable because it is associated with fewer severe cases of pneumonia.

      Key Words

      Abbreviations:

      CPRD ( Clinical Practice Research Datalink), HR ( hazard ratio), ICS ( inhaled corticosteroid), IMPACT ( Informing the Pathway of COPD Treatment), LABA ( long-acting beta2-agonist), LAMA ( long-acting muscarinic antagonist), TCPS ( time-conditional propensity score)
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      References

        • Rabe K.F.
        • Hurd S.
        • Anzueto A.
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
        Am J Respir Crit Care Med. 2007; 176: 532-555
        • Lozano R.
        • Naghavi M.
        • Foreman K.
        • et al.
        Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380: 2095-2128
        • Vogelmeier C.F.
        • Criner G.J.
        • Martinez F.J.
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD Executive Summary.
        Eur Respir J. 2017; 49 (pii: 1700214)
      1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic ostructive pulmonary dsease. 2019 report.
        (Accessed December 12, 2019)
        • Ernst P.
        • Saad N.
        • Suissa S.
        Inhaled corticosteroids in COPD: the clinical evidence.
        Eur Respir J. 2015; 45: 525-537
        • Papi A.
        • Vestbo J.
        • Fabbri L.
        • et al.
        Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial.
        Lancet. 2018; 391: 1076-1084
        • Lipson D.A.
        • Barnhart F.
        • Brealey N.
        • et al.
        Once-daily single-inhaler triple versus dual therapy in patients with COPD.
        N Engl J Med. 2018; 378: 1671-1680
        • Suissa S.
        • Drazen J.M.
        Making sense of triple inhaled therapy for COPD.
        N Engl J Med. 2018; 378: 1723-1724
        • Suissa S.
        • Ariel A.
        Triple therapy trials in COPD: a precision medicine opportunity.
        Eur Respir J. 2018; 521801848
        • Wedzicha J.A.
        • Banerji D.
        • Kostikas K.
        Single-inhaler triple versus dual therapy in patients with COPD.
        N Engl J Med. 2018; 379: 590-593
        • Cazzola M.
        • Rogliani P.
        • Calzetta L.
        • Matera M.G.
        Triple therapy versus single and dual long-acting bronchodilator therapy in chronic obstructive pulmonary disease: a systematic review and meta-analysis.
        Eur Respir J. 2018; 52 (pii: 1801586)
        • Short P.M.
        • Williamson P.A.
        • Elder D.H.J.
        • Lipworth S.I.W.
        • Schembri S.
        • Lipworth B.J.
        The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting beta2-agonist therapy in COPD.
        Chest. 2012; 141: 81-86
        • Manoharan A.
        • Short P.M.
        • Anderson W.J.
        • Lipworth B.J.
        Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: a real-life retrospective cohort study.
        Lung. 2014; 192: 649-652
        • Jick S.S.
        • Kaye J.A.
        • Vasilakis-Scaramozza C.
        • et al.
        Validity of the general practice research database.
        Pharmacotherapy. 2003; 23: 686-689
        • Herrett E.
        • Thomas S.L.
        • Schoonen W.M.
        • Smeeth L.
        • Hall A.J.
        Validation and validity of diagnoses in the general practice research database: a systematic review.
        Br J Clin Pharmacol. 2010; 69: 4-14
        • Herrett E.
        • Gallagher A.M.
        • Bhaskaran K.
        • et al.
        Data resource profile: Clinical Practice Research Datalink (CPRD).
        Int J Epidemiol. 2015; 44: 827-836
        • Suissa S.
        • Dell’Aniello S.
        • Ernst P.
        Comparative effectiveness and safety of LABA-LAMA vs LABA-ICS treatment of COPD in real-world clinical practice.
        Chest. 2019; 155: 1158-1165
        • Suissa S.
        • Moodie E.E.
        • Dell'Aniello S.
        Prevalent new-user cohort designs for comparative drug effect studies by time-conditional propensity scores.
        Pharmacoepidemiol Drug Saf. 2017; 26: 459-468
        • Schneeweiss S.
        • Rassen J.A.
        • Glynn R.J.
        • Avorn J.
        • Mogun H.
        • Brookhart M.A.
