Triple therapy (ICS/LABA/LAMA) in COPD: time for a reappraisal

Lowie Vanfleteren, Leonardo M Fabbri, Alberto Papi, Stefano Petruzzelli, Bartolome Celli, Lowie Vanfleteren, Leonardo M Fabbri, Alberto Papi, Stefano Petruzzelli, Bartolome Celli

Abstract

Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

Keywords: adrenergic β2 receptor agonists; chronic obstructive; exacerbations; glucocorticoids; muscarinic antagonists; pulmonary disease; review; safety.

Conflict of interest statement

Disclosure LV reports grants and personal fees from AstraZeneca, grants from Philips, and Fisher and Paykel, and personal fees from Chiesi, GSK, Pulmonx, Menarini, and Boehringer-Ingelheim, all outside the submitted work. LMF reports grants, personal fees, and nonfinancial support from Boehringer-Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Takeda, AstraZeneca, Novartis, Menarini, Laboratori Guidotti, and Almirall, personal fees and nonfinancial support from Pearl Therapeutics, Mundipharma, and Boston Scientific, personal fees from Kyorin, Bayer, and Zambon, and grants from Pfizer, Dompè, Malesci, Alfasigma, and Vree Health Italia, all outside the submitted work. AP reports grants, personal fees, nonfinancial support, advisory board membership and consultancy work from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Mundipharma, and TEVA, personal fees and nonfinancial support from Menarini, Novartis, and Zambon, and grants from Sanofi, all outside the submitted work. SP is employed by Chiesi, the sponsor of TRILOGY, TRINITY, and TRIBUTE. BC reports grants to the Division of Pulmonary and Critical Care from AstraZeneca, and that he is a consultant for GlaxoSmithKline, Boehringer-Ingelheim, AstraZeneca, Novartis, Pulmonix, Chiesi, and Menarini, all outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
The overall benefit/risk ratio (ie, exacerbations/pneumonia) in the TRIBUTE study. Note: Reproduced with permission from Scuri M, Singh D, Fabbri LM, et al. Risk of pneumonia and exacerbations with single inhaler extrafine triple therapy compared to indacaterol/glycopyrronium: post-hoc analysis of the TRIBUTE study. Am J Respir Crit Care Med. 2018;197:A3030. Abbreviations: BDP/FF/G, beclometasone dipropionate/formoterol fumarate/glycopyrronium; IND/GLY, indacaterol/glycopyrronium.

