Tiotropium in chronic obstructive pulmonary disease - a review of clinical development

Antonio Anzueto, Marc Miravitlles, Antonio Anzueto, Marc Miravitlles

Abstract

Background: Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy is recommended as initial treatment for Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, and D.

Main body: Tiotropium bromide was the first LAMA available for COPD in clinical practice and, because of its long duration of action, is administered once daily. Tiotropium was initially available as an inhalation powder delivered via a dry-powder inhaler (DPI). Later, tiotropium also became available as an inhalation spray delivered via a soft mist inhaler (SMI). The SMI was designed to overcome or minimize some of the issues associated with other inhaler types (eg, the need for strong inspiratory airflow with DPIs). Results of short- and long-term randomized, controlled clinical trials of tiotropium in patients with COPD indicated tiotropium was safe and significantly improved lung function, health-related quality of life, and exercise endurance, and reduced dyspnea, lung hyperinflation, exacerbations, and use of rescue medication compared with placebo or active comparators. These positive efficacy findings triggered the evaluation of tiotropium in fixed-dose combination with olodaterol (a long-acting β2-agonist). In this review, we provide an overview of studies of tiotropium for the treatment of COPD, with a focus on pivotal studies.

Conclusion: Tiotropium is safe and efficacious as a long-term, once-daily LAMA for the maintenance treatment of COPD and for reducing COPD exacerbations. The SMI generates a low-velocity, long-duration aerosol spray with a high fine-particle fraction, which results in marked lung drug deposition. In addition, high inspiratory flow rates are not required.

Keywords: Chronic obstructive pulmonary disease; Dry-powder inhaler; Dyspnea; Exacerbations; HandiHaler®; Long-acting muscarinic antagonist; Lung function; Respimat®; Soft mist inhaler; Tiotropium.

Conflict of interest statement

AA has received consultant fees from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Novartis.

MM has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols, and Novartis; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, Kamada, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis, Sanofi, and Grifols; and research grants from GlaxoSmithKline and Grifols.

Figures

Fig. 1
Fig. 1
Effects of tiotropium in COPD. COPD chronic obstructive pulmonary disease, HRQoL health-related quality of life

