Triple Therapy in COPD

Author(s): Claudio Micheletto*, Alice Sparacino.

Journal Name: Current Respiratory Medicine Reviews

Volume 15 , Issue 2 , 2019

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Graphical Abstract:


Abstract:

Triple inhaled therapy for Chronic Obstructive Pulmonary Disease (COPD) includes an inhaled corticosteroid (ICS), a long-acting b2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator or LABA/ICS combination. There is consistent evidence that the LABA/LAMA/ICS combination has significantly greater effects on trough FEV1, symptoms, quality of life, and exercise performance compared to comparator treatments.

The role of triple therapy in reducing exacerbations in COPD patients is debatable, but recent trials have revealed some intriguing insights.

Three pivotal studies, namely TRILOGY, TRINITY and TRIBUTE have been conducted to evaluate the safety and efficacy of extrafine Beclomethasone/Formoterol Fumarate/Glycopyrronium Bromide (BDP/FF/GB) versus different treatment options for COPD. Extrafine BDP/FF/GB has been compared to an ICS/LABA (BDP/FF) combination in the TRILOGY study, to a LAMA monotherapy (Tiotropium-TIO) and an extemporary triple combination of ICS/LABA + LAMA (BDP/FF + TIO) in the TRINITY study, and to one inhalation of LABA/LAMA per day (Indacaterol/ Glycopyrronium - IND/GLY) in the TRIBUTE study.

Another triple therapy with Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) was recently tested in two further studies that included patients with COPD. The FULFIL study compared the efficacy of the triple FF/UMEC/VI therapy to the ICS/LABA association budesonide/formoterol, while the IMPACT study compared the rate of moderate and severe exacerbations between singleinhaler FF/UMEC/VI and single-inhaler FF/VI or UMEC/VI.

Keywords: COPD, patients, pharmacological treatment, triple therapy, Global Initiative for Chronic Obstructive Lung Disease (GOLD), long-acting muscarinic antagonist (LAMA).

