Abstract
Background
Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups.
Methods
The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed.
Results
Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study.
Conclusions
The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-024-02971-3.
Keywords: Chronic obstructive pulmonary disease, Long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA), mMRC scores, CAT scores, FEV1, Exacerbation rates
Background
Chronic obstructive pulmonary disease (COPD) is globally the third leading cause of death and significantly impacts economic and social aspects [1]. It’s a treatable, but incurable disease marked by airway limitations and symptoms like breathlessness, persistent cough, and sputum production. The primary cause of COPD is smoking, with current smokers showing a higher prevalence than former smokers. After 25 years of smoking, about 25% of previously healthy smokers will have significant COPD, with 30–40% overall developing the disease [2]. The risk of COPD increases the longer an individual smokes. Research indicates ongoing dysregulation in pathways linked with smoking-related lung function decline, such as inflammation abnormalities [3–5], infection and immunity [5–7], epigenetic modifications [8–10], airway hyperresponsiveness [7, 11], excess mucus secretion [12], and changes in airway sizes [13].
The decline in lung function among former smokers aligns with enduring pathophysiological abnormalities in the lung after quitting smoking. The unadjusted FEV1 decline was 39.92 mL/year for current smokers, compared to 34.97 mL/year for former smokers [14]. Late quitters often stop smoking due to COPD, and because smoking cessation has minimal effect on FEV1 once COPD develops, it doesn’t significantly affect the long-term incidence of COPD [2]. Smoking-related emphysema, irreversible after smoking cessation, is linked with decreased lung function [15], potentially due to mechanical stress on adjacent lungs [16]. Traditional medical treatment of COPD can reduce the risk and severity of exacerbations, enhance health, and decelerate disease progression [17, 18]. Long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are commonly used to improve lung function, dyspnea, and overall health, and to decrease exacerbations [19–21]. Currently available LAMAs include tiotropium, glycopyrronium, aclidinium, and umeclidinium, while LABAs include salmeterol, formoterol, indacaterol, vilanterol, and olodaterol. Treatment with LAMA in stable COPD significantly lowers rates of exacerbations and non-serious adverse events, and increases trough FEV1 [22]. Importantly, LABAs and LAMAs show comparable improvements in lung function and health-related quality of life in both current and former smokers [23–25]. Known to boost lung function, symptoms, and overall health, LAMA/LABA combination therapy is more effective than using LAMA or LABA alone [26–29].
In Taiwan, fixed-dose combinations (FDCs) of LABA/LAMA are commonly used in routine clinical practice for patients with COPD. Patients using tiotropium/olodaterol (Tio/Olo) or umeclidinium/vilanterol (Umec/Vi) have shown a significantly lower annual incidence of moderate-to-severe exacerbations compared to those using indacaterol/glycopyrronium (Ind/Gly) [30]. Tio/Olo therapy has led to significant differences in symptoms and exacerbations, maintained similar treatment success rates [31], and improved health-related quality of life [32]. However, it's unclear if the benefits of LABA/LAMA therapy vary between current and former smokers in Taiwan. Similarly, it's uncertain if Tio/Olo treatment differs in health-related quality of life between these two groups. This study aims to examine the difference in clinical outcomes among conventional Tio/Olo therapy, Umec/Vi therapy, and Ind/Gly therapy for current and former smokers at various medical centers and regional hospitals in Taiwan.
Methods
This multicenter validation study, known as TOReTO (NCT04011475), collected retrospective data on patients with COPD from 12 medical centers and regional hospitals in Taiwan. The requirement for informed consent was waived because the data used was de-identified.
Defined
Acute exacerbation (AE) is defined as a complex of lower respiratory events/symptoms (worsening or new onset) related to the underlying COPD, with a duration of 3 days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalization (should all be accompanied by code of ICD-9-491.21 or ICD-10-J44.1). Within the retrospective period, the onset/stop date of COPD exacerbation, severity (mild, moderate, severe), and its outcome (leading to hospitalization or not) will be recorded. In terms of the exacerbation-related therapies, they will be recorded onto the page of “Rescue treatments” in the CRF. Mild exacerbation is a patient with worsening but self-managed symptoms. Moderate exacerbation is a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation is a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1).
Study design
The following criteria were used to include patients in the study: (1) diagnosed with COPD and prescribed LABA/LAMA (FDC) as a new treatment or as a switch from other treatments (i.e., single, dual, or triple) or had received LAMA for at least 3 months before June 30th, 2018, and (2) aged 40 years or older. Patients diagnosed with bronchial asthma, asthma-COPD overlap syndrome, bronchiectasis, cystic fibrosis, or lung cancer were not included. Initially, eligible patients were categorized into former smokers and current smokers. They were then divided into three cohorts based on their COPD prescription: Tio/Olo (cohort A; Spiolto®, Boehringer Ingelheim), Umec/Vi (cohort B; Anoro Ellipta®, GSK), and Ind/Gly (cohort C; Breezhaler®, Novartis Pharma). These patients were on LAMA or had switched from other single, dual, or triple treatments to LABA/LAMA until they either passed away or until one year after the initial index date, whichever came first.
Data collection
Data collected included the following: COPD diagnosis, records of exacerbations and hospitalizations, family history, spirometry data [FEV1 and Forced Vital Capacity (FVC)], questionnaire results [COPD Assessment Test (CAT) and Modified Medical Research Council Dyspnea Scale (mMRC)], treatment related to COPD or previous treatment (within one year before initiation), and the count of moderate-to-severe exacerbations. Whether drug-based or non-drug, during the review period, treatments for COPD will be recorded in the CRF. This includes COPD-related treatments, rescue treatments, oxygen therapy, etc., along with the reasons for any medication changes. Except for rescue treatments, the information of medications and analysis of exacerbations will be recorded every 3 months from the index date until death or the end of June 2019, whichever occurs first. The prescription date before and closest to the index date will also be recorded. With respect to rescue treatments, all records available in the medical chart within the retrospective period will be documented.
Questionnaires for evaluating symptoms and dyspnea
The CAT and mMRC questionnaires were utilized to evaluate the severity of symptoms and dyspnea related to COPD, respectively. For the CAT, lower scores indicate an improvement in symptoms, whereas higher scores suggest a worsening of symptoms [33]. The minimal clinically important difference (MCID) for the mMRC score is − 1 [34].