        High-dimensional propensity score adjustment in studies of treatment effects using health care claims data.
        Epidemiology. 2009; 20: 512-522
        • Suissa S.
        • Dell'Aniello S.
        • Ernst P.
        Concurrent use of long-acting bronchodilators in COPD and the risk of adverse cardiovascular events.
        Eur Respir J. 2017; 49 (pii: 1602245)
        • Suissa S.
        • Dell'Aniello S.
        • Ernst P.
        Long-acting bronchodilator initiation in COPD and the risk of adverse cardiopulmonary events.
        Chest. 2017; 151: 60-67
        • Suissa S.
        • Dell'Aniello S.
        • Ernst P.
        Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.
        Lancet Respir Med. 2018; 6: 855-862
        • Rothnie K.J.
        • Müllerová H.
        • Hurst J.R.
        • et al.
        Validation of the recording of acute exacerbations of COPD in UK primary care electronic healthcare records.
        PLoS One. 2016; 11e0151357
        • Rothnie K.J.
        • Müllerová H.
        • Thomas S.L.
        • et al.
        Recording of hospitalizations for acute exacerbations of COPD in UK electronic health care records.
        Clin Epidemiol. 2016; 8: 771-782
        • Meropol S.B.
        • Metlay J.P.
        Accuracy of pneumonia hospital admissions in a primary care electronic medical record database.
        Pharmacoepidemiol Drug Saf. 2012; 21: 659-665
        • Myers J.A.
        • Rassen J.A.
        • Gagne J.J.
        • et al.
        Effects of adjusting for instrumental variables on bias and precision of effect estimates.
        Am J Epidemiol. 2011; 174: 1213-1222
        • Suissa S.
        Run-in bias in randomised trials: the case of COPD medications.
        Eur Respir J. 2017; 49 (pii: 1700361)
        • Pascoe S.
        • Locantore N.
        • Dransfield M.T.
        • Barnes N.C.
        • Pavord I.D.
        Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials.
        Lancet Respir Med. 2015; 3: 435-442
        • Pavord I.D.
        • Lettis S.
        • Locantore N.
        • et al.
        Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD.
        Thorax. 2016; 71: 118-125
        • Watz H.
        • Tetzlaff K.
        • Wouters E.F.
        • et al.
        Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial.
        Lancet Respir Med. 2016; 4: 390-398
        • Roche N.
        • Chapman K.R.
        • Vogelmeier C.F.
        • et al.
        Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME Trial.
        Am J Respir Crit Care Med. 2017; 195: 1189-1197
        • Brusselle G.G.
        • Bracke K.
        • Lahousse L.
        Targeted therapy with inhaled corticosteroids in COPD according to blood eosinophil counts.
        Lancet Respir Med. 2015; 3: 416-417
        • Iyer A.S.
        • Dransfield M.T.
        Serum eosinophils as a COPD biomarker: Ready for prime time?.
        Lancet Respir Med. 2016; 4: 341-343
        • Suissa S.
        • Ernst P.
        Precision medicine urgency: the case of inhaled corticosteroids in COPD.
        Chest. 2017; 152: 227-231
        • Suissa S.
        • Ernst P.
        Observational studies of inhaled corticosteroid effectiveness in copd: lessons learned.
        Chest. 2018; 154: 257-265
        • Vestbo J.
        • Papi A.
        • Corradi M.
        • et al.
        Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial.
        Lancet. 2017; 389: 1919-1929
        • Suissa S.
        • Coulombe J.
        • Ernst P.
        Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia.
        Chest. 2015; 148: 1177-1183
        • Ernst P.
        • Gonzalez A.V.
        • Brassard P.
        • Suissa S.
        Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia.
        Am J Respir Crit Care Med. 2007; 176: 162-166
        • Suissa S.
        • Patenaude V.
        • Lapi F.
        • Ernst P.
        Inhaled corticosteroids in COPD and the risk of serious pneumonia.
        Thorax. 2013; 68: 1029-1036
        • Quint J.K.
        • Mullerova H.
        • DiSantostefano R.L.
        • et al.
        Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD).
        BMJ Open. 2014; 4e005540

