REALizing and improving management of stable COPD in China: results of a multicentre, prospective, observational study (REAL)

Abstract

Background:

Chronic obstructive pulmonary disease (COPD) management in China is far from adequate; underdiagnosis and undertreatment are major barriers to optimal care and improved patient outcomes.

Objective:

To generate reliable information on COPD management, outcomes, treatment patterns and adherence, and disease knowledge in China in a real-world setting.

Design:

A 52-week multicentre, prospective, observational study.

Methods:

Outpatients (⩾40 years old) diagnosed with COPD were enrolled from 50 secondary and tertiary hospitals across six geographical regions. Data were collected in routine clinical practice.

Results:

Between June 2017 and January 2019, 5013 patients were enrolled and 4978 included in the analysis. Mean [standard deviation (SD)] age was 66.2 (8.9) years, 79.5% were male and 90% had moderate-to-very-severe airflow limitation. Annual rates of overall and severe exacerbation were 0.56 and 0.31, respectively. During 1 year, 1536 (30.8%) patients experienced ⩾1 exacerbation and 960 (19.3%) patients had ⩾1 exacerbation requiring hospitalization/emergency visit. Mean (SD) COPD assessment test score was 14.6 (7.6) at baseline and 10.6 (6.8) at follow-up; however, 42–55% of patients had persistent dyspnoea, chest tightness and wheezing at 1 year. The most prescribed treatments were inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) (36.0%), ICS/LABA + long-acting muscarinic antagonist (LAMA) (17.7%) and LAMA monotherapy (15.3%). Among patients with high exacerbation risk (GOLD Groups C and D), 10.1% and 13.1%, respectively, did not receive any long-acting inhalers; only 53.8% and 63.6% of Group C and D patients with ⩾1 exacerbation during follow-up were prescribed ICS-containing therapy, respectively. Mean (SD) adherence for long-acting inhalers was 59.0% (34.3%). Mean (SD) score for the COPD questionnaire was 6.7 (2.4).

Conclusion:

These results indicate a high burden of severe exacerbations and symptoms in Chinese outpatients with COPD, and low adherence with treatment guidelines, highlighting the need for more effective management nationwide.

Registration:

The trial was registered on 20 March 2017 (ClinicalTrials.gov identifier: NCT03131362).

Plain language summary

The current state of chronic obstructive pulmonary disease management in China

Background: Chronic obstructive pulmonary disease is a chronic inflammatory lung disease characterized by progressive and irreversible airflow limitation. The disease is poorly managed in China, and many patients do not receive a diagnosis or appropriate treatment. Inadequate treatment can cause a ‘flare up’ of symptoms, known as exacerbation, which reduces a patient’s quality of life and increases the risk of hospitalization and death.

Objective: This study aimed to generate reliable, nationally representative information on the current status of chronic obstructive pulmonary disease management in China to help inform future management strategies.

Study Design and Methods: Patients aged ⩾40 years with a diagnosis of chronic obstructive pulmonary disease were eligible for this study. Patients were enrolled from 50 hospitals across 6 regions of China, and their physicians collected study data during routine outpatient visits over the course of 1 year.

Results: Of the 4978 patients included in this study, 90% had moderate-to-very-severe airflow limitation. A substantial proportion of patients had exacerbations (31%), with a large number being admitted to the hospital for treatment or visiting the emergency department (19%). About half of the patients had persistent symptoms related to the disease, including shortness of breath, chest tightness and wheezing. Some patients were prescribed long-acting inhaled treatments that are recommended to help prevent exacerbations. However, there were patients who were not prescribed any long-acting inhalers despite having a high risk of exacerbation. Moreover, patients prescribed long-acting inhalers only used their inhalers 59% of the time. Overall, patients’ knowledge of the disease was poor.

Conclusion: Chinese patients with chronic obstructive pulmonary disease are substantially impacted by exacerbations and chronic symptoms, and do not always receive appropriate treatment. The results from this study emphasize the need for more effective management across the country.

Background

Chronic obstructive pulmonary disease (COPD) is a rapidly rising global public health issue.^1–3 In China, 13.7% of those aged ⩾40 years were affected by COPD in 2018 ⁴ and COPD was responsible for over 0.9 million deaths in 2013, making it one of the leading causes of mortality in the country. ⁵ With increasing air pollution and smoking,^6–8 and an ageing population in China,^9,10 COPD burden and the associated mortality may increase further in the coming decades. Acute exacerbation is a major risk factor for increased mortality and COPD burden (e.g. decline in lung function and quality of life).

Management of exacerbations places an enormous economic burden on both patients and healthcare systems; unfortunately, COPD management in China is far from adequate. The 2013 national guideline for diagnosis and management of COPD in China is currently not referred to in clinical practice.^11–13 Furthermore, pharmacological and non-pharmacological management of COPD in China does not adhere to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) evidence-based strategy document for the management of patients with COPD.^12–16 Underdiagnosis of patients with COPD is also a major barrier to optimal care and improved patient outcomes ¹⁷ that can occur when patients do not recognize early COPD symptoms, and as a result, underreport them.^18,19 Understanding the disease characteristics (including symptoms, exacerbations, and disease severity), disease knowledge among patients, and current treatment patterns are important first steps in improving early detection and optimizing management, which in turn are crucial in modifying the clinical course of COPD and improving patient outcomes.