Statistical analysis
We performed data analyses using Statistical Analysis Software (SAS®) version 9.4 (SAS Institute, Cary, NC, USA). Propensity score matching (PSM) balanced the patient characteristics of three fixed-dose LABA/LAMA combinations before comparison. We calculated the propensity score for three groups using multivariable logistic regression with baseline covariates, including age and history of exacerbation (yes vs no). We then conducted 1:1:1 matching via the nearest neighbor method within a caliper of 0.2 of the propensity score. We compared continuous variables between cohorts using t-tests or Wilcoxon rank sum tests and analyzed categorical variables using the Chi-square test. We used Fisher’s exact test to determine statistical significance in the analysis of contingency tables. We defined a significant difference as a P-value < 0.05.
Results
Patient characteristics
This study involved data collection from 967 patients with COPD. The demographic characteristics of the participants are presented in Table 1. The participants comprised 297 current smokers and 670 former smokers. Specifically, 70 current and 130 former smokers received Tio/Olo treatment, 121 current and 233 former smokers received Umec/Vi, and 69 current and 230 former smokers received Ind/Gly.
Table 1.
Baseline characteristics of patients treated with fixed-dose LABA/LAMA
| Characteristics | Tio/Olo | Umec/Vi | Gly/Ind | P-value | |||
|---|---|---|---|---|---|---|---|
| Current (N = 70) | Former (N = 130) | Current (N = 121) | Former (N = 233) | Current (N = 69) | Former (N = 230) | ||
| Before propensity score matching | |||||||
| Age (years) | 69.3 ± 9.90 | 73.2 ± 8.83 | 69.8 ± 9.48 | 74.3 ± 8.82 | 69.6 ± 9.02 | 72.2 ± 9.61 | < 0.0001* |
| Male (n (%)) | 66 (94.3) | 127 (97.7) | 118 (97.5) | 230 (98.7) | 66 (95.7) | 222 (96.5) | 0.3833 |
| Race (ORIENTAL) | 70 (100.0) | 130 (100.0) | 121 (100.0) | 233 (100.0) | 69 (100.0) | 229 (99.6) | 0.7443 |
| Height (cm) | 164.2 ± 6.27 | 162.9 ± 6.95 | 164.6 ± 7.11 | 163.3 ± 6.50 | 163.7 ± 5.82 | 164.2 ± 6.55 | 0.2705 |
| Weight (kg) | 64.6 ± 12.89 | 64.2 ± 12.86 | 63.5 ± 11.59 | 65.9 ± 11.76 | 64.4 ± 11.00 | 65.1 ± 13.16 | 0.6506 |
| BMI (kg/m2) | 24.0 ± 4.54 | 24.1 ± 4.48 | 23.4 ± 3.81 | 24.6 ± 3.97 | 24.1 ± 3.48 | 24.3 ± 4.64 | 0.1599 |
| GOLD grade | |||||||
| GRADE 1 | 4 (9.5) | 13 (16.9) | 12 (12.1) | 34 (17.6) | 10 (21.7) | 28 (15.7) | 0.5806 |
| GRADE 2 | 19 (45.2) | 36 (46.8) | 45 (45.5) | 103 (53.4) | 22 (47.8) | 96 (53.9) | |
| GRADE 3 | 16 (38.1) | 23 (29.9) | 38 (38.4) | 48 (24.9) | 13 (28.3) | 45 (25.3) | |
| GRADE 4 | 3 (7.1) | 5 (6.5) | 4 (4.0) | 8 (4.1) | 1 (2.2) | 9 (5.1) | |
| GOLD group | |||||||
| GROUP A | 5 (16.1) | 3 (4.1) | 20 (21.3) | 24 (13.4) | 14 (30.4) | 25 (14.5) | 0.0199* |
| GROUP B | 14 (45.2) | 42 (57.5) | 49 (52.1) | 102 (57.0) | 20 (43.5) | 107 (61.8) | |
| GROUP C | 4 (12.9) | 9 (12.3) | 13 (13.8) | 25 (14.0) | 5 (10.9) | 20 (11.6) | |
| GROUP D | 8 (25.8) | 19 (26.0) | 12 (12.8) | 28 (15.6) | 7 (15.2) | 21 (12.1) | |
| After propensity score matching | |||||||
| Age (years) | 69.2 ± 10.86 | 73.2 ± 8.74 | 70.9 ± 9.61 | 73.9 ± 8.96 | 70.2 ± 8.27 | 73.8 ± 8.73 | 0.0073* |
| Male (n (%)) | 48 (92.3) | 92 (97.9) | 46 (97.9) | 99 (98.0) | 47 (97.9) | 92 (97.9) | 0.3703 |
| Race (East Asia) | 52 (100.0) | 94 (100.0) | 47 (100.0) | 101 (100.0) | 48 (100.0) | 94 (100.0) | NA |
| Height (cm) | 163.9 ± 6.36 | 162.6 ± 7.28 | 164.5 ± 8.21 | 163.6 ± 6.91 | 163.8 ± 5.51 | 164.5 ± 6.37 | 0.5980 |
| Weight (kg) | 63.9 ± 13.25 | 63.6 ± 12.51 | 64.0 ± 11.22 | 66.4 ± 11.23 | 66.1 ± 11.28 | 65.9 ± 14.68 | 0.5122 |
| BMI (kg/m2) | 23.8 ± 4.75 | 23.9 ± 4.10 | 23.5 ± 3.52 | 24.5 ± 4.04 | 24.7 ± 3.35 | 24.5 ± 4.97 | 0.3755 |
| GOLD grade | |||||||
| GRADE 1 | 4 (11.8) | 10 (16.1) | 8 (20.0) | 14 (15.1) | 9 (23.1) | 14 (17.5) | 0.5359 |
| GRADE 2 | 15 (44.1) | 32 (51.6) | 16 (40.0) | 52 (55.9) | 18 (46.2) | 39 (48.8) | |
| GRADE 3 | 13 (38.2) | 16 (25.8) | 16 (40.0) | 23 (24.7) | 12 (30.8) | 26 (32.5) | |
| GRADE 4 | 2 (5.9) | 4 (6.5) | 0 (0.0) | 4 (4.3) | 0 (0.0) | 1 (1.3) | |
| GOLD group | |||||||
| GROUP A | 3 (13.0) | 2 (3.7) | 11 (28.2) | 10 (12.0) | 9 (24.3) | 14 (18.9) | 0.1458 |
| GROUP B | 11 (47.8) | 32 (59.3) | 19 (48.7) | 46 (55.4) | 16 (43.2) | 45 (60.8) | |
| GROUP C | 3 (13.0) | 7 (13.0) | 4 (10.3) | 14 (16.9) | 5 (13.5) | 6 (8.1) | |
| GROUP D | 6 (26.1) | 13 (24.1) | 5 (12.8) | 13 (15.7) | 7 (18.9) | 9 (12.2) | |
Data are shown as mean ± SD or number (%). One-way ANOVA or Kruskal Wallis tests were applied for continuous variables and Chi-square tests were applied for categorical variables. *Significant difference. The GOLD grade was determined by the baseline value of Post-bronchodilator FEV1 (% predicted)
SD standard deviation, BMI body mass index, COPD chronic obstruction pulmonary disease, GOLD global initiative for obstructive lung disease, Ind/Gly indacaterol/glycopyrronium, Tio/Olo tiotropium/olodaterol, Umec/Vi umeclidinium/vilanterol
Before PSM, significant differences were noted in age (P < 0.0001) and the GOLD grouping of COPD (P = 0.0199) across the three groups (Table 1). Post-PSM, all characteristics were comparable except age (P = 0.0073) (Table 1). Furthermore, after PSM, former smokers in all three FDC groups were found to be older than current smokers (69.2 ± 10.86 years vs. 73.2 ± 8.74 years, 70.9 ± 9.61 years vs. 73.9 ± 8.96 years, 70.2 ± 8.27 years vs. 73.8 ± 8.73 years; P = 0.0037) (Table 1).
