Effect of tiotropium on COPD exacerbations: A systematic review

Open AccessPublished:March 01, 2016DOI:https://doi.org/10.1016/j.rmed.2016.02.012

      Highlights

      • Systematic review of exacerbation data from randomized trials of tiotropium.
      • Fewer exacerbations and longer time to first event with tiotropium than placebo.
      • Tiotropium more effective at preventing exacerbations than LABA therapy.
      • Limited data are available versus another LAMA or LAMA/LABA combinations.

      Abstract

      Background

      Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.

      Methods

      As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies.

      Results

      Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting β2-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting β2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler® 18 μg/Respimat® 5 μg).

      Conclusions

      The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments.

      Keywords

      1. Introduction

      COPD is characterized by airflow obstruction, and bronchodilators are central to its management [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ]. The aims of pharmacological therapy for COPD are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ]. Short-acting bronchodilators can produce substantial improvements in lung function, but long-acting bronchodilators are more effective at maintaining symptom relief [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ]. Improvements in FEV1 produced by bronchodilation correlate with improvements in breathlessness and health status as well as reduced exacerbation rates [
      • Jones P.W.
      • Donohue J.F.
      • Nedelman J.
      • Pascoe S.
      • Pinault G.
      • Lassen C.
      Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis.
      ].
      Exacerbations are an important component of COPD [
      • Celli B.R.
      • Barnes P.J.
      Exacerbations of chronic obstructive pulmonary disease.
      ,
      • Soler-Cataluna J.J.
      • Martinez-Garcia M.A.
      • Roman S.P.
      • Salcedo E.
      • Navarro M.
      • Ochando R.
      Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
      ], significantly impacting on the burden of disease [
      • Ramsey S.D.
      • Sullivan S.D.
      The burden of illness and economic evaluation for COPD.
      ], leading to a worsening health status and increased risk of future exacerbations and death [
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • Locantore N.
      • Mullerova H.
      • Tal-Singer R.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      ,
      • Spencer S.
      • Calverley P.M.
      • Burge P.S.
      • Jones P.W.
      Impact of preventing exacerbations on deterioration of health status in COPD.
      ]. Exacerbations are also strong predictors of disease progression, quality of life, and prognosis [
      • Spencer S.
      • Calverley P.M.
      • Burge P.S.
      • Jones P.W.
      Impact of preventing exacerbations on deterioration of health status in COPD.
      ,
      • Donaldson G.C.
      • Seemungal T.A.
      • Bhowmik A.
      • Wedzicha J.A.
      Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
      ]. Some patients may be more prone to exacerbations [
      • Soler-Cataluna J.J.
      • Martinez-Garcia M.A.
      • Roman S.P.
      • Salcedo E.
      • Navarro M.
      • Ochando R.
      Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
      ], and the prevention of exacerbations is a priority goal in COPD management [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ].
      Current maintenance therapies for patients at risk of exacerbations include long-acting anticholinergics (also called long-acting muscarinic antagonists [LAMAs]), long-acting β2-agonists (LABAs), LABAs combined with inhaled corticosteroids (ICS), and phosphodiesterase type 4 inhibitors [
      • Montuschi P.
      Pharmacological treatment of chronic obstructive pulmonary disease.
      ,
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ]. For patients at risk of exacerbations in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups C and D, a long-acting anticholinergic or a fixed combination of ICS/LABA is recommended as first-choice therapy [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated.
      ], while for symptomatic patients at lower risk of exacerbations (group B), a LAMA or LABA is recommended. There is now more evidence to inform these choices, and we have therefore undertaken a systematic review of the effects of tiotropium therapy compared with placebo and/or other maintenance therapies in patients with COPD. Unlike other publications (for example, Karner, et al. [
      • Karner C.
      • Chong J.
      • Poole P.
      Tiotropium versus placebo for chronic obstructive pulmonary disease.
      ]), this review includes for the first time all published randomized controlled trials with exacerbation outcomes as prespecified endpoints and with tiotropium as an active treatment arm.
      Tiotropium is a once-daily LAMA shown to reduce exacerbations and improve other important outcomes of COPD [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Cooper C.B.
      • Celli B.R.
      • Jardim J.R.
      • Wise R.A.
      • Legg D.
      • Guo J.
      • et al.
      Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ]. Tiotropium is approved and marketed as a dry-powder formulation delivered via the HandiHaler® device (18 μg; Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim am Rhein, Germany) [
      • Boehringer Ingelheim Limited
      Summary of Product Characteristics (SPC): Spiriva 18 Microgram Inhalation Powder, Hard Capsule.
      ] and as an aqueous solution delivered via the Respimat® inhaler (5 μg; two puffs of 2.5 μg once daily; Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim am Rhein, Germany) in many countries [
      • Boehringer Ingelheim Limited
      Summary of Product Characteristics (SPC): Spiriva Respimat 2.5 Microgram Inhalation Solution.
      ].