The COPD status in China has previously been assessed in cross-sectional, short-term or regional studies, in which key information such as exacerbation frequency, treatment patterns, symptoms and costs may be missed.^4,5,9,13,20 Moreover, study duration and sample size may not be appropriate to examine exacerbation rates and cover seasonality. Data on COPD status in China also vary substantially between regional studies,^4,5,9,13 demonstrating they are likely to be unrepresentative of the nationwide situation. The REALizing and improving the management of stable COPD in China (REAL) study was conducted to generate reliable information on COPD management, outcomes, treatment patterns and adherence, as well as disease knowledge among a large and nationally representative sample of COPD outpatients in China across different hospital tiers by assessing 1-year outcomes in a real-world setting.

Methods

Study design and population

Details on the study design and population have been published previously. ²¹ Briefly, REAL was a multicentre, prospective, observational study conducted at 50 secondary and tertiary hospitals across 6 geographic regions in China. A multistage stratified random sampling method was used to select a nationally representative sample of hospitals with respiratory departments.

Adult outpatients aged ⩾40 years with a clinical diagnosis of COPD [based on the presence of chronic cough, sputum, wheeze, and a history of exposure to harmful factors, and confirmed spirometry post-bronchodilator forced expiratory volume in 1 s (FEV₁)/forced vital capacity <0.7 as per GOLD 2016 criteria] were enrolled during routine visits. Patients who had participated in an interventional clinical trial in the 30 days prior to enrolment and those with an acute exacerbation within the previous 4 weeks were excluded. No additional restrictions for inclusion or exclusion were used to ensure the study population was representative of real-world clinical practice. During the study, patients underwent clinical assessments and received medical care as per routine clinical practice and at the discretion of the treating physician. The ethics committee of the leading site (China-Japan Friendship Hospital) approved the study protocol and informed consent form prior to study initiation (approval number 2016-97). The study was approved by ethics committees at individual study centres and was designed and conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practices, Good Pharmacoepidemiology Practices. All patients provided written informed consent prior to study initiation.

Data collection

All eligible patients were prospectively followed for 12 months, or until study discontinuation, whichever occurred first. The study comprised two on-site visits [baseline (V0) and at study end (V1)] and three telephone follow-ups (TC1–3), which were scheduled every 3 months. Data on demographics, baseline characteristics, disease status, treatment and clinical outcomes were collected at baseline and at follow-up visits, as part of the routine clinical practice, using a standard case report form. Patient-reported outcome questionnaires [COPD questionnaire (COPD-Q), COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnoea scale] were completed. Information on treatment exposure was also collected. If available, spirometry, chest computed tomography imaging, induced sputum and lab test data were collected.

Endpoints

Primary, secondary and exploratory endpoints have been previously described. ²¹ Briefly, data were collected on disease severity [assessed by GOLD 2016 and 2017 combined assessment criteria (Groups A/B/C/D), as defined in the GOLD 2017 evidence-based strategy document ²² ], rate of exacerbations, severe exacerbations requiring hospitalization or an emergency visit, COPD symptoms (assessed by CAT and mMRC), treatment patterns (drug class, maintenance and exacerbation therapy), medication adherence (assessed by actual drug taken days/actual prescribed days) and COPD disease knowledge among patients (assessed by COPD-Q). Mild exacerbations were those requiring an increase in rescue medication ⩾3 puffs/day for ⩾2 consecutive days; moderate exacerbations were those requiring systemic glucocorticosteroids and/or antibiotics; severe exacerbations were those requiring hospitalization or emergency room visit, or leading to death. The COPD-Q tool is a 13-point questionnaire that assesses patients’ knowledge of COPD risk factors, clinical manifestations, medication, oxygen therapy, prevention and prognosis.^23–25 It was specifically designed for individuals with low health literacy and fifth-grade reading level. Every correct answer was scored as 1 point and a higher score indicates a higher level of disease knowledge.

Statistical analysis

As this was an observational study, the data analysis was primarily descriptive. For continuous variables, mean, median, standard deviation (SD) and range were calculated. For categorical variables, frequency counts and percentages were provided. Descriptive statistics were used for the primary endpoints, and the annual exacerbation rate was estimated under the Poisson distribution assumption. Mean and standard error of the annual rates of exacerbation were calculated. A similar approach was used for the analyses of secondary endpoints. All statistical procedures were completed using Statistical Analysis System version 9.2 or later. No imputation of missing data was used; all statistical analyses were carried out on non-missing data only.

Results

Between 30 June 2017 and 29 January 2019, 5097 patients were screened, of whom 5013 were enrolled, and 4978 were included in the analysis (n = 2597 from tertiary and n = 2381 from secondary hospitals) (Figure E1). A total of 772 patients withdrew from the study (n = 565 were lost to follow-up, n = 117 withdrew consent, n = 58 died and n = 32 withdrew for other reasons); 308 (6.2%), 423 (8.5%), 505 (10.1%) and 739 (14.8%) patients dropped out of TC1, TC2, TC3 and V1 visits, respectively. Baseline patient demographics and clinical characteristics have been described previously. ²⁶ Briefly, mean age was 66.2 years, and the majority of patients were male (79.5%). Patients were almost equally sampled from urban and rural areas (55.0% versus 45.0%) (Table 1). A large proportion of patients had smoking history: 2556 (51.3%) former, 1142 (22.9%) current and 1409 (28.3%) passive smokers. Approximately 20% of patients were exposed to dust, while 11.3% and 8.1% were exposed to biofuels and harmful gases, respectively. Concurrent respiratory diseases were reported in 25.9% of patients, with the most frequent being asthma (8.8%), respiratory infections (8.5%) and bronchiectasis (3.0%). The most common nonrespiratory comorbidities were hypertension (20.7%), coronary artery disease (6.3%) and diabetes mellitus (5.1%).