Changes in respiratory obstruction, mMRC dyspnea scale, and health-related quality of life in patients with COPD
No significant differences were observed in the baseline lung functions and mMRC scores after PSM (Table 2). Similarly, there were no notable differences in the total CAT scores for current and former smokers who received Tio/Olo (cohort A), Umec/Vi (cohort B), or Ind/Gly (cohort C) after 6 months and 12 months, respectively (Table 3). However, the scores for phlegm (1.9 ± 1.06 vs. 1.5 ± 1.12, 1.7 ± 1.01 vs. 1.6 ± 0.93, 1.6 ± 0.69 vs. 1.0 ± 0.81, P = 0.0346) and breathlessness (2.2 ± 1.06 vs. 2.0 ± 0.97, 1.9 ± 0.99 vs. 1.5 ± 1.04, 1.5 ± 0.96 vs. 1.4 ± 1.00, P = 0.0123) were higher in current smokers who received Tio/Olo (cohort A), Umec/Vi (cohort B), or Ind/Gly (cohort C) compared to former smokers (Table 3).
Table 2.
Summary of COPD assessment—mMRC and spirometry data [post-FEV1 (% predicted), post-FEV1/FVC (%)] after propensity score matching
| Characteristics | Tio/Olo | Umec/Vi | Gly/Ind | P-value | |||
|---|---|---|---|---|---|---|---|
| Current N = 52 |
Former N = 94 |
Current N = 47 |
Former N = 101 |
Current N = 48 |
Former N = 94 |
||
| mMRC scale | |||||||
| 6 M agoa | 1.5 ± 0.84 | 1.2 ± 0.91 | 1.7 ± 0.69 | 1.7 ± 0.77 | 1.5 ± 0.59 | 1.6 ± 0.79 | 0.0884 |
| 6 Ma | 0.9 ± 0.73 | 1.4 ± 1.03 | 1.2 ± 0.80 | 1.6 ± 0.78 | 1.4 ± 0.53 | 1.3 ± 0.75 | 0.2357 |
| 6 M to 12 Ma | 1.0 ± 1.04 | 1.4 ± 1.27 | 1.5 ± 0.52 | 1.8 ± 0.74 | 1.7 ± 0.52 | 1.5 ± 0.87 | 0.2882 |
| Post-FEV1 (%, pred.) | |||||||
| 6 M agoa | 61.0 ± 17.32 | 63.2 ± 21.79 | 59.1 ± 18.19 | 66.7 ± 21.84 | 63.1 ± 22.08 | 67.5 ± 23.48 | 0.3219 |
| 6 Ma | 52.9 ± 15.59 | 62.2 ± 19.27 | 54.2 ± 20.81 | 62.8 ± 17.23 | 60.3 ± 10.99 | 63.0 ± 25.58 | 0.5786 |
| 6 M to 12 Ma | 62.2 ± 19.81 | 65.9 ± 20.20 | 67.5 ± 18.95 | 69.7 ± 16.05 | 63.9 ± 20.05 | 67.5 ± 32.81 | 0.9168 |
| Post-FEV1/FVC (%) | |||||||
| 6 M agoa | 60.0 ± 11.27 | 59.0 ± 12.11 | 56.7 ± 11.17 | 57.4 ± 11.11 | 57.0 ± 10.52 | 58.4 ± 13.01 | 0.6220 |
| 6 Ma | 57.2 ± 12.32 | 60.2 ± 15.26 | 50.5 ± 5.29 | 53.1 ± 12.44 | 56.8 ± 9.57 | 58.2 ± 16.61 | 0.5860 |
| 6 M to 12 Ma | 59.1 ± 10.58 | 63.0 ± 12.23 | 54.0 ± 13.95 | 62.7 ± 9.75 | 55.5 ± 11.22 | 60.4 ± 16.55 | 0.4377 |
aCompare by index date
Ind/Gly indacaterol/glycopyrronium, M months, Tio/Olo tiotropium/olodaterol, Umec/Vi umeclidinium/vilanterol
Table 3.