      2. Methods

      A systematic literature search (January 2000 to May 2014) of electronic databases was conducted to identify all COPD trials in which exacerbations were a prespecified endpoint and tiotropium was an active treatment arm. As there is no standardized definition of a COPD exacerbation due to the heterogeneity of causes, symptoms and severities [
      • Burge S.
      • Wedzicha J.A.
      COPD exacerbations: definitions and classifications.
      ], our literature search did not limit studies to a specific definition. (For definitions of exacerbation used in selected studies, see Table E1 in the online supplement.) The total hits from the search were assessed for their relevance (based on titles/abstracts), and publications that were deemed potentially relevant were obtained in full and assessed.
      Articles were included if they reported on double-blind, randomized, controlled trials of ≥6 months' duration. Both placebo- and active-controlled (i.e., vs. other maintenance therapies) trials were eligible if exacerbation data were included as a primary or secondary endpoint; blinded studies with additional open-label tiotropium arm(s) were included if appropriate. Prospective studies and subgroup analyses of trials were permitted, provided the data were new and not duplicated elsewhere. Non-blinded open-label studies, review articles, methodology papers, retrospective studies, pooled analyses, case studies, conference findings, congress abstracts, pharmacoeconomic studies, and meeting reports were excluded. The search was limited to trials in humans. The literature search results and article selection were reviewed and verified by the authors to ensure their accuracy.
      Exacerbation outcomes included time to first event (exacerbation/hospitalization due to exacerbation), exacerbation rate, and the proportion of patients with events (exacerbations/hospitalizations due to exacerbation).

      3. Results

      3.1 Summary of search findings

      The search returned a total of 236 hits (Fig. 1). Of these, 195 publications were excluded based on the title/abstract and identification of duplicates. The remaining 41 publications were deemed potentially relevant based on the title and/or abstract. Of these, a further 14 publications were excluded based on duration of study (i.e., <6 months [n = 6]), retrospective nature of study (n = 1), non-appropriate comparator (n = 1), open-label study (n = 2), pooled analysis (n = 3), and lack of data on specific treatments (n = 1). Two additional recent publications were identified during the search [
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ]. In total, 29 publications were deemed relevant for inclusion in the final analysis [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ,
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ,
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Hanania N.A.
      • Crater G.D.
      • Morris A.N.
      • Emmett A.H.
      • O'Dell D.M.
      • Niewoehner D.E.
      Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ,
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ,
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ,
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ,
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ]. Refer to online supplement, Tables E2 and E3, for details of study durations and population size.
      Figure thumbnail gr1
      Fig. 1Systematic review of published manuscripts reporting exacerbation data in trials comparing tiotropium with placebo and/or other maintenance therapies. a Two additional articles included following a final check on any relevant, recently published articles (since May 2014 end of search period and submission date).
      Exacerbations were a primary study endpoint (including subgroup analyses and prospective studies) in 12 publications [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ,
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ,
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ,
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ] and a secondary study endpoint (including subgroup analyses and prospective studies) in 17 publications [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Hanania N.A.
      • Crater G.D.
      • Morris A.N.
      • Emmett A.H.
      • O'Dell D.M.
      • Niewoehner D.E.
      Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ].
      Six studies included an entry criterion that patients must have had one or more exacerbations in the year prior to entry [
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ,
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ,
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ,
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ,
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ], and one study required one or more exacerbations in the 2 years prior to entry [
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ].
      The exacerbation data reported included time to first event, exacerbation rate, and proportion of patients with an event (online supplement, Tables E2 and E3); severe (hospitalized) exacerbation data have been detailed where available. Of the 209 publications that were excluded, 26 reported exacerbations as “other endpoint”. Additional data from open-label comparisons are included for information only [
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ,
      • Kerwin E.
      • Hebert J.
      • Gallagher N.
      • Martin C.
      • Overend T.
      • Alagappan V.K.
      • et al.
      Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study.
      ,
      • Donohue J.F.
      • Fogarty C.
      • Lotvall J.
      • Mahler D.A.
      • Worth H.
      • Yorgancioglu A.
      • et al.
      Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium.
      ].