[1]
Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD Executive Summary. Am J Respir Crit Care Med 2017; 195(5): 557-82.
[2]
Hurts JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363: 1128-38.
[3]
Müllerová H, Shukla A, Hawkins A, Quint J. Risk factors for acute exacerbations of COPD in a primary care population: A retrospective observational cohort study. BMJ Open 2014; 4 e006171
[4]
Solem CT, Sun SX, Sudharshan L, Macahilig C, Katyal M, Gao X. Exacerbation-related impairment of quality of life and work productivity in severe and very severe chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013; 8: 641-52.
[5]
Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH study. Am J Respir Crit Care Med 2008; 178: 332-8.
[6]
Halpin DM, Decramer M, Celli B, et al. Exacerbation frequency and course of COPD. Int J Chron Obstruct Pulmon Dis 2012; 7: 653-61.
[7]
Soler-Cataluna JJ, Martìnez-Garcia MA, Sànchez PR, et al. Severe acute exacerbation and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60: 925-31.
[8]
Ford ES, Murphy LB, Khavjou O, et al. Total and state-specific medical and absenteeism of COPD among adult aged > 18 years in the United States for 2010 and projections through 2020. Chest 2015; 147(1): 31-45.
[9]
Mannino DM, Higuchi K. YU T-C, et al Economic burden of COPD in the presence of comorbodities. Chest 2015; 148(1): 138-50.
[10]
Vestbo J, Vogelmeier C, Small M, Higgins V. Undertanding the GOLD 2011 strategy as applied to a real-world COPD population. Respir Med 2014; 108: 729-36.
[11]
Brusselle G, Prince D. Gruffydd-Jones, et al The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulm Dis 2015; 10: 2207-17.
[12]
Hahn B, Hull M, Blauer-Peterson C, et al. Rates of escalation to triple COPD therapy among incident users of LAMA and LAMA/LABA. Respir Med 2018; 139: 65-71.
[13]
James GD, Donaldson GC, Wedzicha JA, Nazareth I. Trends in management and outcomes of COPD patients in primary care, 2000-2009: A retrospective cohort study. NPJ Prim Care Respir Med 2014; 24: 14015.
[14]
Calverley P, Vlies B. A rationalapproach to single, dual and triple therapy in COPD. Respirology 2016; 21: 581-9.
[15]
Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci 1993; 52: 521-7.
[16]
Barnes PJ. Bronchodilators: basic pharmacology. In: Carveley PMA, Pride NB, Eds. Chronic Obstructive Pulmonary Disease. London: Chapman and Hall 1995; pp. 391-418.
[17]
Calzetta L, Matera MG, Cazzola M. Pharmacological interaction between LABAs and LAMAs in the airways: Optimizing synergy. Eur J Pharmacol 2015; 761: 168-73.
[18]
Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 1998; 94: 557-72.
[19]
Mak JCW, Nishikawa M, Barnes PJ. Glucocorticoid increase beta 2-adrenergic receptor transcription in human lung. Am J Physiol 1995; 12: L41-6.
[20]
Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilatation with QVA 149 versus single bronchodilator therapy: the SHINE study. Eur Resp J 2013; 42(6): 1484-94.
[21]
Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 in COPD. Resp Med 2013; 107: 1538-46.
[22]
D’Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: The 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res 2014; 15: 123-41.
[23]
Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD. Eur Resp J 2015; 45: 869-71.
[24]
Martinez F, Rabe KF, Fergusson GT, et al. Efficacy and safety of glycopyrrolate/formoterol metered dose inhaler formulated using co-suspension delivery technology in patients with COPD. Chest 2017; 151(2): 340-57.
[25]
Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: Two replicate double-blind, parallel group, randomized controlled trial. Lancet Resp Med 2013; 1(3): 210-23.
[26]
Singh D, Corradi M, Spinola M, et al. Extrafine beclomethasone dipropionate/formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease. NPJ Prim Care Respir Med 2016; 26: 16030.
[27]
Keating GM, McCormack PL. Salmeterol/fluticasone propionate: A review of its use in the treatment of chronic obstructive pulmonary disease. Drugs 2007; 67(16): 2383-405.
[28]
Aaron SD, Vandemheen KL, Fergusson D, et al. Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007; 146(8): 545-55.
[29]
Singh D, Brooks J, Hagan G, Cahn A, O’Connor BJ. Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax 2008; 63(7): 592-8.
[30]
Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 180(8): 741-50.
[31]
Jung KS, Park HY, Park SY, et al. Korea Chronic Obstructive Pulmonary disease study group. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: A randomized controlled study. Respir med 2012; 106(3): 382-9.
[32]
Manoharan A, Short PM, Andersn WJ, Lipworth BJ. Impact of long acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: A real-life retrospective cohort study. Lung 2014; 192(5): 649-52.
[33]
Frith PA, Thompson PJ, Ratnavadivel R, et al. Glisten Study Group. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax 2015; 70(6): 519-27.
[34]
Siler TM, Kerwin E, Sousa AR, Donald A, Ali R, Church A. Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies. Respir Med 2015; 109(9): 1155-63.
[35]
Lee SD, Xie CM, Yunus F, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium compared with tiotropium alone in patiets with severe or very severe COPD: A randomized, multicenter study in East Asia. Respirology 2016; 21(1): 119-27.
[36]
Sousa AR, Riley JH, Church A, Zhu CQ, Punekar YS, Fahy WA. The effect of umeclidinium added to inhaled corticosteroid/long- acting β2-agonist in patients with symptomatic COPD: A randomised, double-blind, parallel-group study. NPJ Prim Care Respir Med 2016; 26: 16031.
[37]
Siler TM, Kerwin E, Sousa AR, Donald A, Ali R, Chirch A. Efficacy and safety of umeclidinum added to fluticasone furoate/vilanterol in chronic obstructive disease: Results of two randoized studies. Respir Med 2015; 109(9): 1155-63.
[38]
Hanania NA, Crater GD, Morris AN, et al. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med 2012; 106(1): 91-101.
[39]
Singh D, Corradi M, Spinola M, Petruzzelli S, Papi A. Extrafine beclomethasone diproprionate/formterol fumarate: a review of its effects in chronic obstructive pulmonary disease. NPJ Pim care Med 2016; 26: 16030.
[40]
Singh D, Piccinno A, Borril Z, et al. Tolerability and high dose of the HFA modulate beclomethasone dipropionate/formoterol combination inhaler in asthmatic patients. Pulm Pharmacol Ther 2008; 21(3): 551-7.
[41]
Singh D, Papi A, Corradi M, et al. Single inhaler therapy versus inhaled corticosteroid plus long-acting b2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): A double-blind, parallel group, randomized controlled trial. Lancet 2016; 388: 963-73.
[42]
Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): A double blind, parallel group, randomised controlled trial. Lancet 2017; 389(10082): 1919-29.
[43]
Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): A double-blind, parallel group, randomised controlled trial. Lancet 2018; 391(10125): 1076-84.
[44]
Singh D, Roche N, Halpin D, Agusti A, Wedziche JA, Martinez FJ. Current controversies in the pharmacological treatment of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2016; 194(5): 541-9.
[45]
Salter M, Biggadike K, Matthews JL, et al. Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease. Am J Physiol Lung Cell Mol Physiol 2007; 293(3): L660-7.
[46]
Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): A novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther 2013; 345(2): 260-70.
[47]
Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel long-acting b2 agonist vilanterol in patients with COPD: Arandomized, placebo-controlled trial. Chest 2012; 142: 119-27.
[48]
Slack RJ, Barrett VJ, Morrison VS, et al. In vitro pharmacological characterization of vilanterol, a novel long-acting β2-adrenoceptor agonist with 24-hour duration of action. J Pharmacol Exp Ther 2013; 344(1): 218-30.
[49]
Brealey N, Gupta A, Renaux J, et al. Pharmacokinetics of fluticasone furoate, umeclidinum and vilanterol as a triple therapy in healty volunteers. Int J Clin Pharcacol Ther 2015; 53(9): 753-64.
[50]
Molino A, Calabrese G, Maniscalco M. Patient considerations in the treatment of COPD: Focus on the new combination inhaler fluticasone furoate/umeclidinium/vilanterol. Patient Prefer Adherence 2018; 12: 993-1001.
[51]
Lipson DA, Barnacle H, Birk R, et al. FULFIL trial: Once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Care Med 2017; 196(4): 438-46.
[52]
Halpin DMG, Birk R, Brealey N, et al. Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgropups analyses. EUR Open Res 2018; 4: 00119-2017.
[53]
Lipson DA, Barnahart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018; 378(18): 1671-80.
[54]
Martinez FJ, Boscia J, Feldman G, et al. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: A randomised trial. Respir Med 2013; 107: 550-9.
[55]
Kerwin EM, Scott-Wilson C, Sanford L, et al. A randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPD. Respir Med 2013; 107: 560-9.


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Article Details

VOLUME: 15
ISSUE: 2
Year: 2019
Page: [102 - 111]
Pages: 10
DOI: 10.2174/1573398X15666190314151921

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