Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with persistent airflow limitation caused by toxic particles or gases (Vogelmeier et al., 2017). Globally, 174.5 million (2.4%) people suffer from COPD (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, 2016), and the prevalence in patients over 40 years of age in China is 13.7% (Wang et al., 2018). COPD is now one of the top three causes of death worldwide (Lozano et al., 2012).

With the progression of COPD, the burden of symptoms increases and quality of life declines. Symptomatic patients with COPD (group B and D) account for the vast majority in China (Duan et al., 2020). Furthermore, compared with patients with well-controlled symptoms, more symptomatic patients have a higher risk of acute exacerbations and poorer disease prognosis (Roche et al., 2013; Miravitlles and Ribera, 2017). Thus, we need to pay more attention to this group so as to further optimize the management of patients with symptomatic COPD.

At present, the effectiveness of different inhaled bronchodilators (long-acting muscarinic antagonist (LAMA); inhaled corticosteroids (ICS)/long-acting β₂-agonists (LABA); as well as the combinations LABA/LAMA and ICS/LABA/LAMA) in the treatment of COPD patients is still controversial (Wedzicha et al., 2016; Lipson et al., 2018; Maltais et al., 2019; Suissa et al., 2019; Lipson et al., 2020; Rabe et al., 2020). These therapies have been tested in randomized controlled trials (RCTs) with strict inclusion and exclusion criteria. The effectiveness of treatment evaluated in real-world studies can complement traditional RCTs by providing a comprehensive overview of treatments in routine clinical practice. Previous real-world studies usually selected one or two types of bronchodilators in mono, dual combination or triple combinations for analysis (Kalhan et al., 2021; Sansbury et al., 2021; Xu et al., 2021), and some studies have compared the effect between open triple and closed triple therapy (Ferguson et al., 2020; Huang et al., 2021). However, there is a lack of real-world data on the effects of the inhalation therapies including mono, dual combination and triple combination therapies among patients with symptomatic COPD in China.

Therefore, the purpose of this real-world study was to compare the effectiveness of different inhalation therapies for symptomatic COPD patients in China and to explore the relevant factors that influence the effectiveness of inhalation therapy.

To the best of our knowledge, this is the first real-world study to assess the effectiveness of inhalation therapies including mono, dual combination and triple combination therapies for symptomatic COPD patients in China.

Our results show that the MCID response rate (CAT improved ≥2) in symptomatic COPD patients treated with inhalation therapy was nearly 50% and the inhalation treatment of COPD patients with LAMA/LABA or triple therapy had a higher MCID response rate than LAMA or ICS/LABA. The total MCID response rate is consistent with previous studies showing that 51% of patients treated with umeclidinium/vilanterol, umeclidinium, or salmeterol achieved a clinical important improvement at week 24 (Vogelmeier et al., 2021). The benefits of triple treatment compared with mono and dual therapy are obvious in prospective clinical studies. Lee et al. demonstrated better improvements in St George’s Respiratory Questionnaire (SGRQ) scores in patients on inhaled triple therapy (tiotropium plus budesonide/formoterol) compared with those on monotherapy (tiotropium) (Lee et al., 2016). In the IMPACT study, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) single-inhaler triple therapy was associated with a better clinically meaningful improvement in SGRQ score (defined as a decrease ≥4 units from baseline) compared with ICS/LABA (FF/VI) (Lipson et al., 2018). In the EMAX study, UMEC/VI showed greater improvements in the proportion of CAT responders versus UMEC at week 12 and week 24 (Maltais et al., 2019). A network meta-analysis demonstrated that LABA/LAMA combinations were associated with a greater improvement in SGRQ scores and the Transitional Dyspnea Index (TDI) than monotherapy (Oba et al., 2016). Our study provides consistent evidence in the real world that confirms the benefits of dual bronchodilation on symptom improvement compared with mono-bronchodilator therapy in symptomatic patients with COPD.