Table 1.

Patient demographics and clinical characteristics at baseline.

Characteristics	Patients with COPD at baseline (N = 4978)
Male	3959 (79.5)
Age (years), mean (SD)	66.2 (8.9)
BMI (kg/m2), mean (SD)	22.97 (3.6)
Region of residence
North	1005 (20.2)
Northeast	623 (12.5)
East	1248 (25.1)
South central	904 (18.2)
Southwest	596 (12.0)
Northwest	602 (12.1)
Residence area (N = 4972)
Urban	2735 (55.0)
Rural	2237 (45.0)
Smoking status
Non-smoker	1280 (25.7)
Current smoker	1142 (22.9)
Former smoker	2556 (51.3)
Packs/year, a mean (SD)	42.1 (24.1)
Passive smoker (N = 4975)	1409 (28.3)
Exposure hours, b mean (SD)	20.8 (21.6)
Exposure to noxious particles or gases
No exposure	3397 (68.2)
Dust	996 (20.0)
Harmful gas	404 (8.1)
Biofuels	564 (11.3)
Other noxious substances	73 (1.5)
A family history of respiratory disease c	1715 (34.5)
History of ⩾1 exacerbation in previous 12 months	2459 (49.4)
Severe exacerbations d	1953 (39.2)
Concurrent respiratory diseases e	1287 (25.9)
Asthma	437 (8.8)
Respiratory infection	422 (8.5)
Bronchiectasis	151 (3.0)
Non-respiratory comorbidities e	1981 (39.8)
Hypertension	1028 (20.7)
Coronary artery disease	313 (6.3)
Diabetes mellitus	247 (5.1)
Benign prostatic hyperplasia	168 (3.4)
Chronic gastritis	111 (2.2)
Severity of airflow limitation (GOLD stages) (N = 4518)
Stage I	458 (10.1)
Stage II	1886 (41.7)
Stage III	1558 (34.5)
Stage IV	616 (13.6)
Combined assessment (GOLD 2017 groups) (N = 4976)
Group A	818 (16.4)
Group B	2083 (41.9)
Group C	363 (7.3)
Group D	1712 (34.4)

BMI, body mass index; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; SD, standard deviation.

Data are presented as n (%) unless stated otherwise.

All percentages were calculated based on patients with available data.

^aData were missing for 16 patients.

^bAverage weekly exposure = Average daily exposure hours × Average frequency of exposure (days/week); data were missing for two patients.

^cReported respiratory disease history of patient’s first-degree relatives.

^dRequiring hospitalization or emergency room visit.

^eDiseases with a prevalence >2%.

At baseline, 458 (10.1%), 1886 (41.7%), 1558 (34.5%) and 616 (13.6%) patients were classified as having GOLD stage I, II, III and IV, respectively. As per GOLD 2017 combined assessment criteria, Group B [n = 2083 (41.9%)] constituted the largest group, followed by Group D [n = 1712 (34.4%)]. Almost half of all patients experienced at least one exacerbation during the previous 12 months [n = 2459 (49.4%)] (Table 1).

Acute exacerbations

Overall, the annual rate (per patient) of COPD exacerbations was 0.56 [95% confidence interval (CI): 0.54–0.58]. The annual rates of moderate (requiring systemic corticosteroids and/or antibiotics) and severe exacerbations were 0.17 (95% CI: 0.16–0.18) and 0.31 (95% CI: 0.29–0.33), respectively (Table 2 and Figure 1).

Table 2.

COPD exacerbations at 1-year follow-up by baseline airway limitation severity and baseline GOLD 2017 combined assessment.

	Total (N = 4978)	Severity of airflow limitation (GOLD stages)
		Stage I (N = 458)	Stage II (N = 1886)	Stage III (N = 1558)	Stage IV (N = 616)
Patients with ⩾1 exacerbation, n (%) a	1535 (30.8)	94 (20.5)	514 (27.3)	524 (33.6)	279 (45.3)
Moderate	505 (32.9)	35 (37.2)	212 (41.3)	166 (31.7)	76 (27.2)
Severe	960 (62.5)	45 (47.9)	282 (54.9)	350 (66.8)	210 (75.3)
Annual exacerbation rate (95% CI)	0.56 (0.54–0.58)	0.33 (0.28–0.39)	0.47 (0.44–0.51)	0.64 (0.60–0.68)	0.90 (0.83–0.98)
Moderate	0.17 (0.16–0.18)	0.12 (0.09–0.16)	0.18 (0.17–0.20)	0.18 (0.16–0.20)	0.25 (0.22–0.30)
Severe	0.31 (0.29–0.33)	0.15 (0.12–0.19)	0.22 (0.20–0.24)	0.38 (0.35–0.41)	0.58 (0.53–0.65)
		Combined assessment (GOLD 2017 groups)
		Group A (N = 818)	Group B (N = 2083)	Group C (N = 363)	Group D (N = 1712)
Patients with ⩾1 exacerbation, n (%) a		137 (16.7)	484 (23.2)	119 (32.8)	794 (46.4)
Moderate		63 (46.0)	179 (37.0)	45 (37.8)	218 (27.5)
Severe		49 (35.8)	267 (55.2)	74 (62.2)	569 (71.7)
Annual exacerbation rate (95% CI)		0.26 (0.22–0.29)	0.36 (0.34–0.39)	0.62 (0.54–0.71)	0.93 (0.88–0.98)
Moderate		0.12 (0.10–0.14)	0.13 (0.12–0.15)	0.24 (0.20–0.30)	0.24 (0.21–0.26)
Severe		0.08 (0.06–0.10)	0.17 (0.15–0.18)	0.32 (0.27–0.38)	0.59 (0.55–0.63)