References

    1. Vogelmeier CF, Criner GJ, Martínez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Arch Bronconeumol. 2017;53:128–149.
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report). . Accessed 3 Feb 2020.
    1. Meurs H, Oenema TA, Kistemaker LE, Gosens R. A new perspective on muscarinic receptor antagonism in obstructive airways diseases. Curr Opin Pharmacol. 2013;13:316–323.
    1. Disse B, Speck GA, Rominger KL, Witek TJ, Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64:457–464.
    1. Panning CA, DeBisschop M. Tiotropium: an inhaled, long-acting anticholinergic drug for chronic obstructive pulmonary disease. Pharmacotherapy. 2003;23:183–189.
    1. Spiriva® Handihaler® (tiotropium bromide inhalation powder). Prescribing information 2018. Boehringer Ingelheim International GmbH. . Accessed 3 Feb 2020.
    1. Spiriva® Respimat® (tiotropium bromide inhalation spray). Prescribing information 2018. Boehringer Ingelheim International GmbH. . Accessed 3 Feb 2020.
    1. Malerba M, Foci V, Patrucco F, Pochetti P, Nardin M, Pelaia C, et al. Single Inhaler LABA/LAMA for COPD. Front Pharmacol. 2019;10:390.
    1. Stiolto® Respimat® (tiotropium bromide and olodaterol inhalation spray). Prescribing information 2018. Boehringer Ingelheim International GmbH. . Accessed 3 Feb 2020.
    1. Spiolto® Respimat® (tiotropium and olodaterol inhalation solution). Summary of Product Characteristics 2017. Boehringer Ingelheim International GmbH. . Accessed 3 Feb 2020.
    1. Ibrahim M, Verma R, Garcia-Contreras L. Inhalation drug delivery devices: technology update. Med Devices (Auckl) 2015;8:131–139.
    1. Mahler DA. Peak inspiratory flow rate as a criterion for dry powder inhaler use in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2017;14:1103–1107.
    1. Vincken W, Levy ML, Scullion J, Usmani OS, Dekhuijzen PNR, Corrigan CJ. Spacer devices for inhaled therapy: why use them, and how? ERJ Open Res. 2018;4:00065–02018.
    1. Anderson P. Use of Respimat soft mist inhaler in COPD patients. Int J Chron Obstruct Pulmon Dis. 2006;1:251–259.
    1. Newman SP, Brown J, Steed KP, Reader SJ, Kladders H. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices. Chest. 1998;113:957–963.
    1. Brand P, Hederer B, Austen G, Dewberry H, Meyer T. Higher lung deposition with Respimat soft mist inhaler than HFA-MDI in COPD patients with poor technique. Int J Chron Obstruct Pulmon Dis. 2008;3:763–770.
    1. Pitcairn G, Reader S, Pavia D, Newman S. Deposition of corticosteroid aerosol in the human lung by Respimat soft mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler. J Aerosol Med. 2005;18:264–272.
    1. Zierenberg B. Optimizing the in vitro performance of Respimat. J Aerosol Med. 1999;12(Suppl 1):S19–S24.
    1. Dalby R, Spallek M, Voshaar T. A review of the development of Respimat soft mist inhaler. Int J Pharm. 2004;283:1–9.
    1. Hochrainer D, Hölz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. Comparison of the aerosol velocity and spray duration of Respimat soft mist inhaler and pressurized metered dose inhalers. J Aerosol Med. 2005;18:273–282.
    1. Casaburi R, Briggs D Jr, Donohue JF, Serby CW, Menjoge SS, Witek T Jr. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest. 2000;118:1294–302.
    1. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217–224.
    1. Tonnel AB, Perez T, Grosbois JM, Verkindre C, Bravo ML, Brun M, et al. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis. 2008;3:301–310.
    1. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J. 2006;27:547–555.
    1. Zhou Y, Zhong NS, Li X, Chen S, Zheng J, Zhao D, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med. 2017;377:923–935.
    1. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–1554.
    1. Voshaar T, Lapidus R, Maleki-Yazdi R, Timmer W, Rubin E, Lowe L, et al. A randomized study of tiotropium Respimat soft mist inhaler vs. ipratropium pMDI in COPD. Respir Med. 2008;102:32–41.
    1. 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. Int J Chron Obstruct Pulmon Dis. 2010;5:197–208.
    1. Bateman ED, 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. Respir Med. 2010;104:1460–1472.
    1. Caillaud D, Le Merre C, Martinat Y, Aguilaniu B, Pavia D. A dose-ranging study of tiotropium delivered via Respimat soft mist inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis. 2007;2:559–565.
    1. Littner MR, Ilowite JS, Tashkin DP, Friedman M, Serby CW, Menjoge SS, et al. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1136–1142.
    1. Verkindre C, Bart F, Aguilaniu B, Fortin F, Guérin JC, Le Merre C, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration. 2006;73:420–427.
    1. Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J. 2007;14:465–472.
    1. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J. 2002;19:209–216.
    1. Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ, Jr, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002;122:47–55.
    1. 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. Thorax. 2003;58:399–404.
    1. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA, Jr, Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143:317–326.