An RCT showed that the improvement over time in the total score on the SGRQ was greater in the LABA/LAMA group than in the ICS/LABA group, which is consistent with our results (Wedzicha et al., 2016). We found no difference in the MCID response rate between LAMA/LABA and triple inhalation therapy for symptomatic COPD patients. However, we also had results inconsistent with the Germany DACCORD real-world observational study, in which the response rate of patients with a clinically relevant improvement (CAT score ≥2-unit change from baseline) was higher in patients receiving LAMA/LABA compared with triple therapy patients (62 vs. 47%, respectively; p < 0.001) (Buhl et al., 2018). Poverty, a high rate of smoking, and indoor biomass burning are traditionally considerable issues in Asia (Gordon et al., 2014; Kim et al., 2019). COPD phenotypes in Asia may be somewhat different from those in Western countries (Kim et al., 2019). We believe that this difference may be due to the heterogeneity of the region and the study participants.

Our logistic regression model showed that female patients had a higher incidence of MCID. In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels is related to frequency of symptoms and severe airflow limitation (Oh et al., 2013). Our previous study showed that nearly 70% of female in COPD patients were exposed to biomass smoke exposure alone. It has also been demonstrated that COPD patients with biomass exposure alone have higher CAT scores than patients with only smoke or occupational exposure (Duan et al., 2020). These previous reports also show that female COPD patients have more severe symptoms. We consider that these factors lead to higher MCID, because patients with more severe symptoms are more likely to obtain a 2 units reduction in the CAT score. We also found that patients treated with ICS/LABA/LAMA or LABA/LAMA were more likely to attain MCID than patients treated with LAMA. We have discussed this before, so we will not repeat it here.

In our study, we chose the MCID, which was defined as attaining a CAT decrease ≥2 during the 6 months follow-up, as our main effectiveness indicator in patients treated with inhalation bronchodilators. In clinical practice, it is time-consuming and impractical to monitor several different patient-reported outcome (PRO) measures such as CAT, SGRQ, self-administered computerized-Transition Dyspnea Index (SAC-TDI), and Evaluating Respiratory Symptoms (E-RS) (Vogelmeier et al., 2021). Previous systematic reviews supported the reliability and validity of the CAT and concluded that the tool is responsive to interventions. Furthermore, the correlation between CAT and SGRQ scores is typically quite high (convergent validity using Pearson’s correlation coefficient: 0.69–0.82 and 0.63), which has also been demonstrated in a systematic review (Gupta et al., 2014). Moreover, a large variety of questionnaires brings many difficulties to clinical practice and popularization. We think two or more PRO measures are more suitable for RCTs. A single CAT score for assessing systemic symptoms is more operable in real-world clinical practice and has been used in previous studies (Buhl et al., 2018).

We found no significant differences in the incidence of acute exacerbations during the 6 months follow-up period between different inhalation therapies in symptomatic COPD patients. In the past, there has been controversy regarding the risk of acute exacerbations after treatment with different inhalation therapies (Wedzicha et al., 2016; Lipson et al., 2018; Papi et al., 2018; Maltais et al., 2019; Suissa et al., 2019; Wang et al., 2021). However, we found that there were certain differences in the incidence of hospitalization-related acute exacerbations during the 6-months follow-up period between different inhalation therapies in symptomatic COPD patients. We found that COPD patients treated with LAMA had a lower incidence of severe exacerbations than LABA/LAMA patients. A network meta-analysis showed that all LAMAs are equally effective in preventing moderate-to-severe exacerbations, but the concomitant use of LABA may not enhance the efficacy of LAMAs in preventing COPD exacerbations (Oba and Lone, 2015). The EMAX randomized trial conducted in low exacerbation risk patients with COPD not receiving ICS showed that there was no difference in the occurrence of severe exacerbations between the umeclidinium/vilanterol and umeclidinium treatment groups (Maltais et al., 2019). It is known that previous exacerbation history is a reliable predictor of future exacerbations (Singh et al., 2019; Singh et al., 2020). In our study, the LAMA group had a higher proportion of patients with a history of exacerbations during the previous year than patients treated with LABA/LAMA (65.7 vs. 52.3%, p = 0.016). We think that this difference in the history of acute exacerbation between the LAMA and LABA/LAMA groups may be the main reason for this result.

