1158283

research-article20232023
TAR0010.1177/17534666231158283Therapeutic Advances in Respiratory DiseaseT Yang, B Cai

Therapeutic Advances in
Respiratory Disease Original Research

Treatment patterns in patients with stable

Ther Adv Respir Dis

2023, Vol. 17: 1–17

COPD in China: analysis of a prospective, DOI: 10.1177/

https://doi.org/10.1177/17534666231158283
https://doi.org/10.1177/17534666231158283
17534666231158283

52-week, nationwide, observational cohort

© The Author(s), 2023.

Article reuse guidelines:

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study (REAL) permissions

Correspondence to:
Chen Wang
Ting Yang, Baiqiang Cai, Bin Cao, Jian Kang, Fuqiang Wen, Yahong Chen, Wenhua Jian Department of Pulmonary
and Chen Wang and Critical Care Medicine,
National Clinical Research
Centre for Respiratory
Diseases, China–Japan
Abstract Friendship Hospital, No.
Background: Underdiagnosis and undertreatment pose major barriers to optimal 2, East Yinghua Road,
Chaoyang District, Beijing
management of chronic obstructive pulmonary disease (COPD) in China. 100029, China.

Objective: The REAL trial was performed to generate reliable information on real-world COPD Institute of Respiratory
Medicine, Chinese
management, outcomes and risk factors among Chinese patients. Here, we present study Academy of Medical
Science, Beijing, China
outcomes related to COPD management. wangchen66366@163.com
Design: It is a 52-week, prospective, observational, multicentre study. Ting Yang
Bin Cao
Methods: Outpatients (aged ⩾40 years) enrolled from 50 secondary and tertiary hospitals Department of Pulmonary
across six geographic regions of China were followed up for 12 months, with two onsite visits and Critical Care Medicine,
National Clinical Research
and by telephone every 3 months following baseline. Centre for Respiratory
Results: Between June 2017 and January 2019, 5013 patients were enrolled and 4978 included Diseases, China–Japan
Friendship Hospital,
in the analysis. Mean [standard deviation (SD)] age was 66.2 (8.9) years, the majority of Beijing, China.

patients were male (79.5%) and mean (SD) time since COPD diagnosis was 3.8 (6.2) years. The Institute of Respiratory
Medicine, Chinese
most common treatments at each study visit were inhaled corticosteroids/long-acting beta- Academy of Medical
Science, Beijing, China
agonists (ICSs/LABAs; 28.3–36.0%), long-acting muscarinic antagonists (LAMAs; 13.0–16.2%)
Baiqiang Cai
and ICS/LABA + LAMA (17.5–18.7%), but up to 15.8% of patients at each visit received neither Department of Respiratory
ICS nor long-acting bronchodilators. The use of ICS/LABA, LAMA and ICS/LABA + LAMA and Critical Care Medicine,
Peking Union Medical
differed across regions and hospital tiers; up to fivefold, more patients received neither ICS College Hospital, Beijing,
China
nor long-acting bronchodilators in secondary (17.3–25.4%) versus tertiary hospitals (5.0–
Jian Kang
5.3%). Overall, rates of nonpharmacological management were low. Direct treatment costs Department of Respiratory
and Critical Care Medicine,
increased with disease severity, but the proportion of direct treatment costs incurred due to The First Hospital of
maintenance treatment decreased with disease severity. China Medical University,
Shenyang, China
Conclusion: ICS/LABA, LAMA and ICS/LABA + LAMA were the most frequently prescribed Fuqiang Wen
maintenance treatments for patients with stable COPD in China, although their use differed Department of Respiratory
and Critical Care Medicine,
between region and hospital tier. There is a clear need for improved COPD management West China Hospital,
across China, particularly in secondary hospitals. Sichuan University,
Chengdu, China
Registration: The trial was registered on 20 March 2017 (ClinicalTrials.gov identifier: Yahong Chen
NCT03131362; https://clinicaltrials.gov/ct2/show/NCT03131362). Department of Respiratory
and Critical Care Medicine,
Peking University Third
Hospital, Beijing, China
Plain language summary Wenhua Jian
Treatment patterns in patients with COPD in China State Key Laboratory
of Respiratory Disease,
Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory National Clinical
Research Centre for
lung disease characterized by progressive and irreversible airflow limitation. In China, Respiratory Disease,
Guangzhou Institute of
many patients with this disease do not receive a diagnosis or appropriate treatment. Respiratory Disease, The
Objective: This study aimed to generate reliable information on the treatment patterns First Affiliated Hospital
of Guangzhou Medical
among patients with COPD in China to help inform future management strategies. University, Guangzhou,
China

