Cost-effectiveness of chronic obstructive pulmonary disease population screening in China: based on individual data from WHO Collaborating Centre-initiated ‘Enjoying Breathing Program’

Abstract

Background

Chronic obstructive pulmonary disease (COPD) imposes a significant and growing burden on China and the world. Early detection and diagnosis may be an effective way to alleviate this severe pressure on public health. The Enjoying Breathing Program (the Program), a nationwide one-time and two-step COPD screening and management program with long-term follow-up initiated by the World Health Organization Collaborating Centre (WHO CC), has demonstrated its significant clinical benefit. However, the cost-effectiveness of the Program remains unknown.

Methods

A lifetime Markov model was developed to compare the cost-effectiveness of the Program of COPD screening to no screening from a Chinese healthcare perspective. Patient-level data, including treatment rate, medication cost, transition probability, etc., were sourced from the Program. Other parameter data were sourced from published literature.

Results

Enjoying Breathing Program for COPD screening was proved probably cost-effective compared with no screening in China with an incremental cost of $118, and incremental health benefit gain of 0.021 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of $5,679/QALY which was much less than willingness-to-pay (WTP) of 1×Gross Domestic Product (GDP) per capita in 2022 ($11,814). Sensitivity analysis proved the robustness of the results and subgroup analysis demonstrated health benefits varied among different subgroups. Annual screening and higher compliance may further enhance the cost-effectiveness.

Conclusions

Despite the underlying uncertainty, annual two-step COPD population screening in China may probably be cost-effective compared with no screening and deserves further large-scale implementation.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and chronic respiratory symptoms such as dyspnoea (breathlessness), cough, and sputum production among other symptoms [1]. There were about 251 million COPD cases worldwide in 2016, of which about 113 million to 187 million occurred in China [2]. As the fourth leading cause of years of life lost (YLLs) currently in China, the disease burden of COPD is expected to rise remarkably in the next 30 years and may reach estimated cost of $1.3 trillion, contributing the heaviest economic burden around the world followed by the United States ($1.0 trillion) and India ($0.4 trillion) [3, 4]. Patients with COPD often suffer from a variety of comorbidities. A previous study based on the National Enjoying Breathing Program highlights the heavy disease burden caused by COPD comorbidities [5].

To curb the escalating disease burden, the Chinese government initiated three nationwide comprehensive management programs for COPD, among which, is the National Enjoying Breathing Program (hereafter referred to as “the Program”) initiated by the World Health Organization Collaborating Centre (WHO CC) in November 2017 was the earliest one with the longest follow-up period [6,7,8,9]. The one-time and two-step program began with the use of the COPD screening questionnaire (COPD-SQ, a questionnaire validated for the Chinese population) among people older than 40 years, and then recommended those with questionnaire scores ≥ 16 for portable spirometer test (including 39.3% participants using SP10BT, 44.6% participants using BH-AX-MAPG, and 16.1% participants using other). Then participants with the post-bronchodilator forced expiratory volume in one second/forced vital capacity (FEV₁/FVC) < 0.7 were diagnosed positive and were managed in primary care. Until May 1, 2022, the National Enjoying Breathing Program has distributed 1.7 million paper-based questionnaires with 51,910 people diagnosed with COPD in over fifty varied pilot areas across China [10]. This notable Chinese achievement in COPD care was published and introduced as a cover article by WHO recently [11]. However, given the resource utilization related to this massive population screening program, the cost-effectiveness remained uncertain. The U.S. Preventive Services Task Force (USPSTF) recommended against screening asymptomatic adults for COPD in the U.S. according to its mild benefit, whereas UK researchers suggested systematic case-finding screening in primary care based on the favorable cost-effectiveness analysis results of the cluster-randomised controlled trial (TargetCOPD) [12,13,14]. Recently, a cost-effectiveness analysis of COPD screening in China has been published, however, without real-world individual data, parameters were sourced from outdated references or based on model assumptions [15, 16]. As medication prices change significantly due to varied drug policies such as national medical insurance negotiations and centralized procurement, bias may occur in such analysis. The implementation of this government-led, national program for COPD management provided us with the opportunity to perform the first cost-effectiveness study of COPD population screening based on individual-level data in the Chinese healthcare system. Therefore, by using the most updated medication prices and individual parameter values sourced from real-world data, we conducted this research to reveal the long-term gains of quality-adjusted life years (QALYs), cost and the cost-effectiveness of this nationwide COPD screening program.