      3.2 Effect of tiotropium versus placebo

      Sixteen publications comparing tiotropium with placebo investigated the use of HandiHaler® (18 μg) [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ,
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ], and four reported the effects of Respimat® (5 μg [two puffs of 2.5 μg once daily] and/or 10 μg) [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ].

      3.2.1 Time to first exacerbation event

      There were 14 publications (including subgroup analyses) that compared tiotropium with placebo, with time to first exacerbation as the endpoint [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ,
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ]. Tiotropium was associated with a significantly (p < 0.05) prolonged time to first exacerbation in nine studies [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ] (online supplement, Table E2). In three studies, the time to first hospitalization (severe exacerbation) was also significantly (p < 0.05) prolonged in patients treated with tiotropium compared with placebo (Fig. 2; online supplement, Table E2) [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ].
      Figure thumbnail gr2
      Fig. 2Hazard ratios for an exacerbation of COPD in patients receiving tiotropium versus placebo.

      3.2.2 Exacerbation rate or proportion of patients with exacerbations

      Twenty publications (including subgroup analyses) compared the effect of tiotropium with placebo on the rate of exacerbations or proportion of patients experiencing an exacerbation event [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ,
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ]. Fewer patients treated with tiotropium experienced one or more exacerbations [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ]; these differences reached statistical significance in nine publications [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ]. In addition, the number/rate of exacerbations [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Abrahams R.
      • Moroni-Zentgraf P.
      • Ramsdell J.
      • Schmidt H.
      • Joseph E.
      • Karpel J.
      Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ] and exacerbation days [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tonnel A.B.
      • Perez T.
      • Grosbois J.M.
      • Verkindre C.
      • Bravo M.L.
      • Brun M.
      Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.
      ] were reduced and the probability of remaining exacerbation-free [
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ] was higher in patients receiving tiotropium versus placebo.
      In total, 16 publications examined the effect of tiotropium on severe exacerbations or hospitalizations due to an exacerbation [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Bateman E.
      • Singh D.
      • Smith D.
      • Disse B.
      • Towse L.
      • Massey D.
      • et al.
      Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies.
      ,
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ,
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Dusser D.
      • Bravo M.L.
      • Iacono P.
      The effect of tiotropium on exacerbations and airflow in patients with COPD.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Powrie D.J.
      • Wilkinson T.M.
      • Donaldson G.C.
      • Jones P.
      • Scrine K.
      • Viel K.
      • et al.
      Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ]; in five studies, significantly fewer patients experienced a severe/hospitalized exacerbation in the tiotropium arms versus placebo [
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ,
      • Niewoehner D.E.
      • Rice K.
      • Cote C.
      • Paulson D.
      • Cooper Jr., J.A.
      • Korducki L.
      • et al.
      Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ]. In addition, two studies [
      • Brusasco V.
      • Hodder R.
      • Miravitlles M.
      • Korducki L.
      • Towse L.
      • Kesten S.
      Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
      ,
      • Casaburi R.
      • Mahler D.A.
      • Jones P.W.
      • Wanner A.
      • San P.G.
      • ZuWallack R.L.
      • et al.
      A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
      ] demonstrated that patients receiving tiotropium had significantly fewer hospitalization days due to a severe exacerbation versus those receiving placebo (online supplement, Table E2). However, in two studies [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Chan C.K.
      • Maltais F.
      • Sigouin C.
      • Haddon J.M.
      • Ford G.T.
      A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease.
      ], the number of hospitalizations and hospitalization days due to a severe exacerbation did not differ between tiotropium and placebo (online supplement, Table E2).