Summary of COPD assessment-CAT after propensity score matching
| Characteristics | Tio/Olo | Umec/Vi | Gly/Ind | P-value | |||
|---|---|---|---|---|---|---|---|
| Current N = 52 |
Former N = 94 |
Current N = 47 |
Former N = 101 |
Current N = 48 |
Former N = 94 |
||
| Cough | |||||||
| 6 M agoa | 1.7 ± 1.19 | 1.6 ± 1.04 | 1.4 ± 0.85 | 1.5 ± 1.14 | 1.3 ± 0.75 | 1.0 ± 0.72 | 0.1742 |
| 6 Ma | 1.5 ± 0.96 | 1.2 ± 0.96 | 1.5 ± 0.64 | 1.4 ± 0.88 | 1.1 ± 0.73 | 1.3 ± 0.73 | 0.5526 |
| 6 M to 12 Ma | 1.3 ± 0.47 | 1.0 ± 0.73 | 1.6 ± 1.07 | 1.5 ± 0.95 | 1.3 ± 1.12 | 0.8 ± 0.66 | 0.0888 |
| Phlegm | |||||||
| 6 M agoa | 1.9 ± 1.06 | 1.5 ± 1.12 | 1.7 ± 1.01 | 1.6 ± 0.93 | 1.6 ± 0.69 | 1.0 ± 0.81 | 0.0346* |
| 6 Ma | 1.8 ± 0.85 | 1.5 ± 0.91 | 1.5 ± 1.06 | 1.3 ± 0.63 | 1.2 ± 0.70 | 1.4 ± 0.86 | 0.2836 |
| 6 M to 12 Ma | 1.4 ± 0.67 | 1.3 ± 0.86 | 1.7 ± 1.16 | 1.5 ± 1.10 | 1.4 ± 1.01 | 1.4 ± 0.96 | 0.9291 |
| Chest tightness | |||||||
| 6 M agoa | 1.3 ± 1.07 | 1.1 ± 1.10 | 1.3 ± 0.90 | 1.1 ± 1.03 | 1.1 ± 0.94 | 0.9 ± 0.71 | 0.6676 |
| 6 Ma | 1.2 ± 1.17 | 0.9 ± 1.10 | 0.9 ± 0.88 | 1.0 ± 0.87 | 0.6 ± 0.74 | 0.9 ± 0.77 | 0.8558 |
| 6 M to 12 Ma | 1.0 ± 0.89 | 0.6 ± 0.91 | 1.0 ± 0.82 | 1.1 ± 1.05 | 0.6 ± 0.88 | 0.8 ± 0.68 | 0.3918 |
| Breathlessness | |||||||
| 6 M agoa | 2.2 ± 1.06 | 2.0 ± 0.97 | 1.9 ± 0.99 | 1.5 ± 1.04 | 1.5 ± 0.96 | 1.4 ± 1.00 | 0.0123* |
| 6 Ma | 2.1 ± 0.97 | 2.0 ± 0.99 | 1.9 ± 1.41 | 1.7 ± 1.10 | 1.7 ± 0.91 | 1.5 ± 0.98 | 0.2821 |
| 6 M to 12 Ma | 2.3 ± 1.01 | 1.9 ± 1.00 | 2.4 ± 0.70 | 2.5 ± 1.19 | 1.8 ± 1.09 | 2.2 ± 0.91 | 0.3022 |
| Activities | |||||||
| 6 M agoa | 0.9 ± 0.96 | 0.9 ± 1.16 | 0.8 ± 0.91 | 0.8 ± 0.95 | 0.8 ± 1.08 | 0.6 ± 0.89 | 0.9244 |
| 6 Ma | 0.7 ± 0.75 | 0.8 ± 1.03 | 0.7 ± 1.05 | 0.7 ± 1.00 | 0.9 ± 1.03 | 0.6 ± 0.74 | 0.9854 |
| 6 M to 12 Ma | 1.4 ± 1.29 | 0.9 ± 1.09 | 0.9 ± 0.74 | 1.0 ± 0.94 | 1.2 ± 0.97 | 0.8 ± 0.86 | 0.7507 |
| Confidence | |||||||
| 6 M agoa | 0.4 ± 0.92 | 0.5 ± 1.00 | 0.6 ± 0.76 | 0.6 ± 0.84 | 0.8 ± 0.98 | 0.7 ± 0.92 | 0.3231 |
| 6 Ma | 0.5 ± 0.96 | 0.5 ± 0.79 | 0.5 ± 0.99 | 0.4 ± 0.62 | 0.7 ± 1.20 | 0.3 ± 0.48 | 0.9918 |
| 6 M to 12 Ma | 0.7 ± 0.79 | 0.9 ± 0.94 | 0.9 ± 0.88 | 1.3 ± 1.34 | 1.7 ± 1.12 | 0.7 ± 0.79 | 0.2518 |
| Sleep | |||||||
| 6 M agoa | 1.0 ± 0.97 | 1.2 ± 1.11 | 1.2 ± 1.07 | 0.9 ± 1.00 | 0.9 ± 0.99 | 0.9 ± 0.69 | 0.8659 |
| 6 Ma | 1.2 ± 0.98 | 0.9 ± 0.83 | 0.9 ± 1.06 | 0.8 ± 0.70 | 0.7 ± 0.83 | 0.9 ± 0.79 | 0.6105 |
| 6 M to 12 Ma | 0.7 ± 0.79 | 0.8 ± 0.82 | 0.9 ± 0.99 | 0.9 ± 0.75 | 0.9 ± 0.78 | 0.8 ± 0.77 | 0.9940 |
| Energy | |||||||
| 6 M agoa | 0.8 ± 1.00 | 0.7 ± 0.74 | 0.8 ± 0.90 | 0.8 ± 0.90 | 1.0 ± 0.94 | 0.8 ± 1.06 | 0.8544 |
| 6 Ma | 0.6 ± 0.76 | 0.7 ± 0.77 | 0.8 ± 1.01 | 0.6 ± 0.62 | 0.7 ± 0.61 | 0.6 ± 0.68 | 0.9748 |
| 6 M to 12 Ma | 0.6 ± 0.81 | 0.9 ± 0.79 | 1.1 ± 1.29 | 1.0 ± 0.69 | 1.6 ± 1.24 | 1.0 ± 1.21 | 0.4817 |
| Total score | |||||||
| 6 M agoa | 10.6 ± 5.63 | 10.0 ± 5.68 | 10.3 ± 4.66 | 10.2 ± 5.70 | 8.0 ± 5.23 | 9.7 ± 5.90 | 0.3158 |
| 6 Ma | 9.6 ± 3.56 | 8.9 ± 4.40 | 9.1 ± 5.63 | 9.0 ± 4.63 | 7.8 ± 3.64 | 9.8 ± 5.36 | 0.7045 |
| 6 M to 12 Ma | 9.5 ± 3.95 | 8.7 ± 3.88 | 10.7 ± 3.20 | 11.8 ± 6.55 | 10.4 ± 4.61 | 10.2 ± 6.62 | 0.4851 |
aCompare by index date
Ind/Gly indacaterol/glycopyrronium, M months, Tio/Olo tiotropium/olodaterol, Umec/Vi umeclidinium/vilanterol
Moderate-to-severe exacerbations in patients with COPD
Table 4 displays additional baseline characteristics related to the risk of future exacerbation after PSM. There were significant differences among the three FDC groups in the percentages of patients who had an AE within one year prior to the index date and those who experienced one or more severe exacerbations within one year after the index date (see Additional file 1: Table S1).