CI, confidence interval; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Rate and CI were estimated under the Poisson distribution assumption. Moderate = requiring systemic glucocorticosteroids, and/or antibiotics; Severe = hospitalization, emergency room visit or leading to death. All percentages were calculated based on patients with available data.

^aAll percentages for patients with ⩾1 exacerbation were calculated using overall number of patients with ⩾1 exacerbation as the denominator. Patients who had both moderate and severe exacerbations were counted in both the ‘moderate’ and ‘severe’ categories.

Figure 1.

Acute exacerbations during 1-year follow-up. (a) Annual exacerbation rate by airway limitation severity (GOLD stages) and combined assessment (GOLD 2017 groups). (b) Proportion of patients experiencing at least one COPD exacerbations during 1-year follow-up by airway limitation severity (GOLD stages) and combined assessment (GOLD 2017 groups). Rates and confidence intervals are estimated under the Poisson distribution assumption. Mild = requiring an increase in rescue medication ⩾3 puffs/day for at least 2 consecutive days; Moderate = requiring systemic glucocorticosteroids, and/or antibiotics; Severe = hospitalization, emergency room visit, or leading to death.

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

The annual rates of exacerbation increased progressively for GOLD stages I–IV: 0.33 (95% CI: 0.28–0.39), 0.47 (95% CI: 0.44–0.51), 0.64 (95% CI: 0.60–0.68) and 0.90 (95% CI: 0.83–0.98), respectively. Similarly, in GOLD 2017 Groups A/B/C/D, annual exacerbation rates were 0.26 (95% CI: 0.22–0.29), 0.36 (95% CI: 0.34–0.39), 0.62 (95% CI: 0.54–0.71) and 0.93 (95% CI: 0.88–0.98), respectively (Table 2).

During the 12-month follow-up, 1535 (30.8%) patients experienced at least one exacerbation [moderate, n = 505 (10.1%); severe, n = 960 (19.3%)]. Among those, 47.9% (45/94), 54.9% (282/514), 66.8% (350/524) and 75.3% (210/279) of patients across GOLD stages I–IV, respectively, had a severe exacerbation. Similarly, the proportion of patients experiencing a severe exacerbation increased progressively across GOLD 2017 Groups A/B/C/D: 35.8% (49/137), 55.2% (267/484), 62.2% (74/119) and 71.7% (569/794), respectively (Table 2).

Change in FEV₁ and FEV₁% predicted

Mean (SD) change from baseline in FEV₁, FEV₁% predicted, FVC and FEV₁/FVC ratio were +0.027 L (0.325), +2.211 (13.467), +0.092 L (0.513) and +0.088 (9.042), respectively (Table 3). The mean (SD) change in FEV₁ across GOLD stages I–IV was –0.120 L (0.363), –0.004 L (0.359), +0.079 L (0.314) and +0.141 L (0.249), respectively; the mean (SD) change in FEV₁% predicted across GOLD stages I–IV was –3.884 (14.496), +0.045 (13.911), +4.625 (13.184) and +5.761 (9.630), respectively (Table E1).

Table 3.

COPD disease characteristics at baseline and 1-year follow-up.