      Linked Article

      • Response
        CHESTVol. 158Issue 2
        • In Brief
          Rothnie et al suggest that our findings of no overall difference in the incidence of exacerbations between long-acting muscarinic antagonist–long-acting beta2-agonist–inhaled corticosteroid (LAMA-LABA-ICS) and LAMA-LABA therapy in COPD in real-world clinical practice could be due to the definition of exacerbation that is chosen and the exclusion of patients with asthma.1
        • Full-Text
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      • Different ICSs and the Risk of Pneumonia
        CHESTVol. 157Issue 5
        • In Brief
          We read with great interest the recent article by Suissa et al1 in a recent issue of CHEST (April 2020), in which they found that the incidence of severe pneumonia requiring hospitalization was increased in patients with COPD initiating long-acting muscarinic antagonist, long-acting beta2-agonist, and inhaled corticosteroid (LAMA-LABA-ICS) treatment compared with those initiating LAMA-LABA treatment (hazard ratio, 1.46; 95% CI, 1.03-2.06). We agree with the authors about the safety issue of LAMA-LABA-ICS-associated pneumonia, and our recent study2 on single inhaler triple therapy with LAMA-LABA-ICS showed similar findings, with a higher risk of pneumonia compared with LABA/LAMA (risk ratio [RR], 1.38; 95% CI, 1.14-1.67; I2 = 0) dual therapy.
        • Full-Text
        • PDF
      • Methodologic Issues With Comparative Effectiveness Study on LAMA-LABA-ICS vs LAMA-LABA for the Treatment of COPD in the Clinical Practice Research Datalink
        CHESTVol. 158Issue 2
        • In Brief
          In a previous issue of CHEST (April 2020), we read with interest the article by Suissa et al1 that investigated the effectiveness and safety of long-acting muscarinic antagonist–long-acting beta2-agonist–inhaled corticosteroid (LAMA-LABA-ICS) vs LAMA-LABA for the treatment of COPD in the Clinical Practice Research Datalink. This study found no difference in the rate of acute exacerbations of COPD (AECOPD) in the overall population that compared LAMA-LABA-ICS with LAMA-LABA. However, we have significant concerns with the methods that were used.
        • Full-Text
        • PDF
      • Response
        CHESTVol. 157Issue 4
        • In Brief
          We thank Lipworth et al for their comments on our real-world data study1 of the comparative effects of long-acting muscarinic antagonist (LAMA)-long-acting beta2-agonist (LABA)-inhaled corticosteroid (ICS) vs LAMA-LABA in COPD. Our study finds that LAMA-LABA-ICS shows greater effectiveness at reducing the incidence of exacerbations than LAMA-LABA exclusively in patients with significant eosinophilia or with frequent exacerbations. For all other patients, effectiveness of triple therapy with LAMA-LABA-ICS was no different than with LAMA-LABA, except for a higher incidence of pneumonia with triple therapy.
        • Full-Text
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      • Response
        CHESTVol. 157Issue 5
        • In Brief
          We thank Wang et al for their letter on our real-world study of the comparative effects of triple vs dual bronchodilator therapy COPD as it relates to the risk of pneumonia.1 Indeed, our study found that the inhaled corticosteroid (ICS)-containing triple therapy is associated with an increased incidence of serious pneumonia requiring hospitalization, compared with long-acting muscarinic antagonist, long-acting beta2-agonist. Wang et al remind us that the different ICS have been associated with varying risks of pneumonia.
        • Full-Text
        • PDF
      • Observational Data With Inhaled Corticosteroid/Long-Acting Beta-Agonist/Long-Acting Muscarinic Antagonist May Not Reflect Current Practice With Single Triple Inhalers
        CHESTVol. 157Issue 4
        • In Brief
          We read with interest the observational data of the recent study by Suissa et al1 in this issue of CHEST, which suggested superior real-world benefits of taking inhaled corticosteroid (ICS) with long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) over LABA/LAMA in patients with COPD with blood eosinophil count > 6%, or in those with at least two exacerbations in the past year. Previous post hoc analysis of Calverely et al2 showed that the effect of ICS withdrawal from preexisting triple therapy resulted in 43% increased exacerbations in those patients who had at least two previous exacerbations who also had a eosinophil count > 4% (ie, > 300 cells/μL).
        • Full-Text
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