Methods

In our study, 16,109 COPD patients from 47 different pilot selected randomly across all Chinese regions were diagnosed (76.1% from primary hospitals, 11.1% from secondary hospitals, and 12.8% from tertiary hospitals respectively) by National Enjoying Breathing Program from November 1, 2018, to March 31, 2022 (1,694,245 people attended COPD-SQ and 373,880 people scored no less than 16 in COPD-SQ) (Supplementary Material-Fig. S1). We initiated the cost-effectiveness analysis in April 2022, excluding data collection for the transitional period (November 2017 to October 2018) and any additional pilot data collected after April 2022. Patient baseline information of National Enjoying Breathing Program was detailed in Supplementary Material-Table S1. Ethical approval was obtained from the China-Japan Friendship Hospital (approval number: 2019-41-k29). All participants provided written informed consent for participation. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Model structure

A Markov decision model adapted from a previously validated model was developed using TreeAge Pro 2020 (TreeAge Software, Williamstown, Massachusetts, USA) [14]. The model estimated long-term cost-effectiveness from the Chinese healthcare system perspective of those diagnosed by National Enjoying Breathing Program screening compared to those without population screening (status quo). Participants were moved between 13 mutually exclusive health states over their lifetime (Fig. 1). Health status fell into three categories: disease-free, undiagnosed disease, diagnosed disease and death. COPD health status was defined based on severity classification in the current Global Initiative for Chronic Obstructive Lung Disease 2024 (GOLD 2024) [17]. Specifically, disease-free corresponds to no COPD (FEV₁/FVC ≥ 0.7, normal spirometry), undiagnosed disease corresponds to GOLD 1–3 (FEV₁/FVC < 0.7 without clinical diagnosis), and diagnosed disease corresponds to GOLD 1–4 (confirmed via post-bronchodilator spirometry and clinical evaluation). Population developed diagnosed or undiagnosed COPD may move to a more severe stage during the gradual disease progression. All patients in GOLD stage 4 were assumed to be diagnosed because of the significant symptoms and exacerbations. Diagnosis of COPD could be achieved through two pathways: (1) National Enjoying Breathing Program; (2) routine care (i.e. diagnosis after severe exacerbation requiring hospitalization). It was permissible to move from an undiagnosed state to a diagnosed state, but not the other way around. Patients diagnosed with COPD at each stage had different treatment rates. And only patients under treatment were allowed to improve. The diagnostic process was assumed to have no impact on the progression of the disease itself, consistent with the hypothesis of independence of health states over time. In any health condition, diagnosed or undiagnosed, the patient was at risk of severe exacerbation and death. Patients diagnosed with asthma or asthma-COPD overlap syndrome by physicians were excluded in the study [18]. Median age was 68 years and the model cycle length of this study was 3 months, long enough to capture significant COPD-related events, observe long periods of remission and follow for a lifetime (until death) time horizon. The COPD patient cohort was initialized using the prevalence in the general population from the national cross-sectional China Pulmonary Health (CPH) study [19].

Fig. 1

Markov model structure. COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease

Data values

Most of the data related to the detection and diagnosis of COPD such as transition probability, treatment rates, utility gain from treatment, and screening-related parameters (see details in Table 1) as well as proportions for patients under monotherapy, dual therapy and open, or closed triple therapy were all sourced from National Enjoying Breathing Program (Supplementary Material-Table S2). Statistical methods for extracting key parameters (e.g. transition probability, treatment rate, and utility) from the Enjoying Breathing Program are detailed in Supplement S1. All-cause mortality rates for age groups without COPD were obtained from the 7th Census data released by the National Bureau of Statistics of China and data released by global burden of disease (GBD) (Table S3) [24, 25]. Mortality rates were adjusted for each stage of COPD using data from a study in Taiwan with a more than 10 years follow-up duration [26]. Treatment effects were adjusted using risk ratio (RR) from a Bayesian network meta-analysis of exacerbations and mortality according to diverse medication therapy (Table S4) [20].

Table 1 Model parameters

Health utility values for health states in the model were mainly derived from National Enjoying Breathing Program during the first follow-up visit after diagnosis. These values were calculated using the five-level EuroQol five-dimensional (EQ-5D-5L), its multi-attribute additive model linearly aggregates utility losses across five dimensions via standardized weights, aligning with the proportionality of preferences assumption required for the estimation of QALY [27]. Based on the National Enjoying Breathing Program data, we derived the average utility gain from treatment (0.072). Disutility from severe exacerbation also was sourced from published literature [21].