Clinical characteristics	Patients with COPD (N = 4978)
	At baseline	At 1-year follow-up
COPD signs and symptoms a	4975 (99.9)	4198 (84.3)
Dyspnoea	2864 (57.6)	1753 (41.8)
Wheezing	3296 (66.3)	2311 (55.1)
Chest tightness	3324 (66.8)	2024 (48.2)
Cough	4037 (81.1)	2809 (66.9)
Mucus purulence	4011 (80.6)	2761 (65.8)
CAT score	4976 (100)	4184 (84.0)
CAT total score, mean (SD)	14.6 (7.6)	10.6 (6.8)
Change from baseline, mean (SD)	–	−4.0 (7.2)
mMRC score	4976 (100)	4178 (83.9)
mMRC score, mean (SD)	1.4 (0.99)	1.1 (0.9)
Change from baseline, mean (SD)	–	−0.3 (1.0)
COPD-Q score	4973 (99.9)	4142 (83.2)
COPD-Q total score, mean (SD)	5.9 (2.0)	6.7 (2.4)
Change from baseline, mean (SD)	–	+0.7 (2.5)
Secondary hospitals	2378/2381 (99.9)	2115/2381 (88.8)
Secondary hospitals, mean (SD)	6.1 (1.9)	6.7 (2.6)
Change from baseline, mean (SD)	–	+0.6 (2.9)
Tertiary hospitals	2595/2597 (99.9)	2027/2597 (78.1)
Tertiary hospitals, mean (SD)	5.8 (2.1)	6.6 (2.1)
Change from baseline, mean (SD)	–	+0.8 (2.0)
Blood eosinophil count, n (%)	564	38
<100 cells/μL	186 (33.0)	10 (26.3)
⩾100 and < 150 cells/μL	131 (23.2)	11 (28.9)
⩾150 and < 300 cells/μL	138 (24.5)	12 (31.6)
⩾300 cells/μL	109 (19.3)	5 (13.2)
FEV1, L	4901 (98.5)	807 (16.2)
FEV1, mean (SD)	1.360 (0.586)	1.359 (0.600)
Change from baseline in FEV1, L b	–	792 (15.9)
Change from baseline, mean (SD)	–	+0.027 (0.325)
FEV1%pred	4539 (91.2)	761 (15.3)
FEV1% predicted, mean (SD)	52.511 (20.080)	53.319 (20.954)
Change from baseline in FEV1% predicted b	–	655 (13.2)
Change from baseline, mean (SD)	–	+2.211 (13.467)
FVC, L	4215 (84.7)	753 (15.1)
FVC, mean (SD)	2.405 (0.839)	2.434 (0.881)
Change from baseline in FVC, L b	–	672 (13.5)
Change from baseline, mean (SD)	–	+0.092 (0.513)
FEV1/FVC ratio, %	4210 (84.6)	753 (15.1)
FVC, mean (SD)	51.397 (11.259)	51.655 (12.615)
Change from baseline in FEV1/FVC ratio, % b	–	671 (13.5)
Change from baseline, mean (SD)	–	+0.088 (9.042)

CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; COPD-Q, COPD knowledge questionnaire; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; mMRC, modified Medical Research Council; SD, standard deviation.

Data are presented as n (%) unless stated otherwise. All percentages were calculated based on patients with available data.

^aAll percentages for individual signs and symptoms were calculated using overall number of patients with signs and symptoms as the denominator.

^bChange from baseline in FEV₁, FEV₁% predicted, FVC, and FEV₁/FVC ratio were calculated based on patients with available FEV₁, FEV₁% predicted, FVC, and FEV₁/FVC ratio measurements, respectively, at baseline and 1-year follow-up.

COPD symptoms

The mean (SD) CAT score was 14.6 (7.6) at baseline, and 10.6 (6.8) at 1 year, with a mean (SD) change from baseline of −4.0 (7.2). Mean (SD) mMRC score was 1.4 (0.99) and 1.1 (0.9) at baseline and 1 year, respectively, with a mean (SD) change from baseline of −0.3 (1.0) (Table 3).

At 1 year, 41.8%, 48.2% and 55.1% of patients had persistent dyspnoea, chest tightness and wheezing, respectively (Table 3). The proportion of patients with COPD symptoms progressively increased across GOLD stages I–IV (Table E2).

Treatment pattern and adherence

Inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) combinations [ICS/LABA, n = 848 (36.0%)], ICS/LABA plus long-acting muscarinic antagonist [LAMA; ICS/LABA + LAMA, n = 417 (17.7%)] and LAMA alone [n = 361 (15.3%)] were the most prescribed mono- or combination maintenance therapies (Table 4 and Figure 2). The prescription rates of ICS-containing therapies (ICS/LABA or ICS/LABA + LAMA) differed between GOLD stages I–IV; ICS/LABA therapy was prescribed more frequently in patients with mild disease (stages I–IV: 46.3%, 36.3%, 32.9%, 30.5%, respectively), while ICS/LABA + LAMA therapy was prescribed more frequently in patients with severe disease (11.0%, 13.3%, 20.7%, 27.2%, respectively). However, the prescription of ICS/LABA and ICS/LABA + LAMA was consistent across GOLD 2017 Groups A–D (ICS/LABA: 35.4%, 35.3%, 38.6%, 36.4%, respectively; ICS/LABA + LAMA: 18.0%, 16.8%, 14.3%, 19.0%, respectively) (Table 4 and Table E3).

Table 4.

Distribution of prescribed COPD maintenance therapies at 1-year follow-up by baseline airway limitation severity.