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Therapeutic Advances in
Respiratory Disease Volume 17

Study design and methods: Patients (aged ⩾40 years) were enrolled from 50 hospitals
across 6 regions of China and physicians collected data over the course of 1 year during
routine outpatient visits.
Results: The majority of patients were receiving long-acting inhaled treatments, which
are recommended to prevent worsening of the disease. Up to 16% of patients in this study,
however, did not receive any of these recommended treatments. The proportion of patients
who received long-acting inhaled treatments differed across regions and hospital tiers;
there were about five times more patients in secondary hospitals (about 25%) who did not
receive these treatments compared with those in tertiary hospitals (about 5%). Guidelines
recommend that pharmacological treatment should be complemented by nondrug
treatment, but this was only received by a minority of patients in this study. Patients with
higher disease severity incurred greater direct treatment costs compared with those with
milder disease. Maintenance treatment costs made up a smaller proportion of overall
direct costs for patients with higher disease severity (60–76%) compared with patients
with milder disease (81–94%).
Conclusion: Long-acting inhaled treatments were the most frequently prescribed
maintenance treatments among patients with COPD in China, but their use differed
between region and hospital tier. There is a clear need to improve disease management
across China, especially in secondary hospitals.

Keywords: China, COPD, geographic region, hospital tier, inhaled corticosteroids, long-acting
bronchodilator, maintenance therapy, observational study, treatment patterns

Received: 23 August 2022; revised manuscript accepted: 2 February 2023.

Introduction Appropriate management of COPD is vital for

Chronic obstructive pulmonary disorder (COPD)
is characterized by persistent respiratory symp-
toms and airflow limitation.1 Despite being a pre-
ventable and treatable disease,1 COPD is
predicted to fourth leading cause of death glob-
ally by 2040.2 In 2013, the mortality rate associ-
ated with COPD was higher in China compared
with other countries [age-standardized mortality
rate per 100,000 people (95% uncertainty inter-
val) = 79.44 (71.48–88.79) in China3 versus 50.7
(45.4–55.6) globally].4 In 2018, the estimated
prevalence of COPD in China in those aged
>40 years was reported to be 13.6–13.7%,5,6
which was higher than the estimations reported
10 years prior (8.2%).7
The Chinese Thoracic Society recommends that
physicians follow the Global Initiative for Chronic
Obstructive Lung Disease (GOLD) evidence-
based strategy document guidelines to manage
patients with COPD (definitions of severity are
consistent between the 2017 document and
updated 2021 version).1,8 As per the GOLD strat-
egy document,1 both pharmacological and non-
pharmacological treatments are key elements in
the long-term management of stable COPD.
patients, as more severe disease is associated with
a greater risk of mortality.9 We and others, how-
ever, have shown that real-world treatment pat-
terns may differ from treatment guidelines.10–13
China comprises multiple geographic regions with
a three-tier healthcare system (in general, primary
hospitals provide general care in the community,
secondary hospitals provide comprehensive care
for regions, including referrals from primary care,
while tertiary hospitals also provide specialist ser-
vices, serve wider/multiple regions and are more
often located in urban areas); therefore, under-
standing the current status of COPD management
across these different geographic regions and hos-
pital tiers is fundamental in developing strategies
to improve the long-term management of patients
with COPD. At the time of study initiation, there
was a substantial lack of large-scale, real-world
studies on the clinical management of patients
with stable COPD in China. The REALizing and
improving management of stable COPD in China
(REAL) trial (NCT03131362) was a 52-week,
prospective, observational, multicentre study
designed to obtain reliable information on COPD
management, outcomes and risk factors among a