    1. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;30:472–478.
    1. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093–1103.
    1. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax. 2000;55:289–94.
    1. Drug approval package. Spiriva HandiHaler (tiotropium bromide monohydrate) inhalation powder. U.S. Food & Drug Administration. . Accessed 3 Feb 2020.
    1. Rice KL, Kunisaki KM, Niewoehner DE. Role of tiotropium in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2007;2:95–105.
    1. Anzueto A, Miravitlles M. Pathophysiology of dyspnea in COPD. Postgrad Med. 2017;129:366–374.
    1. Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest. 2003;124:1743–1748.
    1. O'Donnell DE, Flüge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23:832–840.
    1. Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, et al. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest. 2005;128:1168–1178.
    1. Cooper CB, Celli BR, Jardim JR, Wise RA, Legg D, Guo J, et al. Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial. Chest. 2013;144:490–497.
    1. Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD--a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;4:203–223.
    1. Wallace AE, Kaila S, Bayer V, Shaikh A, Shinde MU, Willey VJ, et al. Health care resource utilization and exacerbation rates in patients with COPD stratified by disease severity in a commercially insured population. J Manag Care Spec Pharm. 2019;25:205–217.
    1. de Miguel-Diez J, Hernandez-Vazquez J, Lopez-de-Andres A, Alvaro-Meca A, Hernandez-Barrera V, Jimenez-Garcia R. Analysis of environmental risk factors for chronic obstructive pulmonary disease exacerbation: a case-crossover study (2004-2013) PLoS One. 2019;14:e0217143.
    1. Farias R, Sedeno M, Beaucage D, Drouin I, Ouellet I, Joubert A, et al. Innovating the treatment of COPD exacerbations: a phone interactive telesystem to increase COPD action plan adherence. BMJ Open Respir Res. 2019;6:e000379.
    1. Anzueto A, Miravitlles M. Chronic obstructive pulmonary disease exacerbations: a need for action. Am J Med. 2018;131:15–22.
    1. Miravitlles M, Garcia-Polo C, Domenech A, Villegas G, Conget F, de la Roza C. Clinical outcomes and cost analysis of exacerbations in chronic obstructive pulmonary disease. Lung. 2013;191:523–530.
    1. Wedzicha JA, Calverley PMA, Albert RK, Anzueto A, Criner GJ, Hurst JR, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50:1602265.
    1. Miravitlles M, Soler-Cataluña JJ, Calle M, Molina J, Almagro P, Quintano JA, et al. Spanish guidelines for Management of Chronic Obstructive Pulmonary Disease (GesEPOC) 2017. Pharmacological treatment of stable phase. Arch Bronconeumol. 2017;53:324–335.
    1. Alcazar Navarrete B, Ancochea Bermudez J, Garcia-Rio F, Izquierdo Alonso JL, Miravitlles M, Rodriguez Gonzalez-Moro JM, et al. Patients with chronic obstructive pulmonary disease exacerbations: recommendations for diagnosis. Treatment and Care Arch Bronconeumol. 2019;55:478–487.
    1. Anzueto A, Miravitlles M. Efficacy of tiotropium in the prevention of exacerbations of COPD. Ther Adv Respir Dis. 2009;3:103–111.
    1. Vogelmeier CF, Asijee GM, Kupas K, Beeh KM. Tiotropium and salmeterol in COPD patients at risk of exacerbations: a post hoc analysis from POET-COPD®. Adv Ther. 2015;32:537–547.
    1. Anzueto A, Tashkin D, Menjoge S, Kesten S. One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther. 2005;18:75–81.
    1. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374:1171–1178.
    1. Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, et al. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir J. 2010;36:65–73.
    1. Tashkin DP, Celli B, Kesten S, Lystig T, Mehra S, Decramer M. Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial. Eur Respir J. 2010;35:287–294.
    1. 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. Respir Med. 2010;104:1495–1504.
    1. Tashkin DP, Celli BR, Decramer M, Lystig T, Liu D, Kesten S. Efficacy of tiotropium in COPD patients with FEV1 ≥ 60% participating in the UPLIFT® trial. COPD. 2012;9:289–296.
    1. Morjaria JB, Rigby A, Morice AH. Inhaled corticosteroid use and the risk of pneumonia and COPD exacerbations in the UPLIFT study. Lung. 2017;195:281–288.
    1. Bateman ED, van Dyk M, Sagriotis A. Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study. Pulm Pharmacol Ther. 2008;21:20–25.
    1. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;177:19–26.
    1. Niewoehner DE, Lapidus R, Cote C, Sharafkhaneh A, Plautz M, Johnson P, et al. Therapeutic conversion of the combination of ipratropium and albuterol to tiotropium in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2009;22:587–592.
    1. Griffin J, Lee S, Caiado M, Kesten S, Price D. Comparison of tiotropium bromide and combined ipratropium/salbutamol for the treatment of COPD: a UK general practice research database 12-month follow-up study. Prim Care Respir J. 2008;17:104–110.
    1. Vogelmeier C, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res. 2010;11:135.
    1. Buhl R, Dunn LJ, Disdier C, Lassen C, Amos C, Henley M, et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Eur Respir J. 2011;38:797–803.
