Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO® Trials

Klaus F Rabe, James D Chalmers, Marc Miravitlles, Janwillem W H Kocks, Ioanna Tsiligianni, Alberto de la Hoz, Wenqiong Xue, Dave Singh, Gary T Ferguson, Jadwiga Wedzicha, Klaus F Rabe, James D Chalmers, Marc Miravitlles, Janwillem W H Kocks, Ioanna Tsiligianni, Alberto de la Hoz, Wenqiong Xue, Dave Singh, Gary T Ferguson, Jadwiga Wedzicha

Abstract

Introduction: Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting β2-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naïve patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID.

Methods: Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (delivered via Respimat®) in two replicate, 52-week, parallel-group, double-blind studies (TONADO® 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID.

Results: Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).

Conclusion: In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.

Trial registration: ClinicalTrials.gov identifier: TONADO® 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011).

Keywords: Chronic obstructive pulmonary disease; Exacerbations; Health status; Lung function; Olodaterol; Tiotropium.

Figures

Fig. 1
Fig. 1
Treatment comparison and time to event for tiotropium (5 μg) versus tiotropium/olodaterol (5/5 μg) using the CID composite endpoint score. aLow exacerbation history was defined as at most one moderate exacerbation in the past year (not leading to hospitalisation). CI confidence interval, CID clinically important deterioration, GOLD Global Initiative for Chronic Obstructive Lung Disease, T/O tiotropium/olodaterol, Tio tiotropium
Fig. 2
Fig. 2
Time to first CID in patients treated with tiotropium (5 μg) versus tiotropium/olodaterol (5/5 μg) in the overall patient population. CID clinically important deterioration, T/O tiotropium/olodaterol, Tio tiotropium