Costs associated with questionnaire, portable spirometer and diagnostic test including bronchodilators, large lung function tests, and chest X-rays, all obtained through published literature [15, 16]. Medication costs were weighted by the proportion of different drug utilization for patients in each treated GOLD state according to National Enjoying Breathing Program and drug prices were sourced from an average of bidding prices by provinces in China in 2023 (more details see Supplementary Material-Table S2) [28]. Costs for severe exacerbations associated with an annual rate of severe exacerbation under treatment per year varied by GOLD stage 1–4, and average hospitalization costs, all sourced from data of National Enjoying Breathing Program. Although there are costs associated with program implementation, we decided not to consider such cost due to the difficulty of measuring conductive cost and with reference to previous study. All costs included in the model were in USD and converted to June 2023 price using the Consumer Price Index (CPI). (USD: RMB = 1: 7.2537).

Assessment of cost-effectiveness, sensitivity analysis and subgroup analysis

The primary outcome indicator was the incremental cost-effectiveness ratio (ICER), calculated as the difference in cost between the screening and no screening groups and the difference in QALYs. Willingness-to-pay (WTP) used in this study was 1×China’s Gross Domestic Product (GDP) per capita in 2022 ($11,814). If the ICER is less than the WTP, the screening strategy may be deemed highly cost-effective. A discount rate of 5% has been applied to both cost and QALY values in accordance with the China Guidelines for Pharmacoeconomic Evaluations (2020) [29].

Subgroup analyses were conducted based on various demographic and clinical characteristics, including sex (male and female), cohort age (40 ∼ < 60 years with a median of 54, and ≥ 60 years with a median of 70), education level (high school or less and college and higher), body mass index (BMI) categorized into underweight (< 18.5 kg/m²), normal weight (18.5 kg/m²∼<24.0 kg/m²), and overweight (≥ 24.0 kg/m²), and geographical regions (eastern and western China, rural area and urban area).

The base scenario was set for a one-time screening with a lifetime horizon, integrated with linkage to care data from the National Enjoying Breathing Program, including a spirometer participation rate of 33.17%, a follow-up diagnosis rate of 31.59% (insufficient follow-up in confirming diagnostic probabilities among patients with positive screenings), and treatment rates for GOLD stages 1–4 patients of 42.67%, 71.01%, 78.92%, and 77.93%, respectively. To make the study more generalizable, the model provided additional scenario analyses for time horizon (5, 10, and 20 years), screening intervals (1, 3, 5, and 10 years), spirometer participation rates (80%), follow-up diagnosis probability (80%) and treatment rate (30%, 60%, and 90%). Besides, we set 10% of GOLD stage 1 patients to receive triple therapy compared to a proportion of 30% according to medication records in National Enjoying Breathing Program. In the one-way sensitivity analysis, the upper and lower limits of utility values were from National Enjoying Breathing Program individual-level data, and other parameters (± 20%) were used for the analysis. All parameters were assigned distributions and entered the model for uncertainty testing and probabilistic sensitivity analysis. 10,000 Monte Carlo simulations were performed to test the robustness of the results and generate a cost-effectiveness acceptability curve (CEAC). The analysis was reported in accordance with the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement [30].

Results

Base case results showed Enjoying Breathing Program of COPD screening may result in additional costs of $118, as well as an additional gain of 0.021 QALYs in lifetime horizon analysis, meaning an ICER of $5,679/QALY compared to no screening, which was much less than WTP of 1×GDP per capita and indicating COPD early screening probably may be a highly cost-effective intervention for COPD prevention and control. Meanwhile, 1710 deaths could be averted in 5 years according to base case of a cohort of 100,000 individuals in our model compared to no screening.

Subgroup analysis confirmed the robustness of our results and conclusions as ICERs of all subgroups were below the WTP. Within subgroups, higher screening costs were associated with lower health benefits for males over females, individuals aged ≥ 60 compared to the 40 ∼ < 60 groups, and those with a high school or less versus those with a college and higher. The western region also demonstrated higher health outcomes and costs than the eastern region. Notably, the subgroup analysis revealed a lower ICER for urban screening compared to rural areas. Furthermore, those aged ≥ 60 yielded the highest costs, whereas individuals with higher education level yielded the greatest increase in QALY (more details in Table 2).

Table 2 Base case, subgroup and scenario analysis results

According to scenario analysis, the longer the analysis time horizon was, the less ICER would be, indicating a greater long-term benefit. Compared to one-time screening in a lifetime as base case analysis, annual screening brought more QALYs (0.082) with a slight increase in cost and ICER ($5,142/QALY) much less than WTP. When healthcare coverage is extended and disease management improves with a higher participation rate, optimistic incremental QALYs gain would be obtained at a cost under WTP.

One-way sensitivity analysis showed that treatment effect on mortality (RR) of GOLD stage 3, treatment effect on mortality (RR) of GOLD stage 1, utility gained from treatment, and cost of medication in GOLD stage 2 had the greatest effect on the model. However, the results were robust to the parameter changes, with none of the results being more than 1×GDP per capita (Fig. 2), and one-way sensitivity analysis of incremental cost and effectiveness were detailed in Supplementary Material-Figs. S2 and S3. Probability sensitivity analysis showed that the screening strategy was mostly cost-effective as all CEAC indicated a high probability of being cost-effective at WTP of 1×GDP per capita under all scenarios (Fig. 3). The observed incremental QALY of 0.021 was statistically significant (p < 0.001) in a t-test against zero, confirming the robustness of health benefits.

Fig. 2

Tornado diagram of one-way sensitivity analysis

Blue bar represented the lower limit, orange bar represented the higher limit of the parameter estimation.

Fig. 3

Cost-effectiveness acceptability curves of probabilistic sensitivity analysis

Discussion

COPD is one of the chronic diseases with a heavy disease burden around the world especially in China. Unlike the reduction of disease burden brought by other chronic diseases such as hypertension and diabetes [31], mortality of COPD has been rising and reached as high as 50/100,000, implying a long distance to the achievement of goal of Healthy China 2030 initiative according to which mortality of chronic respiratory disease should be as low as 8.1/100,000 [32, 33]. According to Lancet Commission and GOLD 2024, diagnosis and well management in the early stages of the disease, when lung function has not yet declined in airflow, can significantly reduce exacerbation, death, treatment resource utilization and public economic pressure [17, 34]. However, according to another recent research basing on the Enjoying Breathing Program, substantial patients were lost at the initial diagnosis stage in Chinese current primary healthcare system [35]. This underscores the urgent necessity for implementing targeted screening and diagnostic strategies to enhance the diagnosis rate of COPD. Therefore, our study for the first time explored the long-term health benefits of QALYs and cost brought by National Enjoying Breathing Program screening and found out one-time two-step COPD population screening was highly cost-effective in China. Moreover, annual two-step screening approach was preferable according to the scenario analysis with more QALY gain and more acceptable ICER.

One-way sensitivity analysis for ICER showed that results were most sensitive to treatment effect on mortality (RR) of GOLD stage 3 and GOLD stage 1, which indicated novel interventions reducing mortality may significantly improve the cost-effectiveness of screening. Moreover, costs of drugs in the early stages (GOLD stages 1 and 2) also had a large impact on the model, implying probably a more favorable cost-effectiveness in the future as the drug prices of treatment for COPD in China were expected to decrease due to the national policy of centralized procurement of generic drugs. In our scenario analysis, we also proved better health benefits and cost-effectiveness brought by higher participant rates of the screening and management of the disease. Subgroup analyses show that both urban and rural areas in China can be cost-effective, yet rural regions, with fewer medical resources, require greater investment. To reduce urban-rural health disparities, rural screening program can optimize resource utilization and enhance cost-effectiveness through health education, telemedicine, and regional medical hubs. Therefore, recent coverage of COPD in National Basic Public Health Service Program by Chinese government may further increase the cost-effectiveness of the population screening program for COPD by enhancing accessibility and compliance with the appropriate disease management [36].

To date, we have identified similar international cost-effectiveness analyses of COPD screening, such as the UK’s one-step systematic case-finding for COPD among smokers aged 50 and older based on the TargetCOPD trial, which has shown to be cost-effective, and Canadian studies suggesting two-step COPD screening is likely to be cost-effective in the general population aged 40 and above. Both of these studies highlight the significance and rationale for COPD screening [14, 37]. The USPSTF maintains a recommendation against population-wide COPD screening in asymptomatic adults, citing the mild benefit of screening [38]. Notwithstanding the contrary recommendations from USPSTF and UK research, previous Chinese researches all drew a positive recommendation for COPD screening in China, mainly because of the lower expenditure on screening approach, higher incidence and burden of the disease in China than in the US and UK. However, only one recent Chinese model-based study proved the cost-effectiveness of population-based screening rather than screening in high-risk populations [15]. Our study was the first cost-effectiveness analysis for COPD massive population screening based on the National Enjoying Breathing Program, the first nationwide two-step screening cohort conducted in the primary Chinese healthcare system. Instead of basing on the assumption of clinical practice, outdated medication price and referenced parameters from other countries in previous model analysis, this study is the first to leverage individual data from a Chinese real-world population cohort, for the first time directly obtain the progression transition probabilities, annual severe exacerbation rate and utility for the Chinese population at GOLD stages 1–4. Integrated with the latest prices of drugs and medical services under the influence of multiple current Chinese policies (such as national medical insurance negotiations and centralized procurement), the results of this study may reflect the real-world situation of COPD population screening in China with specific status quo linkage to care coverage in primary healthcare system. It is worth noting that COPD patients often have comorbidities [5], such as hypertension, asthma and bronchiectasis, which substantially elevate risks of hospitalization and mortality. Early COPD screening and preventive measures can slow their progression, reduce treatment cost, and improve patients’ quality of life.