    1. Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H, Yorgancioglu A, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182:155–162.
    1. Decramer ML, Chapman KR, 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. Lancet Respir Med. 2013;1:524–533.
    1. Beier J, Kirsten AM, Mróz R, Segarra R, Chuecos F, Caracta C, et al. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled phase IIIb study. COPD. 2013;10:511–522.
    1. Chapman KR, Beeh KM, Beier J, Bateman ED, D'Urzo A, Nutbrown R, et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med. 2014;14:4.
    1. Dalby RN, Eicher J, Zierenberg B. Development of Respimat® Soft Mist Inhaler™ and its clinical utility in respiratory disorders. Med Devices (Auckl) 2011;4:145–155.
    1. Wachtel H, Kattenbeck S, Dunne S, Disse B. The Respimat® development story: patient-centered innovation. Pulm Ther. 2017;3:19–30.
    1. van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat soft mist inhaler or HandiHaler in COPD patients. Respir Med. 2009;103:22–29.
    1. Boehringer Ingelheim. Boehringer Ingelheim announces FDA approval of Spiriva® Respimat® (tiotropium bromide) inhalation spray for the maintenance treatment of COPD. . Accessed 3 Feb 2020.
    1. Rau-Berger H, Mitfessel H, Glaab T. Tiotropium Respimat® improves physical functioning in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2010;5:367–373.
    1. Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369:1491–1501.
    1. Anzueto A, Calverley PMA, Mueller A, Metzdorf N, Haensel M, Jardim JR, et al. Demographic characteristics and clinical outcomes in patients from Latin America versus the rest of the world: a TIOSPIR® post-hoc analysis. Arch Bronconeumol. 2018;54:140–148.
    1. Anzueto A, Wise R, Calverley P, Dusser D, Tang W, Metzdorf N, et al. The tiotropium safety and performance in Respimat® (TIOSPIR®) trial: spirometry outcomes. Respir Res. 2015;16:107.
    1. Calverley PM, Tetzlaff K, Dusser D, Wise RA, Mueller A, Metzdorf N, et al. Determinants of exacerbation risk in patients with COPD in the TIOSPIR study. Int J Chron Obstruct Pulmon Dis. 2017;12:3391–3405.
    1. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215.
    1. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68:48–56.
    1. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012:CD009285.
    1. Bateman ED. Tiotropium Respimat increases the risk of mortality: con. Eur Respir J. 2013;42:590–593.
    1. Barnes NC, Jones PW, Davis KJ. Safety of tiotropium through the Handihaler: why did meta-analyses and database studies appear to give a false alarm? Thorax. 2014;69:598–599.
    1. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. Responses available from: . BMJ. 2011;342:d3215.
    1. Disse B, Metzdorf N, Martin A, Cerasoli F, Leimer I. Mortality associated with tiotropium mist inhaler? A critical appraisal of the authors' selection and use of previously communicated tiotropium Respimat data BMJ 2011;342:d3215.
    1. 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. Respir Med. 2013;107:854–862.
    1. Andersen L, Høimark L, Nielsen LP. Respimat mist inhaler safety. BMJ (online) 2011;342:d3215.
    1. Miravitlles M, Price D, Rabe KF, Schmidt H, Metzdorf N, Celli B. Comorbidities of patients in tiotropium clinical trials: comparison with observational studies of patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:549–564.
    1. Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4) Eur Respir J. 2015;45:969–979.
    1. Beeh KM, Westerman J, Kirsten AM, Hebert J, Grönke L, Hamilton A, et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32:53–59.
    1. O'Donnell DE, Casaburi R, Frith P, Kirsten A, De Sousa D, Hamilton A, et al. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD. Eur Respir J. 2017;49:1601348.
    1. Maltais F, O'Donnell D, Gáldiz Iturri JB, Kirsten AM, Singh D, Hamilton A, et al. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2018;12:1753465818755091.
    1. Singh D, Ferguson GT, Bolitschek J, Grönke L, Hallmann C, Bennett N, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med. 2015;109:1312–1319.
    1. Beeh KM, Derom E, Echave-Sustaeta J, Grönke L, Hamilton A, Zhai D, et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) Int J Chron Obstruct Pulmon Dis. 2016;11:193–205.
    1. Troosters T, Maltais F, Leidy N, Lavoie KL, Sedeno M, Janssens W, et al. Effect of bronchodilation, exercise training, and behavior modification on symptoms and physical activity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198:1021–32.
    1. Calverley PMA, Anzueto AR, Carter K, Grönke L, Hallmann C, Jenkins C, et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial. Lancet Respir Med. 2018;6:337–344.
    1. Suissa S. Improving the efficiency of randomized trials: the DYNAGITO example. COPD. 2020;17:4–6.
    1. Miravitlles M, Urrutia G, Mathioudakis AG, Ancochea J. Efficacy and safety of tiotropium and olodaterol in COPD: a systematic review and meta-analysis. Respir Res. 2017;18:196.
    1. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J. 2019;53:1900164.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere