An Evaluation Of Single And Dual Long-Acting Bronchodilator Therapy As Effective Interventions In Maintenance Therapy-Naïve Patients With COPD

Abstract

Background: Ideally, treatment recommendations for maintenance therapy-naïve patients with COPD should be based on studies conducted specifically in this population. We have reviewed evidence from previous studies of pharmacological treatments in maintenance therapy-naïve patients with COPD and performed a new post-hoc analysis of dual bronchodilator treatment in this population, aiming to assess the effectiveness of these interventions.

Materials and methods: A literature review identified clinical trials that included analyses of patients with COPD who were maintenance therapy-naïve with long-acting β2-agonists (LABA) or long-acting muscarinic antagonists (LAMA). Additionally, a post-hoc subgroup analysis was conducted for maintenance therapy-naïve patients with COPD in two large phase III, randomized, double-blind, 24-week trials investigating the efficacy of aclidinium bromide/formoterol fumarate (AB/FF) fixed-dose combination versus monotherapy or placebo (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]).

Results: Treatment-naïve patients with COPD often represent a population of patients at the earliest stage at which most patients seek treatment. Of nine relevant studies identified, all reported positive findings for efficacy of LABA, LAMA, or LABA/LAMA treatment in maintenance therapy-naïve populations. Improvements were observed in lung function, symptoms, and health status versus monotherapy or placebo. Post-hoc analysis of ACLIFORM and AUGMENT demonstrated that AB/FF was effective in improving lung function in patients who had received no prior maintenance therapy. AB/FF showed improvements in 1 hr post-dose FEV1, trough FEV1, and patient-reported outcomes versus placebo and monotherapies. Combined with reviews of previous studies in maintenance therapy-naïve patients, these findings suggest that earlier intervention with a dual bronchodilator maintenance therapy, such as AB/FF, may provide significantly greater benefits than LAMA or LABA mono-bronchodilator therapy as a first maintenance treatment for COPD.

Conclusion: These data show that therapeutic intervention is effective in treatment-naïve patients. Intervention with dual bronchodilator therapy as a first maintenance treatment for COPD may provide greater benefits than LAMA or LABA monotherapy.

Keywords: COPD; LABA; LAMA; treatment-naïve.

Conflict of interest statement

DS is supported by the NIHR Manchester Biomedical Research Centre; and has received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards and research grants from various pharmaceutical companies including Apellis, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A, Cipla, Genentech, GlaxoSmithKline, Glenmark, Johnson & Johnson, Mundipharma, Novartis, Peptinnovate Ltd., Pfizer Inc, Pulmatrix, Skyepharma, Teva, Theravance Biopharma, Menarini, and Verona Pharma. ADD has received research, consulting, and lecturing fees from Almirall, Altana, AstraZeneca, Boehringer Ingelheim (Canada) Ltd, Forest Laboratories, GlaxoSmithKline, KOS Pharmaceuticals, Merck Canada, Methapharm, Novartis Canada/USA, ONO Pharmaceutical Co., Pfizer Canada, Schering-Plough, Sepracor, and SkyePharma. JFD has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, GSK, Mylan, Theravance, and Sunovion. He is a member of the Data Monitoring Committee for AstraZeneca. EMK has participated in consulting, advisory boards, speaker panels, or received travel reimbursement from Amphastar Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cipla, Chesi, Forest Laboratories LLC, GSK, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva Pharmaceutical Industries Ltd., and Theravance Biopharma. He has conducted multicenter clinical research trials for ~40 pharmaceutical companies. EM, FC, and DJ are employees of AstraZeneca and former employees of Almirall S.A., Barcelona, Spain. AR is a former employee of Almirall S.A., Barcelona, Spain and was an employee of AstraZeneca at the time the study was conducted. The authors report no other conflicts of interest in this work.

© 2019 Singh et al.

Figures

Figure 1

Treatment differences in trough FEV1 for (A) monotherapies and (B) dual therapies among the relevant publications identified in the literature search. Notes: Data are least square means differences unless stated otherwise. P-values and 95% CI included where available. aMean difference. ***P<0.001 versus placebo. Panel B is reproduced from the original publication Singh et al 2016, with a simplification of the figure to include only maintenance treatment-naïve subgroups. Reproduced from Singh D, Gaga M, Schmidt O, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO(R) studies. Respir Res. 2016;17(1):73. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/ and http://creativecommons.org/publicdomain/zero/1.0/. Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second.

Figure 2

Changes in SGRQ total score for (A) monotherapies and (B) dual therapies; (C) changes in TDI focal score for dual therapies, among the relevant publications identified in the literature search. Notes:aSGRQ total units. *P<0.05; ***P <0.001 versus placebo. Panels B and C are reproduced from the original publication Singh et al 2016, with the simplification of the figure to include only maintenance treatment-naïve subgroups. Reproduced from Singh D, Gaga M, Schmidt O, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO(R) studies. Respir Res. 2016;17(1):73. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/ and http://creativecommons.org/publicdomain/zero/1.0/. Abbreviations: CI, confidence interval; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Figure 3

Change from baseline in (A) 1 hr morning post-dose FEV1 and (B) trough FEV1 for treatment-naïve patients, at Week 24 of ACLIFORM and AUGMENT (post-hoc analysis; ITT population). Notes: **P<0.01; ***P<0.001. All data are LS mean changes from baseline. Analyses are based on the mixed model for repeated measures: treatment effects and treatment comparisons. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ). Abbreviations: AB, aclidinium bromide; CI, confidence interval; FEV1, forced expiratory volume in 1 sec; FF, formoterol fumarate; ITT, intent-to-treat; LS, least squares.

Figure 4

Patient-reported outcomes changes from baseline for treatment-naïve patients (A) TDI focal score at Week 24, (B) E-RS total score, (C) early morning COPD symptom severity and (D) nighttime COPD symptom severity over 24 weeks of ACLIFORM and AUGMENT (post-hoc analysis; ITT population). Notes: *P<0.05; **P<0.01; ***P<0.001. All data are LS mean changes from baseline. Analyses are based on the mixed model for repeated measures: treatment effects and treatment comparisons. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ). Abbreviations: AB, aclidinium bromide; CI, confidence interval; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating-Respiratory Symptoms; FF, formoterol fumarate; LS, least squares; TDI, Transition Dyspnea Index.

Figure 5

Changes from baseline for SGRQ total score for treatment-naïve patients, at Week 24 of ACLIFORM and AUGMENT (post-hoc analysis; ITT population). Notes: *P<0.05; **P<0.01; ***P<0.001. All data are LS mean changes from baseline. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ). The analysis was based on a mixed model for repeated measures: treatment effects and treatment comparisons. Abbreviations: AB, aclidinium bromide; CI, confidence interval; FF, formoterol fumarate; ITT, intent to treat; SGRQ, St George’s Respiratory Questionnaire.