Table 4.
Characteristics at baseline related to future exacerbation in patients receiving fixed-dose LABA/LAMA after propensity score matching
| Characteristics | Tio/Olo | Umec/Vi | Gly/Ind | P-value | |||
|---|---|---|---|---|---|---|---|
| Current N = 52 |
Former N = 94 |
Current N = 47 |
Former N = 101 |
Current N = 48 |
Former N = 94 |
||
| Prior mod-to-severe AE happened in past 1 year | |||||||
| Yes | 10 (19.2) | 20 (21.3) | 11 (23.4) | 24 (23.8) | 10 (20.8) | 18 (19.1) | 0.9712 |
| No | 42 (80.8) | 74 (78.7) | 36 (76.6) | 77 (76.2) | 38 (79.2) | 76 (80.9) | |
| Prior severe AE happened in past 1 year | |||||||
| Yes | 4 (7.7) | 6 (6.4) | 7 (14.9) | 11 (10.9) | 3 (6.3) | 8 (8.5) | 0.5757 |
| No | 48 (92.3) | 88 (93.6) | 40 (85.1) | 90 (89.1) | 45 (93.8) | 86 (91.5) | |
| AE happened in 1 year after index date | |||||||
| Yes | 5 (9.8) | 15 (16.0) | 1 (2.1) | 18 (17.8) | 8 (16.7) | 23 (24.5) | 0.0199* |
| No | 46 (90.2) | 79 (84.0) | 46 (97.9) | 83 (82.2) | 40 (83.3) | 71 (75.5) | |
| Prior ICS used in past 1 year | |||||||
| Yes | 7 (13.5) | 10 (10.6) | 5 (10.6) | 7 (6.9) | 5 (10.4) | 5 (5.3) | 0.5571 |
| No | 45 (86.5) | 84 (89.4) | 42 (89.4) | 94 (93.1) | 43 (89.6) | 89 (94.7) | |
| Count of prior exacerbation happened in past 1 year | |||||||
| 0.2 ± 0.51 | 0.5 ± 1.43 | 0.3 ± 0.49 | 0.5 ± 1.15 | 0.3 ± 0.72 | 0.4 ± 0.97 | 0.9651 | |
| ≧ 2 moderate exacerbations happened in 1 year after index date | |||||||
| Yes | 2 (3.9) | 1 (1.1) | 1 (2.1) | 4 (4.0) | 2 (4.2) | 4 (4.3) | 0.8058 |
| No | 49 (96.1) | 93 (98.9) | 46 (97.9) | 97 (96.0) | 46 (95.8) | 90 (95.7) | |
| ≧ 1 severe exacerbations happened in 1 year after index date | |||||||
| Yes | 1 (2.0) | 7 (7.4) | 0 (0.0) | 7 (6.9) | 2 (4.2) | 15 (16.0) | 0.0048* |
| No | 50 (98.0) | 87 (92.6) | 47 (100.0) | 94 (93.1) | 46 (95.8) | 79 (84.0) | |
Data are shown as mean ± SD or number (%). One-way ANOVA or Kruskal Wallis tests were applied for continuous variables and Chi-square tests were applied for categorical variables
AE acute exacerbation, ICS inhaled corticosteroid, Ind/Gly indacaterol/glycopyrronium, SD standard deviation, Tio/Olo tiotropium/olodaterol, Umec/Vi umeclidinium/vilanterol
The primary endpoint is defined as the time to the first AE among the three treatment groups, analyzed separately for current and former smokers as shown in Fig. 1A. As both the treatment and smoking status may influence the occurrence of AE, the time to the first AE between current and former smokers was separately analyzed across the three treatment cohorts as shown in Fig. 1B, to assess the impact of current and former smoking status on the time to the first AE under each treatment regimen. Both Tio/Olo and Umec/Vi significantly reduced the occurrence of AEs or serious AEs in current smokers (Fig. 2).
Fig. 1.
Kaplan–Meier curve of time to first acute exacerbation after propensity score matching. A Comparison between current smoker and former smoker. B current smoker versus former smoker
Fig. 2.
This document compares the rates of all exacerbations in the year before and after the index date. It focuses on A acute exacerbation, and B severe acute exacerbation
However, cardiovascular diseases are common comorbidities in COPD patients, and their relationship with COPD has been increasingly recognized in recent years. The ETHOS study has shown that the risk of cardiovascular events increases following AE in these patients. In our study, we presented the proportion of different comorbidities in each cohort (see Additional file 1: Table S2). However, due to the limited number of cases, further analysis of the impact of comorbidities on AE would make statistical analysis difficult.
Discussion
Long-term evidence suggests that LAMA/LABA therapy exhibits a similar safety profile in both current and former smokers [35]. In Taiwan, it was observed that former smokers with COPD tended to be older than current smokers (Table 1). This study yielded several key findings. First, we found no significant difference in lung function changes or dyspnea between current and former smokers treated with LABA/LAMA. Second, current smokers may have experienced worse health-related quality of life outcomes than former smokers, including phlegm and breathlessness, six months prior to the index date (Table 3). However, these differences disappeared after receiving LABA/LAMA treatment. Lastly, the time to the first AE in current smokers was analyzed separately for the three therapy groups. The time difference between them was significant (Fig. 1A). While a significant difference was observed in the rates of severe exacerbations between current and former smokers receiving Umec/Vi (P = 0.0114) (Fig. 1B).
Patients with COPD treated with LABA/LAMA therapy experienced fewer exacerbations, greater improvement in FEV1, a lower risk of pneumonia, and improved quality of life [36]. However, a recent randomized controlled trial reported no significant differences in CAT, mMRC, or actual outcomes when using LAMA/LABA FDCs in patients with COPD [37]. The ability of dual bronchodilators with LAMA/LABA FDCs to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large randomized controlled trials [38]. Our study showed that the FEV1/FVC ratio of the LABA/LAMA combination remained < 0.7 and 50%pred ≤ FEV1 < 80%pred throughout the study period, indicating moderate pulmonary obstruction. Hence, using LAMA/LABA FDCs did not significantly improve lung obstruction in patients with COPD in this study, including both current and former smokers.