      3.2.3 Subgroup analyses

      In general, the eight subgroup analyses comparing tiotropium with placebo displayed similar trends for exacerbation reductions to those observed in the primary studies, although not all outcomes were statistically significant [
      • Decramer M.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Mehra S.
      • Tashkin D.P.
      Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.
      ,
      • Decramer M.
      • Molenberghs G.
      • Liu D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • et al.
      Premature discontinuation during the UPLIFT study.
      ,
      • Fukuchi Y.
      • Fernandez L.
      • Kuo H.P.
      • Mahayiddin A.
      • Celli B.
      • Decramer M.
      • et al.
      Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial.
      ,
      • Hanania N.A.
      • Sharafkhaneh A.
      • Celli B.
      • Decramer M.
      • Lystig T.
      • Kesten S.
      • et al.
      Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.
      ,
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ,
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ,
      • Tang Y.
      • Massey D.
      • Zhong N.S.
      Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ]. In prespecified subgroup analyses of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, tiotropium significantly reduced the rate of exacerbations in patients with COPD aged <50 years (p = 0.02) [
      • Morice A.H.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Tashkin D.
      • Decramer M.
      COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT).
      ]. Tiotropium reduced the number of exacerbations per patient-year by 16% versus control in patients naïve to maintenance therapy prior to the study; however, this failed to reach statistical significance (p = 0.08) [
      • Troosters T.
      • Celli B.
      • Lystig T.
      • Kesten S.
      • Mehra S.
      • Tashkin D.P.
      • et al.
      Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.
      ].
      In a post-hoc subanalysis of the Veteran Affairs Study (despite not being adequately powered), tiotropium reduced the likelihood of having at least one exacerbation versus placebo in the entire patient group (rate ratio [95% confidence interval (CI)]: 0.81 [0.66–0.99]; p = 0.037), with no statistically significant difference between the African American and Caucasian subgroups (p = 0.34) [
      • Rice K.L.
      • Leimer I.
      • Kesten S.
      • Niewoehner D.E.
      Responses to tiotropium in African-American and Caucasian patients with chronic obstructive pulmonary disease.
      ].

      3.3 Effect of tiotropium versus active comparators

      3.3.1 Tiotropium monotherapy versus salmeterol

      Two publications (including subgroup analyses) directly compared tiotropium with salmeterol [
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ,
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ]. In the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD®) trial, tiotropium significantly prolonged the time to first exacerbation (187 vs. 145 days; hazard ratio [HR] [95% CI], 0.83 [0.77–0.90]; p < 0.001) and severe exacerbation (HR [95% CI], 0.72 [0.61–0.85]; p < 0.001) in patients with moderate to very severe COPD when compared with salmeterol [
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ] (Fig. 3; online supplement, Table E3).
      Figure thumbnail gr3
      Fig. 3Hazard ratios for an exacerbation of COPD in patients receiving tiotropium versus an active comparator. a Reciprocal HR and 95% CI for tiotropium versus tiotropium plus fluticasone-salmeterol were derived and not as reported in the Aaron et al., 2007
      [
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ]
      (the reported unadjusted of HR [95% CI], 0.80 [0.60–1.08] are inconsistent with the results presented in the text and are therefore a likely error in the original publication
      [
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ]
      ); b The reciprocal HR and 95% CIs for tiotropium versus active comparator were derived and not statistically reported in the original publications where values for active comparator versus tiotropium were given.
      In addition, tiotropium reduced the annual rate of exacerbations versus salmeterol (0.64 vs. 0.72; rate ratio [95% CI], 0.89 [0.83–0.96]; p = 0.002), as well as the annual rate of moderate exacerbations (0.54 vs. 0.59; rate ratio [95% CI], 0.93 [0.86–1.00]; p = 0.048) and severe exacerbations (0.09 vs. 0.13; rate ratio [95% CI], 0.73 [0.66–0.82]; p < 0.001) (online supplement, Table E3). Of those patients who experienced an exacerbation in this trial, 44% had moderate (GOLD stage 2) COPD at trial onset.
      In subgroup analyses of POET-COPD®, tiotropium significantly prolonged the time to first exacerbation (HR [95% CI], 0.88 [0.79–0.99]; p = 0.028) and first severe exacerbation (HR [95% CI], 0.66 [0.48–0.91]; p = 0.012), reduced rates of severe exacerbations (rate ratio [95% CI], 0.70 [0.57–0.85]; p < 0.001) in GOLD stage 2 patients [
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ], significantly prolonged the time to first exacerbation (HR [95% CI], 0.79 [0.65–0.97; p = 0.028), and reduced the annual exacerbation rate (rate ratio [95% CI], 0.77 [0.63–0.94]; p = 0.012) in maintenance therapy-naïve patients when compared with salmeterol [
      • Vogelmeier C.
      • Fabbri L.M.
      • Rabe K.F.
      • Beeh K.M.
      • Schmidt H.
      • Metzdorf N.
      • et al.
      Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients.
      ].