References

    1. Cazzola M, Matera MG. POINT: should LAMA/LABA combination therapy be used as initial maintenance treatment for COPD? Yes. Chest. 2018;154(4):746–748. doi: 10.1016/j.chest.2018.06.022.
    1. Barrecheguren M, Miravitlles M. COUNTERPOINT: should LAMA/LABA combination therapy be used as initial maintenance treatment for COPD? No. Chest. 2018;154(4):749–751. doi: 10.1016/j.chest.2018.06.024.
    1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report). 2019. . Accessed 15 Jun 2020.
    1. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of COPD: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56–e69. doi: 10.1164/rccm.202003-0625ST.
    1. National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. 2019. . Accessed 15 Jun 2020.
    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. doi: 10.1016/j.chest.2016.02.646.
    1. Calzetta L, Ora J, Cavalli F, Rogliani P, O'Donnell DE, Cazzola M. Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: a pair-wise and network meta-analysis. Respir Med. 2017;129:189–198. doi: 10.1016/j.rmed.2017.06.020.
    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. doi: 10.1136/thoraxjnl-2014-206732.
    1. Oba Y, Keeney E, Ghatehorde N, Dias S. Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2018;12:CD012620.
    1. Buhl R, de la Hoz A, Xue W, Singh D, Ferguson GT. Efficacy of tiotropium/olodaterol compared with tiotropium as a first-line maintenance treatment in patients with COPD who are naïve to LAMA, LABA and ICS: pooled analysis of four clinical trials. Adv Ther. 2020;37:4175–4189. doi: 10.1007/s12325-020-01411-0.
    1. Buhl R, Singh D, de la Hoz A, Xue W, Ferguson GT. Benefits of tiotropium/olodaterol compared with tiotropium in patients with COPD receiving only LAMA at baseline: pooled analysis of the TONADO® and OTEMTO® studies. Adv Ther. 2020;37:3485–3499. doi: 10.1007/s12325-020-01373-3.
    1. van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J. 2012;21(1):101–108. doi: 10.4104/pcrj.2011.00102.
    1. De Soyza A, Calverley PM. Large trials, new knowledge: the changing face of COPD management. Eur Respir J. 2015;45(6):1692–1703. doi: 10.1183/09031936.00179714.
    1. McCoy CE. Understanding the use of composite endpoints in clinical trials. West J Emerg Med. 2018;19(4):631–634. doi: 10.5811/westjem.2018.4.38383.
    1. Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111–124. doi: 10.1081/COPD-200053377.
    1. Alma HJ, de Jong C, Jelusic D, et al. Thresholds for clinically important deterioration versus improvement in COPD health status: results from a randomised controlled trial in pulmonary rehabilitation and an observational study during routine clinical practice. BMJ Open. 2019;9(6):e025776. doi: 10.1136/bmjopen-2018-025776.
    1. Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10(4):407–415. doi: 10.1016/0197-2456(89)90005-6.
    1. Anzueto AR, Vogelmeier CF, Kostikas K, et al. The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:1325–1337. doi: 10.2147/COPD.S133307.
    1. Singh D, Maleki-Yazdi MR, Tombs L, Iqbal A, Fahy WA, Naya I. Prevention of clinically important deteriorations in COPD with umeclidinium/vilanterol. Int J Chron Obstruct Pulmon Dis. 2016;11:1413–1424. doi: 10.2147/COPD.S101612.
    1. Rabe KF, Halpin DMG, Han MK, et al. Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial. Respir Res. 2020;21(1):177. doi: 10.1186/s12931-020-01431-y.
    1. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005–1012. doi: 10.1056/NEJMoa021322.
    1. Celli BR, Decramer M, Liu D, Metzdorf N, Asijee GM, Tashkin DP. Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial. Respir Res. 2016;17(1):48. doi: 10.1186/s12931-016-0361-4.
    1. Briggs A, Spencer M, Wang H, Mannino D, Sin DD. Development and validation of a prognostic index for health outcomes in chronic obstructive pulmonary disease. JAMA Intern Med. 2008;168(1):71–79. doi: 10.1001/archinternmed.2007.37.
    1. Jones RC, Donaldson GC, Chavannes NH, et al. Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(12):1189–1195. doi: 10.1164/rccm.200902-0271OC.
    1. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Eur Respir J. 2015;45(4):969–979. doi: 10.1183/09031936.00136014.
    1. Maltais F, Beck E, Webster D, et al. Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients [abstract P5557] Eur Respir J. 2010;36(suppl 54):1014s.
    1. Buhl R, de la Hoz A, Voss F, Singh D, Ferguson GT. Efficacy of tiotropium/olodaterol compared with tiotropium in patients naïve to LAMA, LABA and ICS: pooled analysis of four clinical trials. Am J Respir Crit Care Med. 2019;199:A7098.
    1. Panettieri RA., Jr Bronchodilators, receptors and cross-talk: together is better? Postgrad Med. 2015;127(7):771–780. doi: 10.1080/00325481.2015.1080589.
    1. Rogliani P, Matera MG, Ora J, Cazzola M, Calzetta L. The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis. Int J Chron Obstruct Pulmon Dis. 2017;12:3469–3485. doi: 10.2147/COPD.S146338.
    1. Donohue JF, Jones PW, Bartels C, et al. Correlations between FEV1 and patient-reported outcomes: a pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2018;49:11–19. doi: 10.1016/j.pupt.2017.12.005.
    1. Naya IP, Tombs L, Muellerova H, Compton C, Jones PW. Long-term outcomes following first short-term clinically important deterioration in COPD. Respir Res. 2018;19(1):222. doi: 10.1186/s12931-018-0928-3.
    1. Curran-Everett D, Milgrom H. Post-hoc data analysis: benefits and limitations. Curr Opin Allergy Clin Immunol. 2013;13(3):223–224. doi: 10.1097/ACI.0b013e3283609831.
    1. Singh D, Fabbri LM, Vezzoli S, Petruzzelli S, Papi A. Extrafine triple therapy delays COPD clinically important deterioration vs ICS/LABA, LAMA, or LABA/LAMA. Int J Chron Obstruct Pulmon Dis. 2019;14:531–546. doi: 10.2147/COPD.S196383.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