References

    1. Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. [Accessed November 19, 2018]. Available from: . Published 2019.
    1. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterolglycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374(23):2222–2234.
    1. 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):1076–1084.
    1. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016;388(10048):963–973.
    1. 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):1919–1929.
    1. Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378(18):1671–1680.
    1. Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(4):438–446.
    1. Lipson DA, Barnhart F, Brealey N. Reduction in all-cause mortality with single inhaler triple therapy (FF/UMEC/VI) versus dual therapy (FF/VI and UMEC/VI) in symptomatic patients with COPD: prespeci-fied analysis of the Phase III IMPACT Trial. Am J Respir Crit Care Med. 2018;197:A1015.
    1. Vestbo J, Fabbri L, Papi A, et al. Inhaled corticosteroid containing combinations and mortality in COPD. Eur Respir J. 2018;1801230
    1. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease American Thoracic Society. Am J Respir Crit Care Med. 1995;152(5 Pt 2):S77–S121.
    1. O’Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23(6):832–840.
    1. Hohlfeld JM, Vogel-Claussen J, Biller H, et al. Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial. Lancet Respir Med. 2018;6(5):368–378.
    1. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19(2):217–224.
    1. Niewoehner DE, Rice K, Cote C, 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(5):317–326.
    1. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543–1554.
    1. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest. 2004;125(6):2309–2321.
    1. Singh S, Loke YK, Furberg CD, Review AS. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(12):1439–1450.
    1. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175–1185.
    1. Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 1: Saskatchewan cohort study. Chest. 2012;142(2):298–304.
    1. Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in COPD: part 2: reassessment in the larger Quebec cohort. Chest. 2012;142(2):305–311.
    1. Calverley PM, Anderson JA, Celli B, et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010;65(8):719–725.
    1. Suissa S, Dell’aniello S, Ernst P. Long-acting bronchodilator initiation in COPD and the risk of adverse cardiopulmonary events. Chest. 2017;151(1):60–67.
    1. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789.
    1. Celli B, Decramer M, Kesten S, et al. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(10):948–955.
    1. Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387(10030):1817–1826.
    1. Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. Thorax. 2016;71(1):15–25.
    1. Suissa S, Dell’Aniello S, Ernst P. Concurrent use of long-acting bronchodilators in COPD and the risk of adverse cardiovascular events. Eur Respir J. 2017;49(5):1602245.
    1. Calzetta L, Rogliani P, Matera MG, Cazzola M. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest. 2016;149(5):1181–1196.
    1. Calverley PMA, Anzueto AR, Carter K, 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(5):337–344.
    1. No authors listed Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis. 1987;136(1):225–244.
    1. Brown HM, Storey G, George WH. Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma. Br Med J. 1972;1(5800):585–590.
    1. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(5):1256–1276.
    1. Celli BR, MacNee W. ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932–946.
    1. Burrows B, Bloom JW, Traver GA, Cline MG. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med. 1987;317(21):1309–1314.
    1. Kerstjens HA, Brand PL, Hughes MD, et al. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group. N Engl J Med. 1992;327(20):1413–1419.
    1. Djukanović R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992;145(3):669–674.
    1. Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;167(3):418–424.
    1. Pauwels RA, Löfdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med. 1999;340(25):1948–1953.
    1. Vestbo J, Sørensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 1999;353(9167):1819–1823.
    1. Lung Health Study Research Group. Wise R, Connett J, Weinmann G, Scanlon P, Skeans M. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343(26):1902–1909.
    1. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320(7245):1297–1303.
    1. Jones PW, Willits LR, Burge PS, Calverley PMA. Inhaled steroids in obstructive lung disease in Europe study investigators. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J. 2003;21(1):68–73.
    1. Nannini LJ, Poole P, Milan SJ, Holmes R, Normansell R. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;11:CD003794.
    1. Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC. Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J. 2002;20(4):819–825.
    1. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(4):580–584.
    1. Iannella H, Luna C, Waterer G. Inhaled corticosteroids and the increased risk of pneumonia: what’s new? A 2015 updated review. Ther Adv Respir Dis. 2016;10(3):235–255.
    1. Ferguson GT, Tashkin DP, Skärby T, et al. Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: the 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. Respir Med. 2017;132:31–41.
    1. Miravitlles M, Soler-Cataluña JJ, Calle M, et al. Spanish COPD Guidelines (GesEPOC) 2017. Pharmacological treatment of stable chronic obstructive pulmonary disease. Arch Bronconeumol (English Ed) 2017;53(6):324–335.
    1. Postma DS, Rabe KF. The asthma–COPD overlap syndrome. N Engl J Med. 2015;373(13):1241–1249.