FEV1 is a diagnostic lung function test, whereas mMRC and CAT evaluate symptoms. Dyspnea is a key predictor of COPD mortality [39]. The mMRC dyspnea scale can forecast the risk of exacerbations in patients with COPD and is the variable most closely linked to death risk [40]. The CAT measures the impact of COPD on a person’s life and how it changes over time. After using LABA/LAMA FDC, patients with COPD showed significant improvement in their CAT scores compared to their baseline [41]. Whether considering the median change from baseline or the proportion of CAT responders, 58.2% of patients experienced clinically relevant improvements by the end of the follow-up period [41]. However, this study found no significant changes in mMRC scores and total CAT scores 6 and 12 months after patients with COPD began LABA/LAMA combination therapy.
The goal of medical therapy in patients with stable COPD is to reduce symptoms and reduce the risk of future events (i.e., disease progression, worsening, and mortality). The Tio/Olo significantly inhibited cigarette smoke extract-induced human bronchial epithelial cell death, mitochondrial dysfunction, and autophagy [42]. Patients with exacerbated dyspnea benefited most from Tio/Olo [43]. In the TRONARTO study, which included patients with moderate-to-severe COPD and varying inspiratory flow rates, Tio/Olo treatment resulted in a significant improvement in lung function (FEV1) [44]. Tio/Olo improved symptoms and lung function in patients with COPD in Japan [45]. For the patients with CAT ≥ 10 in Japanese, the use of Tio/Olo showed statistically significant improvements in mean total CAT scores, FEV1, and FVC [45].
In the UK, the incidence of any and moderate exacerbations in patients with COPD increases with age. The incidence of major exacerbations is similar across genders, but more prevalent in patients over 80 years of age [46]. For patients with severe COPD, stopping smoking can slow down the accelerated deterioration of lung function and reduce smoking-related complications [47, 48]. Our study found that those who quit smoking experienced a higher frequency of adverse events (Fig. 1). However, those who previously had COPD and smoked were older and likely had more dyspnea and concerns about airflow limitation than current smokers with COPD. It's presumed that many patients with COPD continue to smoke until symptoms become noticeable. Quitting might not be possible until their symptoms associated with smoking become severe [49, 50]. Therefore, further analysis of the received cases is needed, and the results should be interpreted with caution.
This study has several limitations. Firstly, the retrospective study design inherently led to a lack of data integrity. To reflect common practices in Taiwan’s COPD management, we didn’t address missing data. Since this study is based on a retrospective analysis of medical records, data related to patients who underwent a self-management program were not included in the data collection. Secondly, we assumed that the patients may have relatively stable COPD symptoms and pulmonary function, which may not necessitate regular follow-up pulmonary function tests in routine practice. Those in stable conditions might be less willing to undergo these tests. Thirdly, this is a retrospective study, meaning data was collected retrospectively rather than prospectively, making it susceptible to significant biases. As patients were not randomly assigned to receive one of the three treatments, there is an inherent bias in how treatments were assigned, potentially influencing the outcomes. Additionally, the medications were administered via different inhalers, and whether patients had sufficient inhalation force and coordination also impacted the physicians’ initial treatment choices. Imbalances in baseline characteristics and patient numbers between groups are common in non-randomized real-world studies. Differences in patient characteristics between current and former smokers suggest a greater burden of COPD symptoms and less frequent use of COPD maintenance therapy among current smokers. Imbalances in baseline characteristics and patient numbers between groups are common in nonrandomized real-world studies. Differences in patient characteristics between current and former smokers suggest a greater burden of COPD symptoms and less frequent use of COPD maintenance therapy among current smokers. Fourthly, patients self-reported their smoking history, which we didn’t validate with exhaled carbon monoxide levels. Among those who quit smoking, many did so late, with evident and severe symptoms. Additionally, due to the absence of a rigorous operational definition in the medical records regarding smoking status, we hypothesize that individuals who ceased smoking at a younger age are more likely to be misclassified as non-smokers in medical records. The accurate documentation or verification of smoking habits is an important consideration. Ensuring the validity of such data may be achieved by cross-referencing self-reported smoking status provided by enrolled patients with their medical records. Fifth, select patients based on whether they are transitioning from another maintenance inhaled therapy or new to therapy. Local non-clinical reasons may influence drug selection, and the most severe patients are often the last to receive them. Further analysis of the transitions between different LABA/LAMA combinations could provide valuable insights into the clinical efficacy of each therapeutic regimen and patient responses, potentially uncovering significant phenomena or patterns. Factors such as patient age, hand-mouth coordination, and the adequacy of inhalation strength may influence physicians’ decisions regarding which LABA/LAMA combination to prescribe. Investigating the transitions between medications represents a promising direction for future research. Sixth, current evidence suggests that adding ICS is appropriate for specific patients (e.g., those with blood eosinophil counts > 300 or frequent exacerbations). At the outset of our study, we attempted to exclude patients with asthma or asthma-COPD overlap syndromes. Statistics on exposure to ICS and history of exacerbations in the year before enrollment for each cohort are presented in the table. There were no significant differences between groups after PSM. Seventh, in our study, FEV1 was assessed post-bronchodilator; however, we did not analyze whether patients had a bronchodilator response (BDR). We understand that BDR affects medication selection, particularly ICS use. Therefore, we excluded patients from the study from the outset with asthma or asthma-COPD overlap. Grouping patients by PSM did not show significant differences in the proportion of past ICS use, minimizing this concern. Eighth, our study did not include an analysis of polypharmacy, but it is a variable worthy of inclusion in future studies. This study was a retrospective, real-world study. Although the exact proportion is unknown, in clinical practice we almost universally prescribe a mucolytic agent (N-acetylcysteine) to patients with COPD. Lastly, we only collected clinical data for one year following COPD treatment. The shorter follow-up period may limit the interpretation of time until the first moderate-to-severe exacerbation. Therefore, further long-term studies may be necessary.
Conclusions
To our knowledge, this is the first nationwide, real-world, multicenter study evaluating fixed-dose LABA/LAMA in COPD among current and former smokers in Taiwan. Our study found no significant difference in the improvement of shortness of breath or the worsening of breathing among current or former smokers who received different LABA/LAMA FDCs. However, there was a slight difference in reducing the incidence of moderate to severe exacerbations. Since this was a non-randomized study, the findings should be interpreted with caution.
Supplementary Information
Acknowledgements
We thank all patients and investigators involved in the study. We also thank study nurses, and other clinical staff. The operation, data management, planned and post-hoc statistics, and writing support during the development of this manuscript in the clinical study was outsourced to Formosa Biomedical Technology Corp.