      3.3.2 Tiotropium monotherapy versus indacaterol

      One publication compared tiotropium with indacaterol [
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ]. In the second, prespecified superiority analysis, the annualized rate of exacerbations was shown to be higher with indacaterol than with tiotropium (0.90 vs. 0.73; rate ratio [95% CI], 1.24 [1.12–1.37]; p < 0.0001), showing superiority of tiotropium [
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ]. In addition, the time to first moderate or severe exacerbation was longer with tiotropium (HR [95% CI], 1.20 [1.07–1.33]; p = 0.0012) over a 1-year period [
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ]. The HR and 95% CIs presented here for tiotropium versus indacaterol for time to first moderate or severe exacerbation were derived by inverting the HRs and CIs reported in the referenced publication (HR [95% CI], 0.83 [0.75–0.93]; p = 0.0012) (Fig. 3; online supplement, Table E3).
      In a separate subgroup analysis of patients with exacerbations treated with ICS and/or antibiotics, exacerbation rates were higher in the indacaterol group than in the tiotropium group [
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ]. However, in patients stratified by ICS at baseline, the rates of severe exacerbations were not significantly different between the two groups. Overall, fewer patients in the tiotropium group experienced an exacerbation during the study than those in the indacaterol group.

      3.3.3 Tiotropium monotherapy versus dual and/or triple therapy

      Six publications compared tiotropium with dual (either LABA/LAMA or LABA/ICS) and/or triple therapy (online supplement, Table E3) [
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ,
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ,
      • Hanania N.A.
      • Crater G.D.
      • Morris A.N.
      • Emmett A.H.
      • O'Dell D.M.
      • Niewoehner D.E.
      Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.
      ,
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ,
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ].
      The Effect of QVA149 Versus NVA237 and Tiotropium on COPD Exacerbations (SPARK) study compared tiotropium versus a combination of glycopyrronium 50 μg/indacaterol 110 μg (QVA149) and glycopyrronium alone (NVA237) in patients at risk of an exacerbation [
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ]. Overall, the incidence of severe exacerbations was low, with no significant differences observed between tiotropium and the glycopyrronium/indacaterol combination; however, in patients receiving glycopyrronium alone, there was an increase in severe exacerbations compared with tiotropium (rate ratio [95% CI], 1.43 [1.05–1.97]; p = 0.025; online supplement, Table E3). The rate of moderate or severe exacerbations was not significantly lower with the glycopyrronium/indacaterol combination versus tiotropium (rate ratio [95% CI], 0.90 [0.79–1.02]; p = 0.10), nor with glycopyrronium alone versus tiotropium (rate ratio [95% CI], 1.03 [0.91–1.16]; p = 0.68).
      Two publications reporting three studies compared the LAMA/LABA combination of umeclidinium/vilanterol with tiotropium [
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ]. In one 24-week blinded study, in which the time to first COPD exacerbation event was an additional endpoint, the risk of an exacerbation was reduced with the LAMA/LABA combination compared with tiotropium (HR [95% CI], 0.5 [0.3–1.0]; p = 0.044); however, the number of patients with events was low in both treatment groups (n = 16 [4%] vs. 29 [6%], respectively) [
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ]. Furthermore, a numerically greater proportion of patients who experienced an exacerbation were receiving additional ICS treatment in the umeclidinium/vilanterol group (n = 12 [75%]) compared with tiotropium (n = 20 [69%]) [
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      ]. In contrast, in two other blinded studies, the risk of a COPD exacerbation was numerically higher in the umeclidinium/vilanterol group when compared with tiotropium, though these results were not significant (HR [95% CI], 1.2 [0.5–2.6]; p = 0.71; and HR [95% CI], 1.9 [1.0–3.6]; p = 0.06, respectively) [
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      ].
      When compared with the salmeterol plus fluticasone combination, tiotropium was not associated with significant differences either in the rate of exacerbations (rate ratio [95% CI], 0.97 [0.84–1.12]; p = 0.656) or the rate of hospitalizations (13% vs. 16%; p = 0.085) in patients with COPD and a clinical history of exacerbations (online supplement, Table E3) [
      • Wedzicha J.A.
      • Calverley P.M.
      • Seemungal T.A.
      • Hagan G.
      • Ansari Z.
      • Stockley R.A.
      The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
      ]. In a second study, there were no significant differences in exacerbation rates with tiotropium plus salmeterol/fluticasone combination versus tiotropium alone (p = 0.531) (online supplement, Table E3) [
      • Hanania N.A.
      • Crater G.D.
      • Morris A.N.
      • Emmett A.H.
      • O'Dell D.M.
      • Niewoehner D.E.
      Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.
      ].
      In a multicenter trial of patients with moderate or severe COPD who had at least one exacerbation treated with corticosteroids or antibiotics in the 12 months prior to randomization [
      • Aaron S.D.
      • Vandemheen K.L.
      • Fergusson D.
      • Maltais F.
      • Bourbeau J.
      • Goldstein R.
      • et al.
      Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
      ], neither dual therapy with tiotropium and salmeterol, nor triple therapy with tiotropium, salmeterol, and fluticasone, was associated with any significant differences in the proportion of patients experiencing at least one exacerbation, time to first exacerbation event, or mean number of exacerbations when compared with tiotropium alone. However, unlike dual therapy, triple therapy was associated with a significant reduction in the rate of severe exacerbations requiring hospitalization compared with tiotropium monotherapy (relative risk, 0.53; p = 0.01) (online supplement, Table E3).