2 journals.sagepub.com/home/tar

representative sample of patients with COPD in
China across different hospital tiers.14 Baseline15
and primary outcomes16 have been previously
reported. Here, we report secondary and explora-
tory outcomes from the REAL trial.
Methods
Study design and population
Details of the study design and population have
been previously published.14 Briefly, the REAL
study (NCT03131362) was conducted at 50 ter-
tiary and secondary hospitals across six geo-
graphic regions in China. Hospitals were selected
using a multistage, cluster sampling approach,
and patients were consecutively enrolled during
routine clinical visits between 30 June 2017 and
29 January 2019. Key inclusion criteria were (1)
outpatients, (2) aged ⩾40 years, (3) clinically
diagnosed with COPD [based on presence of
chronic cough, sputum, wheeze and a history of
exposure to harmful factors, and confirmed
spirometry postbronchodilator forced expiratory
volume in 1 s (FEV1)/forced vital capacity <0.7 as
per the 2016 GOLD strategy document]17 and
(4) provision of informed consent. Patients were
required to have stable COPD; those with an
acute exacerbation within 4 weeks prior to enrol-
ment were excluded.
Data collection
Patients were followed for 12 months, with two
onsite visits (V0: at baseline; V1: at 1 year) and a
telephone contact (TC) follow-up every 3 months
following V0 (TC1–3). Baseline data were col-
lected using case report forms (CRFs) at V0;
symptoms, drug treatment, nondrug treatment,
exacerbations, comorbidities, complications and
direct costs were collected via CRFs at V0, V1
and TC1–3. Spirometry was performed as per
usual clinical practice and was collected if availa-
ble during study visits. Disease severity was
assessed by measurement of airflow limitation
(postbronchodilator FEV1) and assessment of
symptoms/risk of exacerbations (GOLD 2016
and GOLD 2017 A/B/C/D classification).
Outcomes
The primary objective was to observe the 1-year
clinical outcomes of patients with COPD under
routine clinical treatment. Secondary and
journals.sagepub.com/home/tar
T Yang, B Cai et al.
exploratory outcomes addressed in this report
included the distribution of COPD maintenance
therapy by disease severity, geographic region and
hospital tier, the distribution of pharmacological
and nonpharmacological treatments at each fol-
low-up visit and mean total direct cost of COPD
management over 1 year.
Statistical analysis
Statistical analysis was performed on the full anal-
ysis set (FAS), including all patients who fulfilled
eligibility criteria and were successfully enrolled.
Sample size calculation has been published previ-
ously.14 Data analysis was primarily descriptive in
nature; for continuous variables, mean, median,
standard deviation (SD) and range were calcu-
lated, and for categorical variables, percentages
were calculated. Patients lost to follow-up were
withdrawn from the study and the reasons for
withdrawal or discontinuation were determined.
No imputation of missing data was used; all sta-
tistical analyses were carried out on nonmissing
data only. Statistical analysis was performed using
SAS version 9.4.
Results
Patient demographics and baseline
characteristics
Between 30 June 2017 and 29 January 2019,
5097 patients were screened, of whom 5013 were
enrolled, with 4978 patients included in the FAS.
Patients originated from six geographic regions:
north-east: N = 623 (12.5%), north: N = 1005
(20.2%), east: N = 1248 (25.1%), south-central:
N = 904 (18.2%), north-west: N = 602 (12.1%)
and south-west: N = 596 (12.0%). Approximately
half the patients were recruited from tertiary hos-
pitals (N = 2597, 52.2%) and the other half from
secondary hospitals (N = 2381, 47.8%). Among
the 4978 patients included in the FAS, a total of
772 withdrew from the study due to lost to fol-
low-up (n = 565), withdrawal of consent (n = 117),
death (n = 58) or other reasons (n = 32); the num-
ber of patients who dropped out of TC1, TC2,
TC3 and V1 visits were 308 (6.2%), 423 (8.5%),
505 (10.1%) and 739 (14.8%), respectively.
Baseline patient demographics and characteristics
for the overall cohort have been previously pub-
lished.15 Briefly, the mean (SD) age was 66.2
(8.9) years and the majority of patients were male
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Therapeutic Advances in
Respiratory Disease Volume 17