    1. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting β-agonists and inhaled corticosteroids compared with long-acting β-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA. 2014;312(11):1114–1121.
    1. Bafadhel M, Pavord ID, Russell REK. Eosinophils in COPD: just another biomarker? Lancet Respir Med. 2017;5(9):747–759.
    1. Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198(3):329–339.
    1. Calverley PMA, Tetzlaff K, Vogelmeier C, et al. Eosinophilia, frequent exacerbations, and steroid response in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(9):1219–1221.
    1. Rabe KF, Beghé B, Fabbri LM. Peripheral eosinophil count as a biomarker for the management of COPD: not there yet. Eur Respir J. 2017;50(5):1702165.
    1. Hartjes FJ, Vonk JM, Faiz A, et al. Predictive value of eosinophils and neutrophils on clinical effects of ICS in COPD. Respirology. 2018;23(11):1023–1031.
    1. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016;4(9):731–741.
    1. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med. 2017;377(17):1613–1629.
    1. Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. [Accessed December 21, 2016]. Available from: . Published 2017.
    1. 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):592–598.
    1. Jung KS, Park HY, Park SY, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respir Med. 2012;106(3):382–389.
    1. Hanania NA, Crater GD, Morris AN, Emmett AH, O’Dell DM, Niewoehner DE. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med. 2012;106(1):91–101.
    1. Frith PA, Thompson PJ, Ratnavadivel R, et al. 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):519–527.
    1. Siler TM, Kerwin E, Singletary K, Brooks J, Church A. Efficacy and safety of umeclidinium added to fluticasone propionate/salmeterol in patients with COPD: results of two randomized, double-blind studies. COPD. 2016;13(1):1–10.
    1. Aaron SD, Vandemheen KL, Fergusson D, et al. 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):545–555.
    1. 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):741–750.
    1. Lee SD, Xie CM, Yunus F, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium compared with tiotropium alone in patients with severe or very severe COPD: a randomized, multicentre study in East Asia. Respirology. 2016;21(1):119–127.
    1. Siler TM, Kerwin E, Tombs L, Fahy WA, Naya I. Triple therapy of umeclidinium + inhaled corticosteroids/long-acting beta2 agonists for patients with COPD: pooled results of randomized placebo-controlled trials. Pulm Ther. 2016;2(1):43–58.
    1. Short PM, Williamson PA, Elder DHJ, Lipworth SIW, Schembri S, Lipworth BJ. The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Chest. 2012;141(1):81–86.
    1. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294.
    1. Brusselle G, Price D, Gruffydd-Jones K, et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis. 2015;10(1):2207–2217.
    1. Simeone JC, Luthra R, Kaila S, et al. Initiation of triple therapy maintenance treatment among patients with COPD in the US. Int J Chron Obstruct Pulmon Dis. 2017;12:73–83.
    1. Miyazaki M, Nakamura H, Takahashi S, et al. The reasons for triple therapy in stable COPD patients in Japanese clinical practice. Int J Chron Obstruct Pulmon Dis. 2015;10:1053–1059.
    1. Martinez FJ, Rabe KF, Calverley PMA, et al. Determinants of response to roflumilast in severe COPD: pooled analysis of two randomized trials. Am J Respir Crit Care Med. 2018;198(10):1268–1278.
    1. Singh D, Papi A, Vezzoli S, et al. CHF5993 pMDI (extrafine beclometasone dipropionate:BDP, formoterol fumarate:FF, glycopyrronium bromide:GB) reduces clinically important deteriorations (CID) in COPD: post-hoc analysis of TRILOGY study. Eur Respir J. 2017;50(Suppl 61):PA533.
    1. Singh D, Fabbri L, Papi A, et al. Extrafine triple therapy reduces exacerbations in GOLD B COPD patients: post-hoc analysis of TRILOGY and TRINITY. Eur Respir J. 2017;50(Suppl 61):OA2898.
    1. Singh D, Papi A, Vezzoli S, et al. Effect of CHF5993 pMDI (extrafine beclometasone dipropionate:BDP, formoterol fumarate:FF, glycopyrronium bromide: GB) on clinically important deteriorations (CID) in COPD: post-hoc analysis of TRINITY study. Eur Respir J. 2017;50(Suppl 61):PA3949.
    1. Scuri M, Singh D, Fabbri LM, et al. Single inhaler extrafine triple therapy reduces clinically important deterioration (CID) in COPD compared to indacaterol/glycopyrronium: post-hoc analysis of the TRIBUTE study. Am J Respir Crit Care Med. 2018;197:A1013.
    1. Scuri M, Singh D, Fabbri LM, et al. Single inhaler extrafine triple therapy improves clinical outcomes in GOLD B COPD patients: post-hoc analysis of the TRIBUTE study. Am J Respir Crit Care Med. 2018;197:A3041.
    1. Scuri M, Singh D, Fabbri LM, et al. Risk of pneumonia and exacerbations with single inhaler extrafine triple therapy compared to indacaterol/glycopyrronium: post-hoc analysis of the TRIBUTE study. Am J Respir Crit Care Med. 2018;197:A3030.
    1. Suissa S, Drazen JM. Making sense of triple inhaled therapy for COPD. N Engl J Med. 2018;378(18):1723–1724.
    1. Janson C, Stratelis G, Miller-Larsson A, Harrison TW, Larsson K. Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:3055–3064.
    1. Sonnappa S, Martin R, Israel E, et al. Risk of pneumonia in obstructive lung disease: a real-life study comparing extra-fine and fine-particle inhaled corticosteroids. PLoS One. 2017;12(6):e0178112.
    1. Vanfleteren L, Ullman A, Fabbri LM. Time for a longer and better life for patients with COPD. Eur Respir J. 2018;51(1):1702569.
    1. Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budes-onide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled tr. Lancet Respir Med. 2018;6(10):747–758.

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