      3.4 Additional information from open-label comparisons

      3.4.1 Tiotropium monotherapy versus glycopyrronium and placebo

      One publication compared open-label tiotropium with glycopyrronium bromide [
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ,
      • Kerwin E.
      • Hebert J.
      • Gallagher N.
      • Martin C.
      • Overend T.
      • Alagappan V.K.
      • et al.
      Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study.
      ], and another compared each agent with placebo [
      • Kerwin E.
      • Hebert J.
      • Gallagher N.
      • Martin C.
      • Overend T.
      • Alagappan V.K.
      • et al.
      Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study.
      ].
      In the SPARK study, when tiotropium was compared with glycopyrronium, there were no significant differences for the annual rates of moderate or severe exacerbations (0.93 vs. 0.95) or severe exacerbations (0.08 vs. 0.12) [
      • Wedzicha J.A.
      • Decramer M.
      • Ficker J.H.
      • Niewoehner D.E.
      • Sandstrom T.
      • Taylor A.F.
      • et al.
      Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study.
      ].
      In a 1-year open-label study, tiotropium reduced the risk of exacerbations (time to first moderate or severe exacerbation) by 34% compared with placebo (HR [95% CI], 0.66 [0.52–0.85]; p = 0.001) [
      • Kerwin E.
      • Hebert J.
      • Gallagher N.
      • Martin C.
      • Overend T.
      • Alagappan V.K.
      • et al.
      Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study.
      ]. The risk reduction was 39% with glycopyrronium versus placebo (HR [95% CI], 0.61 [0.46–0.82]; p = 0.001). While glycopyrronium was associated with a 35% reduction in the rate of moderate or severe exacerbations compared with placebo (0.54 vs. 0.80; rate ratio [95% CI], 0.66 [0.50–0.87]; p = 0.003), the effect of tiotropium was not significantly different from placebo (rate ratio [95% CI], 0.80 [0.59–1.11]; p = 0.179). Both glycopyrronium and tiotropium were superior to placebo in reducing moderate exacerbations treated with systemic corticosteroids (odds ratio [95% CI], 0.61 [0.43–0.87; p = 0.006 and 0.62 [0.41–0.93]; p = 0.021, respectively) or antibiotics (odds ratio [95% CI], 0.69 [0.50–0.96]; p = 0.026 and 0.65 [0.44–0.95]; p = 0.026, respectively) [
      • Kerwin E.
      • Hebert J.
      • Gallagher N.
      • Martin C.
      • Overend T.
      • Alagappan V.K.
      • et al.
      Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study.
      ].

      3.4.2 Tiotropium monotherapy versus indacaterol and placebo

      One publication compared open-label tiotropium with indacaterol and placebo [
      • Donohue J.F.
      • Fogarty C.
      • Lotvall J.
      • Mahler D.A.
      • Worth H.
      • Yorgancioglu A.
      • et al.
      Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium.
      ]. Over 26 weeks, tiotropium was associated with numerical reductions in exacerbations versus placebo (HR [95% CI], 0.76 [0.56–1.03]; p = 0.080) but did not significantly reduce the rate of exacerbations compared with placebo (rate ratio [95% CI], 0.70 [0.48–1.03]; p = 0.070). Indacaterol 150 μg did appear to have a significant benefit over placebo in terms of time to first COPD exacerbation (HR [95% CI], 0.69 [0.51–0.94]; p = 0.019) and the rate of exacerbations (rate ratio [95% CI], 0.67 [0.46–0.99]; p = 0.044) in this study.