Abbreviations
- COPD
Chronic obstructive pulmonary disease
- FDCs
Fixed-dose combinations
- Ind/Gly
Indacaterol/glycopyrronium
- LABA
Long-acting beta-agonist
- LAMA
Long-acting muscarinic antagonist
- PSM
Propensity score matching
- Tio/Olo
Tiotropium/olodaterol
- Umec/Vi
Umeclidinium/vilanterol
Author contributions
YTL, YHT, MJH, NHC, SLC, CWT, YFW, YKW, MCC, SFL, WHH, TMY, CLL, PHK, MSL made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This study was fully sponsored by Boehringer Ingelheim Taiwan Ltd.
Availability of data and materials
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study followed the institutional guidelines of the “Declaration of Helsinki Ethical Principles” for all procedures involving human participants. The study was approved by the Research Ethics Committee of National Taiwan University Hospital (201908002RSA), China Medical University Hospital (CMUH108-REC3-119), and Far Eastern Memorial Hospital (108148-E); the Institutional Review Board of Taichung Veterans General Hospital (SE19299B), Chiayi Christian Hospital (IRB2019066), Chang Gung Medical Foundation (201901282B0), E-Da Hospital (EMRP-108-105), MacKay Memorial Hospital (19CT048be), Taipei Tzu Chi Hospital (08-FS-090), and Cheng Hsin General Hospital ([727]108B-43).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Contreras-Garza BM. Update on clinical aspects of COPD. N Engl J Med. 2019;381:2484–5. [DOI] [PubMed] [Google Scholar]
- 2.Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006;61:935–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hogg JC. Why does airway inflammation persist after the smoking stops? Thorax. 2006;61:96–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Rutgers SR, Postma DS, ten Hacken NH, Kauffman HF, van Der Mark TW, Koeter GH, Timens W. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax. 2000;55:12–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Shiels MS, Katki HA, Freedman ND, Purdue MP, Wentzensen N, Trabert B, Kitahara CM, Furr M, Li Y, Kemp TJ, et al. Cigarette smoking and variations in systemic immune and inflammation markers. J Natl Cancer Inst. 2014;106:dju294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wilkinson TM, Patel IS, Wilks M, Donaldson GC, Wedzicha JA. Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;167:1090–5. [DOI] [PubMed] [Google Scholar]
- 7.Lapperre TS, Postma DS, Gosman MM, Snoeck-Stroband JB, ten Hacken NH, Hiemstra PS, Timens W, Sterk PJ, Mauad T. Relation between duration of smoking cessation and bronchial inflammation in COPD. Thorax. 2006;61:115–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Belinsky SA, Palmisano WA, Gilliland FD, Crooks LA, Divine KK, Winters SA, Grimes MJ, Harms HJ, Tellez CS, Smith TM, et al. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res. 2002;62:2370–7. [PubMed] [Google Scholar]
- 9.Soria JC, Rodriguez M, Liu DD, Lee JJ, Hong WK, Mao L. Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers. Cancer Res. 2002;62:351–5. [PubMed] [Google Scholar]
- 10.Wang G, Wang R, Strulovici-Barel Y, Salit J, Staudt MR, Ahmed J, Tilley AE, Yee-Levin J, Hollmann C, Harvey BG, et al. Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation. PLoS ONE. 2015;10: e0120824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339:1194–200. [DOI] [PubMed] [Google Scholar]
- 12.Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med. 1996;153:1530–5. [DOI] [PubMed] [Google Scholar]
- 13.Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2645–53. [DOI] [PubMed] [Google Scholar]
- 14.Oelsner EC, Balte PP, Bhatt SP, Cassano PA, Couper D, Folsom AR, Freedman ND, Jacobs DR Jr, Kalhan R, Mathew AR, et al. Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study. Lancet Respir Med. 2020;8:34–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Oelsner EC, Smith BM, Hoffman EA, Folsom AR, Kawut SM, Kaufman JD, Manichaikul A, Lederer DJ, Schwartz JE, Watson KE, et al. Associations between emphysema-like lung on CT and incident airflow limitation: a general population-based cohort study. Thorax. 2018;73:486–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bhatt SP, Bodduluri S, Hoffman EA, Newell JD Jr, Sieren JC, Dransfield MT, Reinhardt JM, Investigators CO. Computed tomography measure of lung at risk and lung function decline in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196:569–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Choi JY, Rhee CK. Diagnosis and treatment of early chronic obstructive lung disease (COPD). J Clin Med. 2020;9:3426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zhou Y, Zhong NS, Li X, Chen S, Zheng J, Zhao D, Yao W, Zhi R, Wei L, He B, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med. 2017;377:923–35. [DOI] [PubMed] [Google Scholar]
- 19.Melani AS. Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8:479–501. [DOI] [PubMed] [Google Scholar]
- 20.Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013. 10.1002/14651858.CD010177.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014. 10.1002/14651858.CD009285.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Koarai A, Sugiura H, Yamada M, Ichikawa T, Fujino N, Kawayama T, Ichinose M. Treatment with LABA versus LAMA for stable COPD: a systematic review and meta-analysis. BMC Pulm Med. 2020;20:111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Bhatt SP, Anderson JA, Brook RD, Calverley PMA, Celli BR, Cowans NJ, Crim C, Martinez FJ, Newby DE, Vestbo J, et al. Cigarette smoking and response to inhaled corticosteroids in COPD. Eur Respir J. 2018;51:1701393. [DOI] [PubMed] [Google Scholar]
- 24.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;35:287–94. [DOI] [PubMed] [Google Scholar]
- 25.Tashkin DP, Goodin T, Bowling A, Price B, Ozol-Godfrey A, Sharma S, Sanjar S. Effect of smoking status on lung function, patient-reported outcomes, and safety among COPD patients treated with glycopyrrolate inhalation powder: pooled analysis of GEM1 and GEM2 studies. Respir Res. 2019;20:135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Sion KYJ, Huisman EL, Punekar YS, Naya I, Ismaila AS. A network meta-analysis of long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA) combinations in COPD. Pulm Ther. 2017;3:297–316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting beta-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. Thorax. 2016;71:15–25. [DOI] [PubMed] [Google Scholar]