Moreover, we found the medication proportion of triple therapy in GOLD stage 1 was the determinant parameter resulting in the significant variance in QALY gains between the previous model study and our study. According to the National Enjoying Breathing Program, around 30% of GOLD stage 1 patients have been medicated with triple therapy whereas in previous model analysis assumption was made that only single therapy was medicated for GOLD stage 1 patients without any utilization of triple therapy. As disclosed by one previous large-scale cross-sectional survey in China [39], more than 10% of GOLD stage 1 patients with complications and comorbidities utilized triple therapy and we believe this proportion may increase as triple therapy has been recommended by GOLD 2024 for initial treatment for COPD patients with blood eosinophil (eos) count ≥ 300 cells/µl. Meanwhile, the price reduction of closed triple therapy due to National Reimbursement Drug List (NRDL) negotiation may accelerate this trend. Those above-mentioned factors led to significantly less QALY gains and much higher ICERs in previous model analysis compared to our study. Therefore, a conservative recommendation of a “two-step, every two-year screening strategy” was made in previous model analysis given the WTP of 1×GDP per capita, despite the annual two-step screening strategy with the most QALY gains yet ICER ($13,671/QALY) above the WTP of 1×GDP per capita. Our study provided more positive evidence to support the annual two-step population screening strategy of COPD, due to the lower ICER ($5,142/QALY) much less than WTP of 1×GDP per capita. Our conclusion was robust across the sensitivity and scenario analysis such as under the scenario of the reduction of triple therapy utilization proportion in GOLD stage 1 to 10%. Our study, along with other similar COPD screening modeling studies around the world [14,15,16], showed that the incremental QALYs obtained from massive COPD screening are relatively modest at the individual level, compared to those interventions in severe diseases such as tumors and rare diseases. We observed the similar modest incremental QALYs gained in other chronic diseases such as hypertension and diabetes [40, 41]. Nevertheless, considering the substantial prevalence of COPD, the aggregate QALY benefits generated by COPD screening are significant, exerting a considerable impact on public health.

Our study still has some limitations. First, as key parameters such as transition probability, state utility, medication proportion, etc. were mainly sourced from National Enjoying Breathing Program, the generalization of the results should be taken cautiously. Second, due to the lack of follow-ups of the control group (regular practice without screening) and participants scored under the cut-off value of COPD-SQ and portable spirometer, as well as restricted follow-up time and limited follow-up frequency, some parameters such as incidence and mortality in the control group could not be obtained from National Enjoying Breathing Program, and were instead sourced from other studies, which may bring certain bias to our research. However, we compared and justified all parameters in our study with corresponding researches and conducted sensitivity analysis. Third, we had not accounted for the impact of individual’s smoking cessation caused by screening. Fourth, the key model parameters were predominantly informed by the National Enjoying Breathing Program. However, with the recent launch of other two national cohorts of COPD management in China, it is necessary to contextualize our model within these cohorts to further validate its applicability and accuracy in the evolving epidemiological context [42, 43]. Fifth, while we recognize the importance of culturally specific utility values, resource and time constraints precluded conducting a localized COPD exacerbation utility valuation study at this stage. Future research will prioritize establishing a China-specific utility measurement framework to enhance precision. Moreover, despite the preferable cost-effectiveness of the present screening procedure in National Enjoying Breathing Program, further research should be conducted on optimization of inclusion criteria and screening procedure such as related issues of starting age for screening, selection of questionnaire and spirometer with the optimal cut-off value besides the screening frequency and steps being investigated in previous model analysis.

Conclusion

Our study confirmed that the National Enjoying Breathing Program for COPD screening in China was highly cost-effective with ICER far below the WTP of 1×GDP per capita across varied scenarios and sensitivity analysis. Annual two-step screening and better linkage to care after inclusion of the National Basic Public Health Service Program may improve the cost-effectiveness and lead to better health outcomes.