      4. Discussion

      Clinicians need clear advice from guidelines and initiatives such as GOLD on the best first-choice therapies for managing patients with COPD, particularly when considering outcomes such as effects on exacerbation rates. Tiotropium is the most widely studied LAMA and, as such, there is a considerable amount of data available. However, to our knowledge, this is the first systematic review of all published randomized, controlled trials designed to assess exacerbations outcomes (as prespecified endpoints) in patients with COPD who were receiving tiotropium via HandiHaler® or Respimat® (compared with placebo and/or other maintenance therapies).
      Overall, tiotropium appears to be associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) than either placebo or active comparator treatment. To date, there are limited data available to suggest an additional clinical benefit (in terms of exacerbation reduction) when using LAMA/LABA combinations or a LABA/ICS in combination with a LAMA.
      Generally, exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler® 18 μg/Respimat® 5 μg), a finding in line with evidence from the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) study (N = 17,135), which demonstrated similar exacerbation efficacy and safety profiles for the two formulations [
      • Wise R.A.
      • Anzueto A.
      • Cotton D.
      • Dahl R.
      • Devins T.
      • Disse B.
      • et al.
      Tiotropium Respimat inhaler and the risk of death in COPD.
      ].
      Both LAMAs and LABAs are effective treatments for patients with COPD and are widely used in clinical practice; however, differences in exacerbation outcomes between various treatments have been demonstrated in the literature. For example, tiotropium, a once-daily LAMA, significantly decreased the annual rate of exacerbations for patients with moderate to very severe COPD compared with salmeterol, a twice-daily LABA [
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ]. A trend for lower rates of exacerbations was evident with tiotropium compared with indacaterol, a once-daily LABA [
      • Decramer M.L.
      • Chapman K.R.
      • Dahl R.
      • Frith P.
      • Devouassoux G.
      • Fritscher C.
      • et al.
      Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.
      ], and indacaterol did not show non-inferiority to tiotropium in terms of the annual rate of exacerbations. These findings indicate that tiotropium may be more effective than LABAs in terms of exacerbation reduction, irrespective of once-daily or twice-daily regimens, suggesting that the effect is not simply related to sustained bronchodilation. It has been postulated that differences in duration and mechanism of action may account for their exacerbation outcome profiles; however, evidence is currently lacking and further prospective, randomized studies are needed to compare directly the exacerbation efficacy of these agents.
      Potential mechanisms that may contribute to the preventive effects of tiotropium on COPD exacerbations might include inhibition of the action of acetylcholine in the lung, which may lead to suppression of acetylcholine-mediated release of chemotactic substances involved in the modulation of inflammatory responses [
      • Buhling F.
      • Lieder N.
      • Kuhlmann U.C.
      • Waldburg N.
      • Welte T.
      Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro.
      ]. Inhibition of acetylcholine may translate into additional effects beyond that of bronchodilation (i.e., anti-inflammatory effects), and the reduction of proliferation and mucus secretion [
      • Buhling F.
      • Lieder N.
      • Kuhlmann U.C.
      • Waldburg N.
      • Welte T.
      Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro.
      ,
      • Sato E.
      • Koyama S.
      • Okubo Y.
      • Kubo K.
      • Sekiguchi M.
      Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity.
      ,
      • Casarosa P.
      • Bouyssou T.
      • Germeyer S.
      • Schnapp A.
      • Gantner F.
      • Pieper M.
      Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs.
      ,
      • Pelaia G.
      • Vatrella A.
      • Busceti M.T.
      • Gallelli L.
      • Calabrese C.
      • Terracciano R.
      • et al.
      Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD.
      ].
      Although beyond the scope of this review, an important clinical question is whether the exacerbation-prevention properties of tiotropium can be considered a class effect. While LAMAs all demonstrate a high affinity and potency toward the muscarinic M3 receptor, tiotropium has been shown to have a much longer dissociation from the receptors than either aclidinium or glycopyrronium [
      • Casarosa P.
      • Bouyssou T.
      • Germeyer S.
      • Schnapp A.
      • Gantner F.
      • Pieper M.
      Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs.
      ,
      • Tautermann C.S.
      • Kiechle T.
      • Seeliger D.
      • Diehl S.
      • Wex E.
      • Banholzer R.
      • et al.
      Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor.
      ]. Tiotropium therefore provides an effective and long-lasting (>24 h) blockade of the M3 receptors [
      • Alagha K.
      • Palot A.
      • Sofalvi T.
      • Pahus L.
      • Gouitaa M.
      • Tummino C.
      • et al.
      Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases.