Furthermore, inhalation treatment of COPD patients with ICS/LABA presented a lower incidence of severe exacerbations than LABA/LAMA. In previous research, there has been controversy regarding the risk of severe exacerbations between different inhalation treatments. In a real-world clinical practice setting of COPD treatment, the hazard ratio (HR) of severe COPD exacerbations associated with LABA/LAMA relative to ICS/LABA was 0.94. This study showed that combined LABA/LAMA inhalers appear to be as effective as combined ICS/LABA inhalers in preventing COPD exacerbations (Suissa et al., 2019), but an RCT demonstrated that the time to the first severe exacerbation was longer in the LABA/LAMA group than in the ICS/LABA group (HR 0.81; 95% CI, 0.66 to 1.00; p = 0.046) (Wedzicha et al., 2016). Another RCT showed that the annual rate of severe exacerbations during treatment was 0.15 among those assigned to ICS/LABA and 0.19 among those assigned to LABA/LAMA (Lipson et al., 2018). We consider that this difference may be due to the heterogeneity of the study population and the history of severe exacerbations between LABA/LAMA and ICS/LABA groups in the previous year. In our study, we also found that patients treated with LABA/LAMA had a higher incidence of severe exacerbation than those on triple inhalation therapy, which was consistent with a previous study. A matched cohort of 1,647 patients with COPD in a UK primary care database found that triple therapy reduced the exacerbation risk (HR 0.87, 95% CI 0.76–0.99) compared with LAMA/LABA dual therapy (Voorham et al., 2019). In the IMPACT study, triple therapy resulted in a lower rate of hospitalization due to COPD than LABA/LAMA (rate ratio with triple therapy, 0.66; 95% CI, 0.56 to 0.78; 34% difference; p < 0.001), but the rate was not significantly lower with triple therapy than with ICS/LABA (rate ratio with triple therapy, 0.87; 95% CI, 0.76 to 1.01; 13% difference; p = 0.06), which is consistent with our study (Lipson et al., 2018). This trial also demonstrated that these benefits were observed regardless of the patients’ blood eosinophil levels at randomization. We think this difference may be related to the effect of ICS on exacerbation prevention (Singh et al., 2019). Finally, in the multivariate analysis, we showed that the incidence of severe exacerbations in patients receiving LABA/LAMA treatment was higher than that of patients on triple inhalation therapy, which indirectly reflects the differences in the rate of severe exacerbations in other treatment groups, which may be related to the history of exacerbation before treatment.

There are some limitations to this study. First, the study did not correct the Charlson comorbidity index due to the limitations of real-world studies, but we evaluated other chronic pulmonary diseases, concurrent malignancy, severe heart, liver, or kidney diseases based on actual diagnoses from case records, which may reduce the confounding deviation of comorbidities to a certain extent. Second, according to current COPD treatment guidelines, blood eosinophil counts should be taken into consideration when deciding whether to initiate ICS treatment in combination with a LABA and/or LAMA (Singh et al., 2019). Our study did not include blood eosinophils in the multivariate analysis, which could cause a certain selection bias. However, it is likely that blood eosinophil counts were not considered in the treatment decisions observed in the current study, since the study was conducted prior to the inclusion of this recommendation. We also excluded patients diagnosed with asthma in our study, which may reduce this bias. Third, our study may have a relatively low incidence of exacerbation due to the short follow-up time. In the future, we may need to further explore and carry out follow-up studies on the acute exacerbations of these patients. Additionally, we did not include COPD patients in the less symptomatic groups into the study due to the fact that there are fewer COPD patients in groups A and C (8.7%) in these 12 comprehensive hospitals (Supplementary Table S3). In the future, we may need to cooperate with community hospitals to further expand the number of patients in groups A and C to supplement real-world data. Finally, we did not discuss the impact of the different types of inhalers, which may have influenced the selection of medications based on patient preference. However, these patients received inhalation training at the patient health management office after receiving the inhaler at their first visit. Therefore, each of our participants was able to use the inhaler correctly after assessment and inhalation training.

The incidence of MCID in symptomatic COPD patients treated with inhalation therapy was nearly 50%. Patients treated with LABA/LAMA or ICS/LABA/LAMA were more likely to attain MCID than patients treated with LAMA. Patients treated with LABA/LAMA had a higher incidence of severe exacerbations than patients given ICS/LABA/LAMA.