Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide and entails a significant economic and social burden (Lozano et al., 2012; Vos et al., 2012). In China, COPD is the fifth most common cause of death, accounting for 31.1% of the world’s total deaths from COPD (Yin et al., 2016; GBD 2017 Causes of Death Collaborators, 2018). Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an episode of worsening symptoms that negatively impacts health status (Vogelmeier et al., 2017). AECOPD is a frequent cause of hospital admission and accounts for 50%–75% of the health care costs incurred by patients with COPD (Celli et al., 2004).

COPD patients usually experience about 0.5–3.5 exacerbations per year (Hurst et al., 2010). However, greater frequency of exacerbations is associated with accelerated lung function decline (Donaldson et al., 2002), quality of life impairment (Seemungal et al., 1998) and increased mortality (Soler-Cataluña et al., 2005). Systemic corticosteroids (SCs) in COPD exacerbations shorten recovery time and improve lung function (Global, 2021), and a dose of 40 mg prednisone per day for 5 days is recommended for management of exacerbations of COPD (Leuppi et al., 2013). However, because of adverse effects such as osteoporosis and bone fractures, glucose intolerance, and myopathy (Kwong et al., 1987; Decramer et al., 1994; Henzen et al., 2000), nebulized budesonide alone may be a suitable alternative to SCs and provides similar benefits to intravenous methylprednisolone (Ding et al., 2016). Because the cost of budesonide is higher than that of methylprednisolone, the Global Initiative for Chronic Obstructive Lung Disease guideline (GOLD) states that the choice between these options may depend on local cost issues (Global, 2021).

The present real-world study assesses the efficacy, safety, and cost-effectiveness of nebulized budesonide versus intravenous methylprednisolone for AECOPD patients from the perspective of the Chinese healthcare system.

For the logistic regression analysis, clinical efficacy and readmission within 1 year after discharge were used as dependent variables, and all possible influencing factors were included as independent variables. Consistent with the results of the basic analysis, the choice of budesonide or methylprednisolone as the main drug had no significant effect on clinical efficacy but had a significant effect on readmission within 1 year after discharge (Table 6).

Because the costs did not follow a normal distribution, generalized linear model analyses were used to examine the associated factors for direct medical and medication costs. Total hospitalization and total medication costs were taken as dependent variables respectively, and all possible influencing factors were included as independent variables. The gamma distribution was used to perform generalized linear regression with identity as the connection function. The results indicate that patients treated with budesonide had greater total hospitalization and total medication costs (Table 7).

Because this study is retrospective, bootstrapping was used to reduce sampling error, and a CEAC was drawn. When the clinical efficacy rate was used as the effect indicator, the results show that the probability of methylprednisolone being cost-effective at a willingness to pay (WTP) of 40,000 CNY was more than 90% (Figure 1). However, when the rate of no readmission within 1 year was used as the effect indicator, and the WTP was more than 23,000 CNY, nebulized budesonide became cost-effective (Figure 2). These findings are consistent with the results of the basic analysis, which indicates that the analysis is robust.

To our knowledge, this is the first study to use real-world patient-level data to investigate the differences in clinical effectiveness and pharmacoeconomics between nebulized budesonide and intravenous methylprednisolone in the treatment of AECOPD. There are three main findings.

First, for hospitalized patients with AECOPD, nebulized budesonide and intravenous methylprednisolone both improved lung function and blood gas analysis and had similar clinical efficacy. These results are in agreement with the findings of Ding et al. (2016) and the recommendations of expert consensus in China (Cai et al., 2014).

Second, in addition to clinical efficacy, this study also explored the effect of the two interventions in reducing the risk of readmission, which is an important indicator for evaluating the long-term effect on COPD patients. Readmission rates within 1 year after discharge were relatively high for both groups, at 25.7% in the budesonide group and 39.9% in the methylprednisolone group. A history of exacerbations is the most reliable predictor of exacerbations in COPD patients (Donaldson and Wedzicha, 2006; Hurst et al., 2010) and the patients in this study were therefore likely to be readmitted for acute exacerbations. This result may therefore be related to the frequent-exacerbation phenotype of hospitalized patients, especially in China, where most patients are already in group D according to the GOLD guidelines when they first visit a doctor.

Third, in economic terms, when clinical efficacy was used as the short-term efficacy indicator, the CMA results indicated that intravenous methylprednisolone was cost-effective due to lower total costs. However, from a long-term perspective, the CEA results indicated that nebulized budesonide cost 22,276.62 CNY extra compared with intravenous methylprednisolone, while saving one readmission within 1 year after discharge. Therefore, an average cost of one hospitalization for an acute exacerbation can be used as the threshold for WTP. A number of studies have found that AECOPD contributes significantly to the costs of COPD (Rutten-van Mölken et al., 1999; Hilleman et al., 2000; Miravitlles et al., 2002; Toy et al., 2010). In China, a large-scale retrospective study conducted by Liang et al. found that mean expenditure per admission increased from 19,760 CNY in 2009 to 20,118 CNY in 2017 (a growth rate of 0.11%) (Liang et al., 2020). On this trend, by 2021 mean expenditure per admission would have reached 20,206.20 CNY. In terms of willingness to pay, nebulized budesonide was not cost-effective compared with intravenous methylprednisolone because the ICER (22,276.62 CNY) was higher than the WTP (20,206.20 CNY).

A key strength of the present study is that it uses real-world data that are likely to provide reasonably good estimates of absolute event probabilities and costs in actual clinical practice. In addition, for a more comprehensive assessment, its economic evaluation includes different effect indicators, namely, clinical efficacy and no readmission within 1 year after discharge, which correspond to short-term and long-term effects, respectively.

However, the limitations of this study should be noted. First, because it is a single-center retrospective study, the sample size is small and the data identified from the electronic medical record database were incomplete. Second, the analysis focused on direct medical costs and paid no attention to direct nonmedical or indirect costs, which may have influenced the results. Third, the use of mean expenditure per admission, without considering the negative impact of readmission on patients’ lung function and quality of life, may have led to an underestimation of the WTP threshold.

In conclusion, compared with intravenous methylprednisolone, nebulized budesonide is not a cost-effective strategy in terms of either short-term or long-term effect. Large-scale multicenter studies are required to validate the findings of this study.