      ,
      • Kruse A.C.
      • Li J.
      • Hu J.
      • Kobilka B.K.
      • Wess J.
      Novel insights into M3 muscarinic acetylcholine receptor physiology and structure.
      ]. In line with these kinetic properties, preclinical data suggest that tiotropium should provide the greatest level of bronchoprotection of all three LAMAs when applied at equieffective doses [
      • Casarosa P.
      • Bouyssou T.
      • Germeyer S.
      • Schnapp A.
      • Gantner F.
      • Pieper M.
      Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs.
      ]. It is speculative as to whether LAMAs have anti-inflammatory effects: most of the studies suggesting that LAMAs have anti-inflammatory and anti-remodelling properties have been conducted in vitro, and clinical studies showing definite anti-inflammatory activity for any LAMA are lacking. Few studies have directly compared the exacerbation efficacy of LAMAs, and this is worthy of further investigation.
      Unlike LAMAs, which mediate their bronchodilator effects through inhibition of cholinergic pathways, LABAs mediate their effects, in part, through stimulation of β2-adrenergic receptors. Recent studies suggest that genetic variation in these receptors may play an important role in treatment response [
      • Rabe K.F.
      • Fabbri L.M.
      • Israel E.
      • Kogler H.
      • Riemann K.
      • Schmidt H.
      • et al.
      Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial.
      ], with some genotypes associated with a limited response to β2-adrenergic drugs and others a full response; however, in clinical practice these genotypes are difficult to identify.
      There are both strengths and limitations of this systematic review that should be considered when evaluating the findings. A total of 29 publications were selected for review, including large studies that were specifically powered to evaluate exacerbations [
      • Bateman E.D.
      • Tashkin D.
      • Siafakas N.
      • Dahl R.
      • Towse L.
      • Massey D.
      • et al.
      A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.
      ,
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ,
      • Wise R.A.
      • Anzueto A.
      • Cotton D.
      • Dahl R.
      • Devins T.
      • Disse B.
      • et al.
      Tiotropium Respimat inhaler and the risk of death in COPD.
      ], and studies that were large and of a long enough duration to evaluate exacerbations in subgroup analyses [
      • Tashkin D.P.
      • Celli B.
      • Senn S.
      • Burkhart D.
      • Kesten S.
      • Menjoge S.
      • et al.
      A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
      ,
      • Vogelmeier C.
      • Hederer B.
      • Glaab T.
      • Schmidt H.
      • Rutten-van Molken M.P.
      • Beeh K.M.
      • et al.
      Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
      ]. In terms of limitations, the results are generally reported in a descriptive manner, and direct comparisons between trials are not conclusive due to differences in study designs and other potential methodological shortcomings. The lack of standardization in endpoints and outcomes between trials precluded the ability to pool data from different studies and perform a formal meta-analysis of the exacerbation data. Definitions used to describe an exacerbation event, including severity, differed between trials, and it is unknown whether these differences may have influenced results; however, there appears to be consistency in the results of the individual studies reviewed here.
      Since our search was restricted to English-language papers and mainstream journals (electronic search of the main databases), we cannot discount the possibility that some studies may have been excluded from this review; however, due to the comprehensive and rigorous literature search process, we are confident that all key studies published at the time were captured and included.
      Although not all studies were powered to show differences in exacerbation outcomes, current evidence indicates that tiotropium appears to demonstrate benefits over placebo and the LABAs salmeterol and indacaterol, while providing results comparable with the LAMA glycopyrronium and the fixed LAMA/LABA combination QVA149 (glycopyrronium/indacaterol).

      Conflicts of interest

      DMGH has received personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim and Novartis, and personal fees from GlaxoSmithKline and Pfizer. CV has received personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cytos, GlaxoSmithKline, Janssen, Mundipharma, Novartis and Takeda, and grants and personal fees from Grifols. MPP and NM are employees of Boehringer Ingelheim. FR was an employee of Boehringer Ingelheim at the time of manuscript submission. AA has received personal fees from AstraZeneca, Bayer-Schering Pharma, Boehringer Ingelheim, Dey Pharma, GlaxoSmithKline and Pfizer.

      Acknowledgements and funding

      Writing assistance was provided by Leigh Prevost and Natalie Dennis from PAREXEL, which was funded by Boehringer Ingelheim.
      All authors contributed to drafting the article and critically revising the content of the manuscript, and made the decision to submit this work for publication. All authors read and approved the final manuscript.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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