	Severity of airflow limitation (GOLD stages)
	Stage I (N = 458)	Stage II (N = 1886)	Stage III (N = 1558)	Stage IV (N = 616)	Total (N = 4978)
Mono or combination therapy a	n = 164	n = 827	n = 781	n = 367	n = 2358
ICS	0	2 (0.2)	1 (0.1)	2 (0.5)	5 (0.2)
ICS/LABA	76 (46.3)	300 (36.3)	257 (32.9)	112 (30.5)	848 (36.0)
ICS/LABA + SABA	3 (1.8)	7 (0.8)	10 (1.3)	3 (0.8)	25 (1.1)
ICS/LABA + methylxanthines	5 (3.0)	26 (3.1)	23 (2.9)	10 (2.7)	65 (2.8)
ICS/LABA + TCM	3 (1.8)	7 (0.8)	3 (0.4)	2 (0.5)	16 (0.7)
ICS/LABA + LAMA	18 (11.0)	110 (13.3)	162 (20.7)	100 (27.2)	417 (17.7)
ICS/LABA + LAMA + SABA	0	5 (0.6)	5 (0.6)	5 (1.4)	18 (0.8)
ICS/LABA + LAMA + methylxanthines	1 (0.6)	8 (1.0)	18 (2.3)	7 (1.9)	35 (1.5)
ICS/LABA + LAMA + TCM	1 (0.6)	8 (1.0)	10 (1.3)	6 (1.6)	27 (1.1)
LAMA	28 (17.1)	166 (20.1)	109 (14.0)	25 (6.8)	361 (15.3)
LAMA + SABA	0	0	3 (0.4)	2 (0.5)	5 (0.2)
LAMA + methylxanthines	1 (0.6)	12 (1.5)	11 (1.4)	6 (1.6)	31 (1.3)
LAMA + TCM	2 (1.2)	19 (2.3)	5 (0.6)	2 (0.5)	31 (1.3)
LAMA + LABA	2 (1.2)	10 (1.2)	9 (1.2)	6 (1.6)	27 (1.1)
LAMA + LABA + SABA	0	1 (0.1)	0	0	1 (0.0)
LAMA + LABA + methylxanthines	0	1 (0.1)	0	0	1 (0.0)
LAMA + LABA + TCM	0	8 (1.0)	5 (0.6)	4 (1.1)	17 (0.7)
LABA	1 (0.6)	10 (1.2)	6 (0.8)	4 (1.1)	21 (0.9)
SABA	3 (1.8)	13 (1.6)	17 (2.2)	10 (2.7)	49 (2.1)
SAMA	0	2 (0.2)	1 (0.1)	0	3 (0.1)
SABA/SAMA	0	0	1 (0.1)	2 (0.5)	3 (0.1)
Methylxanthines	4 (2.4)	12 (1.5)	14 (1.8)	6 (1.6)	41 (1.7)
Methylxanthines + SABA	0	2 (0.2)	5 (0.6)	1 (0.3)	13 (0.6)
Methylxanthines + TCM	0	9 (1.1)	9 (1.2)	3 (0.8)	27 (1.1)
TCM	2 (1.2)	17 (2.1)	19 (2.4)	9 (2.5)	53 (2.2)
None of the medications described above	9 (5.5)	23 (2.8)	14 (1.8)	7 (1.9)	58 (2.5)
Medications used in any form a	n = 164	n = 827	n = 781	n = 367	n = 2358
ICS	2 (1.2)	5 (0.6)	6 (0.8)	4 (1.1)	19 (0.8)
ICS/LABA	112 (68.3)	501 (60.6)	520 (66.6)	259 (70.6)	1534 (65.1)
	Severity of airflow limitation (GOLD stages)
	Stage I (N = 458)	Stage II (N = 1886)	Stage III (N = 1558)	Stage IV (N = 616)	Total (N = 4978)
LABA	4 (2.4)	52 (6.3)	50 (6.4)	25 (6.8)	133 (5.6)
LAMA	54 (32.9)	365 (44.1)	354 (45.3)	174 (47.4)	1019 (43.2)
SABA	8 (4.9)	40 (4.8)	61 (7.8)	37 (10.1)	169 (7.2)
SAMA	1 (0.6)	9 (1.1)	12 (1.5)	8 (2.2)	32 (1.4)
SABA/SAMA	0	3 (0.4)	3 (0.4)	5 (1.4)	11 (0.5)
Methylxanthines	14 (8.5)	94 (11.4)	116 (14.9)	56 (15.3)	303 (12.8)
Mucolytics	22 (13.4)	155 (18.7)	142 (18.2)	67 (18.3)	403 (17.1)
TCM	10 (6.1)	89 (10.8)	79 (10.1)	34 (9.3)	234 (9.9)
Others	25 (15.2)	156 (18.9)	174 (22.3)	86 (23.4)	456 (19.3)
Neither ICS nor long-acting bronchodilator b	18 (11.0)	84 (10.2)	91 (11.7)	43 (11.7)	273 (11.6)

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist; TCM, traditional Chinese medicine.

Data are presented as n (%) unless stated otherwise.

^aMedications classified by drug class.

^bThis class denotes prescriptions without ICS, LABA, ICS/LABA, or LAMA.

Figure 2.

Distribution of maintenance medications for COPD at 1-year follow-up. (a) Distribution of prescribed mono- and combination maintenance therapies for COPD. Mono- or combination therapies with bronchodilators and/or ICS (prescribed for ⩾1% of patients) are shown, with no prohibition of use with mucolytics and other classes of medication. (b) Distribution of medications prescribed in any form for COPD. Percentages of patients prescribed each class of medication are indicated.

COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist; TCM, traditional Chinese medicine.

Despite having more symptoms and being at increased risk of exacerbations, 111 (12.1%) patients in GOLD 2017 Group B, 19 (10.1%) in Group C and 123 (13.1%) in Group D were not prescribed ICS or long-acting bronchodilators (Table E3). In addition, the prescription rates for ICS-containing therapy among patients experiencing exacerbations did not differ during the 1-year follow-up (Table 5). Among patients in GOLD Groups C and D who experienced at least one exacerbation during the 1-year follow-up, 53.8% (64/119) and 63.6% (505/794), respectively, were prescribed ICS-containing therapy. This included 18 (15.1%) and 182 (22.9%) patients, respectively, receiving triple therapy (ICS/LABA + LAMA).