- 28.Rodrigo GJ, Price D, Anzueto A, Singh D, Altman P, Bader G, Patalano F, Fogel R, Kostikas K. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017;12:907–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Mammen MJ, Pai V, Aaron SD, Nici L, Alhazzani W, Alexander PE. Dual LABA/LAMA therapy versus LABA or LAMA monotherapy for chronic obstructive pulmonary disease. A systematic review and meta-analysis in support of the American Thoracic Society clinical practice guideline. Ann Am Thorac Soc. 2020;17:1133–43. [DOI] [PubMed] [Google Scholar]
- 30.Hsieh MJ, Chen NH, Cheng SL, Tao CW, Wei YF, Wu YK, Chan MC, Liu SF, Hsu WH, Yang TM, et al. Comparing clinical outcomes of tiotropium/olodaterol, umeclidinium/vilanterol, and indacaterol/glycopyrronium fixed-dose combination therapy in patients with chronic obstructive pulmonary disease in Taiwan: a multicenter cohort study. Int J Chron Obstruct Pulmon Dis. 2022;17:967–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Spielmanns M, Schildge S, Diedrich JP, Valipour A. Therapeutic success in swiss COPD patients receiving dual bronchodilation therapy as COPD maintenance treatment. Clin Pract. 2022;12:46–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Valipour A, Avdeev S, Barczyk A, Bayer V, Fridlender Z, Georgieva M, Kudela O, Medvedchikov A, Miron R, Sanzharovskaya M, et al. Therapeutic success of tiotropium/olodaterol, measured using the clinical COPD Questionnaire (CCQ), in routine clinical practice: a multinational non-interventional study. Int J Chron Obstruct Pulmon Dis. 2021;16:615–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD assessment test. Eur Respir J. 2009;34:648–54. [DOI] [PubMed] [Google Scholar]
- 34.Cazzola M, Hanania NA, MacNee W, Rudell K, Hackford C, Tamimi N. A review of the most common patient-reported outcomes in COPD–revisiting current knowledge and estimating future challenges. Int J Chron Obstruct Pulmon Dis. 2015;10:725–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Tashkin DP, Goodin T, Bowling A, Price B, Ozol-Godfrey A, Sharma S, Sanjar S. Effect of smoking status on lung function, patient-reported outcomes, and safety among patients with COPD treated with indacaterol/glycopyrrolate: pooled analysis of the FLIGHT1 and FLIGHT2 studies. Respir Med. 2019;155:113–20. [DOI] [PubMed] [Google Scholar]
- 36.Horita N, Goto A, Shibata Y, Ota E, Nakashima K, Nagai K, Kaneko T. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017;2:CD012066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Muraki M, Kunita Y, Shirahase K, Yamazaki R, Hanada S, Sawaguchi H, Tohda Y. A randomized controlled trial of long-acting muscarinic antagonist and long-acting beta2 agonist fixed-dose combinations in patients with chronic obstructive pulmonary disease. BMC Pulm Med. 2021;21:26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Cazzola M, Page C, Rogliani P, Calzetta L, Matera MG. Dual bronchodilation for the treatment of COPD: from bench to bedside. Br J Clin Pharmacol. 2022;88:3657–73. [DOI] [PubMed] [Google Scholar]
- 39.Chan HP, Mukhopadhyay A, Chong PL, Chin S, Wong XY, Ong V, Chan YH, Lim TK, Phua J. Prognostic utility of the 2011 GOLD classification and other multidimensional tools in Asian COPD patients: a prospective cohort study. Int J Chron Obstruct Pulmon Dis. 2016;11:823–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Cabrera Lopez C, Casanova Macario C, Marin Trigo JM, de Torres JP, Sicilia Torres R, Gonzalez JM, Polverino F, Divo M, Pinto Plata V, Zulueta JJ, Celli B. Comparison of the 2017 and 2015 global initiative for chronic obstructive lung disease reports impact on grouping and outcomes. Am J Respir Crit Care Med. 2018;197:463–9. [DOI] [PubMed] [Google Scholar]
- 41.Vogelmeier CF, Worth H, Buhl R, Criee CP, Guckel E, Kardos P. Impact of switching from triple therapy to dual bronchodilation in COPD: the DACCORD ‘real world’ study. Respir Res. 2022;23:109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Chen CH, Li YR, Lin SH, Chang HH, Chai WH, Chan PC, Lin CH. Tiotropium/Olodaterol treatment reduces cigarette smoke extract-induced cell death in BEAS-2B bronchial epithelial cells. BMC Pharmacol Toxicol. 2020;21:74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Spielmanns M, Tamm M, Schildge S, Valipour A. Swiss experience in therapy with dual bronchodilation in chronic obstructive pulmonary disease in relation to self-reported physical functionality. J Clin Med Res. 2021;13:392–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Mahler DA, Ludwig-Sengpiel A, Ferguson GT, de la Hoz A, Ritz J, Shaikh A, Watz H. TRONARTO: a randomized, placebo-controlled study of tiotropium/olodaterol delivered via soft mist inhaler in COPD patients stratified by peak inspiratory flow. Int J Chron Obstruct Pulmon Dis. 2021;16:2455–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Sato A, Miyazaki A, Nakamura S. Effectiveness of tiotropium/olodaterol in the real world: a post hoc subgroup analysis after the first year of use. Adv Ther. 2022;39:4692–706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Oshagbemi OA, Keene SJ, Driessen JHM, Jordan R, Wouters EFM, de Boer A, de Vries F, Franssen FME. Trends in moderate and severe exacerbations among COPD patients in the UK from 2005 to 2013. Respir Med. 2018;144:1–6. [DOI] [PubMed] [Google Scholar]
- 47.Pride NB. Smoking cessation: effects on symptoms, spirometry and future trends in COPD. Thorax. 2001;56(Suppl 2):ii7–10. [PMC free article] [PubMed] [Google Scholar]
- 48.Thomsen M, Nordestgaard BG, Vestbo J, Lange P. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med. 2013;1:543–50. [DOI] [PubMed] [Google Scholar]
- 49.Wang J, Li C, Jia C, Liu Y, Liu J, Yan X, Fang Y. Smoking, smoking cessation and tobacco control in rural China: a qualitative study in Shandong Province. BMC Public Health. 2014;14:916. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Wang R, Jiang Y, Yao C, Zhu M, Zhao Q, Huang L, Wang G, Guan Y, Michael E, Zhao G. Prevalence of tobacco related chronic diseases and its role in smoking cessation among smokers in a rural area of Shanghai, China: a cross sectional study. BMC Public Health. 2019;19:753. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.