Table 5.

ICS prescriptions in patients with COPD exacerbations by baseline GOLD 2017 combined assessment at 1-year follow-up.

	Combined assessment (GOLD 2017 groups)
	Group A (N = 818)	Group B (N = 2083)	Group C (N = 363)	Group D (N = 1712)	Total (N = 4978)
Patients with ⩾1 exacerbation in the 12 months before baseline	100 (12.2)	283 (13.6)	363 (100)	1712 (100)	2459 (49.4)
ICS or ICS/ LABA prescribed at baseline	61 (61.0)	158 (55.8)	221 (60.9)	1080 (63.1)	1521 (61.9)
ICS/LABA + LAMA prescribed at baseline	26 (26.0)	62 (21.9)	69 (19.0)	385 (22.5)	543 (22.1)
Patients with ⩾1 exacerbation during the 1-year study follow-up (from baseline to study end)	137 (16.7)	484 (23.2)	119 (32.8)	794 (46.4)	1535 (30.8)
ICS or ICS/LABA prescribed during 1-year study follow-up	85 (62.0)	299 (61.8)	64 (53.8)	505 (63.6)	954 (62.1)
ICS/LABA + LAMA prescribed during 1-year study follow-up	34 (24.8)	118 (24.4)	18 (15.1)	182 (22.9)	353 (23.0)

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist.

Data are presented as n (%) unless stated otherwise. All percentages were calculated based on patients with available data.

Mean (SD) adherence for long-acting inhalers was 59.0% (34.3). COPD medication adherence was similar across GOLD stages and GOLD 2017 groups (Table E4). Mean COPD medication adherence ranged from 53.5% to 64.7% for GOLD stages I–IV, and from 57.7% to 60.7% for GOLD 2017 Groups A–D.

Patient COPD knowledge

Overall, mean COPD-Q scores were 5.9 at baseline and 6.7 at 1-year follow-up. The latter ranged from 5.2 to 7.4 across geographical regions and did not differ between tertiary and secondary hospitals, indicating patients’ poor understanding of COPD. Overall, the mean (SD) change from baseline in COPD-Q score at 1-year follow-up was +0.7 (2.5), and the corresponding change for tertiary and secondary hospitals was +0.8 (2.0) and +0.6 (2.9), respectively (Table 3).

Discussion

REAL is the first nationwide study designed to collect prospective longitudinal real-world data on the management and clinical outcomes of a large cohort of Chinese outpatients with COPD managed at secondary and tertiary hospitals. Overall, findings from the study revealed a high burden of severe exacerbations, airflow limitation, and symptoms in this population. This high disease burden may be explained by the lack of adherence to guideline-recommended treatment among healthcare providers, as well as poor medication adherence and disease awareness among patients, highlighting the need for more effective management.

Our study enrolled a nationally representative population of adults aged ⩾40 years with COPD. The majority of patients in our study were male, which is consistent with previous studies. Nationwide cross-sectional studies in China have demonstrated a higher prevalence of COPD among males,^20,27 while the prevalence is more similar between the sexes in Europe and the United States. ²⁸ These data further demonstrate that the population in the REAL study is nationally representative. Compared with previous studies,^15,29 our study also comprised a larger patient population and included patients from a broader range of geographic regions.

Most COPD outpatients had moderate-to-very-severe airflow limitation, with GOLD stages II–IV accounting for 90% of the study population. More than one-third of patients were classified as GOLD Group D, with persistent symptoms and a high risk of exacerbations. This could be explained by the enrolment of patients from secondary and tertiary hospitals, where patients with mild disease are not routinely managed. This could also be due to patients at early stages of the disease with mild symptoms not seeking medical attention for COPD symptoms or not being diagnosed by physicians. ³⁰

One of the key goals of the study was to collect data on the annual exacerbation rate. Overall, about 30% of patients experienced at least one exacerbation during the 1-year follow-up, which was lower than that reported in the year prior to study enrolment (49.4%). The annual exacerbation rates in our study are lower than those reported previously (37–71%),^31–33 which may be explained by underreporting of exacerbations, particularly those of moderate severity [the reported frequency of moderate exacerbations (10.1%) was lower than that of severe exacerbations (19.3%)]. Exacerbations tend to be underreported when there are fewer symptoms or episodes of symptom worsening.^18,19 Previous studies have shown that a large number (50–68%) of COPD exacerbations are not reported and are, therefore, left untreated, which increases the risk of disease progression^18,19 and mortality. ³⁴ In our study, a high proportion of patients experienced severe exacerbations (which included those that resulted in death) regardless of COPD severity. Patients not recognizing their symptoms early, thereby underreporting them, may also result in underdiagnosis of COPD. It has been demonstrated across 27 countries that the lack of reported respiratory symptoms and less severe airflow limitation were positively associated with underdiagnosis. ³⁵ Our findings highlight the need to increase understanding of risk factors for exacerbation to facilitate earlier detection, reduce treatment delays and prevent exacerbations from becoming severe. The ECLIPSE study has shown that patients with severe COPD have a history of frequent exacerbations and that past exacerbation may predict the occurrence of future exacerbations. ³⁶ To facilitate increased knowledge of exacerbations among physicians, further analysis of risk factors for COPD exacerbation in the REAL study is underway and will be subsequently published.

Underreporting of COPD exacerbations may have been more marked during the COVID-19 pandemic, which led to fewer hospital visits. Conversely, COVID-19 control measures, such as use of masks and implementation of lockdowns, may have had a positive effect on COPD outcomes due to reduced upper respiratory tract infections. Accordingly, a national level analysis from the United Kingdom showed a 48% reduction in emergency admissions for COPD exacerbations during the UK-wide COVID-19 lockdown. ³⁷ Moreover, reporting of moderate exacerbations in our study could have been influenced by variations in the standard indications for COPD hospitalization across China, with less strict administration and control.

A large proportion of patients had persistent COPD symptoms, including dyspnoea, wheezing, chest tightness and cough, throughout the study follow-up, which may indicate disease progression, as many of these symptoms were more common in severe/very severe cases than in mild/moderate cases. These symptoms were previously associated with exacerbation occurrence in the ECLIPSE study. ³⁶ Understanding the symptoms associated with COPD may help improve physician’s disease awareness and facilitate early intervention before substantial disease progression. Further analysis of symptoms associated with exacerbation severity in the REAL study will be subsequently published.

The substantial burden of severe exacerbations, airflow limitation and persistent symptoms in this study suggest suboptimal management of COPD in China. Accordingly, we found substantial discrepancies between the real-world treatment patterns and the treatment guidelines for clinical practice, ¹⁴ supporting previous findings^15,29 but providing evidence that these discrepancies are likely nationwide. The most prescribed maintenance therapies in the REAL study were ICS/LABA, ICS/LABA + LAMA, and LAMA (15.3–36.0%), but 11.6% of patients were not prescribed ICS or long-acting bronchodilators, the mainstay long-term inhaled medications for symptom alleviation and exacerbation risk reduction. In addition, ICS appeared to be overprescribed in patients with GOLD 2017 Group A disease (ICS/LABA: 35.4%; ICS/LABA + LAMA: 18.0%) and GOLD stage I disease (ICS/LABA: 46.3%; ICS/LABA + LAMA: 11.0%). The treatment guidelines recommend bronchodilator therapy alongside vaccination, smoking cessation and rehabilitation for patients with mild disease as the risks associated with ICS treatment may outweigh the benefits in this patient population.^14,38 Notably, prescription rates for ICS-containing therapies were similar across GOLD groups but differed based on airflow limitation, suggesting that the main goal of COPD maintenance therapy in China is to relieve symptoms and that attention to history of acute exacerbation is lacking. Indeed, COPD maintenance therapy is mostly prescribed based on pulmonary function rather than exacerbation risk in China, given that exacerbation risk evaluation is more complex. ¹³ These data, however, highlight the need for physicians to prescribe treatment based on exacerbation risk to prevent disease progression and improve patient outcomes.

Our findings reinforce those in previous studies and further emphasize the need for COPD management and treatment standardization nationwide in accordance with existing guidelines. In addition, our findings support the importance of increasing physicians’ disease and symptom awareness to enable early intervention and improve treatment based on exacerbation risk. Among patients, treatment adherence is key, and this may be influenced by patients’ understanding of their disease; ³⁹ we and others have demonstrated that patients with COPD are poorly informed about their disease and its treatment. ¹³ It is critical to put in place strategies to improve patients’ awareness and knowledge of COPD. To fully address the challenges of COPD management in China, substantial attention should be on improving both physicians’ and patients’ disease knowledge.

The study results should be viewed in the context of the following limitations. First, patients with early-stage COPD and those with mild symptoms were underrepresented as the study only included patients who were diagnosed with COPD and visited the outpatient respiratory department of secondary and tertiary hospitals. It is important for these patients to be characterized to help improve early detection and intervention of the disease. Second, the COVID-19 pandemic may have discouraged patients with COPD from visiting the hospitals, which may have resulted in underreporting of outcomes. Third, the fixed-dose combinations of LABA/LAMA dual therapy and ICS/LABA/LAMA triple therapy were not available in China during the study period. In addition, the implementation of the national hierarchical medical system allowed some patients to obtain their prescription medications from a community hospital, and the prescription rates in the community hospitals were not captured in the reporting of treatment patterns in this study. These factors may impact the extent to which our findings represent current treatment patterns among COPD patients in China. Nonetheless, our findings reinforce the discrepancies identified in previous studies between real-world clinical practice and current treatment guidelines, and further demonstrate that standardization efforts should be rolled out nationwide. Finally, data were confined to examinations and tests performed in routine clinical practice; thus, not all assessment data were available.

Conclusion

In conclusion, findings from this large real-world study revealed that most Chinese outpatients with COPD have moderate-to-very-severe airflow limitation, with a high burden of acute exacerbations and symptoms. Overall, we reinforce the findings of previous studies but reveal that substantial inconsistencies between clinical practice and international COPD guidelines are present across China. This is coupled with poor disease knowledge, suboptimal medication adherence and low uptake of regular examinations among patients. Evidence-based prescription of ICS-containing treatment in patients at high risk of exacerbation, as well as treatment adherence, needs to be improved. There is an urgent need for standardization of outpatient management of COPD in China and improvement of both physicians’ and patients’ disease knowledge. Based on the study findings, any approach in addressing the challenges of COPD management in China should be nationwide.