Table 1. Patient demographics and clinical characteristics at baseline. (79.5%) (Table 1). Mean (SD) time since COPD
diagnosis was 3.8 (6.2) years. Respiratory symp-
Characteristics Patients (N = 4978)
toms at baseline included shortness of breath
Age (years), mean (SD) 66.2 (8.9) (57.6%), wheezing (66.3%), chest tightness
(66.8%), cough (81.1%) and purulent mucus
Male, n (%) 3959 (79.5)
(80.6%).
Weight (kg), mean (SD) 62.7 (11.4)
Patient demographics and baseline characteris-
BMI (kg/m2), mean (SD) 23.0 (3.6)
tics according to geographic region and hospital
Smoking status, n (%) tier are presented in Supplementary Table S1.
Mean age was similar between regions (63.1–
Nonsmoker 1280 (25.7)
67.7 years) and hospital tiers (65.7–66.7 years).
Current smoker 1142 (22.9) The proportion of males varied between regions
(65.0–89.2%), but was consistent between hos-
Former smoker 2556 (51.3) pital tiers (79.0–80.0%). The mean time since
Second-hand smoking, n (%) (N = 4975) COPD diagnosis varied across regions (2.3–
4.2 years) and was longer in secondary (4.5 years)
Yes 1409 (28.3) compared with tertiary (3.1 years) hospitals.
No 3566 (71.7)
According to disease severity assessed by air-
Pack-years (N = 3682), mean (SD) 42.1 (24.1) flow limitation, 10.1%, 41.7%, 34.5% and
Exposure to noxious particles or gases, n (%) 13.6% of patients had mild, moderate, severe
and very severe disease, respectively. Per
No exposure 3397 (68.2) GOLD 2016 combined assessment classifica-
Dust 996 (20.0) tion, 11.4%, 22.0%, 12.0% and 54.6% of
patients were in groups A, B, C and D, respec-
Harmful gas 404 (8.1) tively; per GOLD 2017 combined assessment,
Biofuels 564 (11.3)
16.4%, 41.9%, 7.3% and 34.4% of patients
were in groups A, B, C and D, respectively
Other noxious substances 73 (1.5) (Table 2). A larger proportion of patients in
secondary versus tertiary hospitals had high dis-
Residence area, n (%) (N = 4972)
ease severity (severe versus very severe airflow
Urban 2735 (55.0) limitation: 52.0% versus 44.4%; GOLD 2016
group C versus group D: 74.9% versus 58.6%;
Rural 2237 (45.0)
GOLD 2017 group C versus group D: 52.7%
Time since COPD diagnosis (years) (N = 4952), 3.8 (6.2) versus 31.6%) (Supplementary Table S2).
mean (SD) Compared with other regions, the north had
COPD signs and symptoms (N = 4975), n (%)
the highest proportion of patients with mild or
moderate COPD and the lowest proportion of
Shortness of breath 2864 (57.6) patients with severe or very severe COPD,
regardless of disease severity assessment
Wheezing 3296 (66.3)
method (Supplementary Table S2).
Chest tightness 3324 (66.8)
The majority of patients (95%) received ⩾1
Cough 4037 (81.1)
concomitant medication for respiratory dis-
Mucus purulence 4011 (80.6) eases, including drugs for obstructive airway
diseases (93.5%), cough and cold preparations
Number of exacerbations in previous 12 months, n (%)
(36.8%), unspecified herbal and traditional
0 2516 (50.6) Chinese medicine (TCM, 25.6%), antibacteri-
als for systemic use (25.5%) and corticosteroids
1 1440 (28.9)
for systemic use (10.1%) (Supplementary Table
⩾2 1014 (20.4) S3). Other concomitant medications received
BMI, body mass index; COPD, chronic obstructive pulmonary disease; SD, standard by ⩾1% of patients included calcium channel
deviation. blockers (9.7%), agents acting on the renin–
All percentages were calculated based on patients with available data.
angiotensin system (7.0%), drugs used in

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 T Yang, B Cai et al.

Table 2. COPD disease severity classified by airflow ICS nor long-acting bronchodilators at each
limitation, GOLD 2016 and GOLD 2017. visit (Table 3). A full list of pharmacological
Severity of airflow V0 V1 treatments at baseline and 1 year can be found
limitation (GOLD in the REAL baseline15 and final outcomes16
stage), n (%) N = 4518 N = 711 publications.

Mild 458 (10.1) 67 (9.4) Distribution of prescribed stable COPD mainte-

Moderate 1886 (41.7)
Severe 1558 (34.5)
Very severe 616 (13.6)
GOLD 2016, n (%) N = 4699
A 536 (11.4)
B 1034 (22.0)
C 563 (12.0)
D 2566 (54.6)
GOLD 2017, n (%) N = 4976
A 818 (16.4)
B 2083 (41.9)
C 363 (7.3)
D 1712 (34.4)
COPD, chronic obstructive pulmonary disease; GOLD,
Global Initiative for Chronic Obstructive Lung Disease; V0,
baseline visit; V1, visit at 1 year.
All percentages were calculated based on patients with
available data.
diabetes (4.3%), antithrombotic agents (3.7%)
and unspecified herbal and TCM (3.3%)
(Supplementary Table S4).
298 (41.9) nance therapies at baseline and 1 year according to
geographic region and hospital tier. At baseline,
248 (34.9) more patients in the north-west received ICS/
LABA (36.2%) than in other regions (22.9–
98 (13.8)
34.0%), and more patients in the east received
N = 1519 LAMA (24.8%) or ICS/LABA + LAMA (25.9%)
compared with other regions (LAMA: 8.7–16.0%;
123 (8.1) ICS/LABA + LAMA: 7.1–21.8%). Except for a
167 (11.0) large increase in the proportion of patients receiv-
ing ICS/LABA monotherapy in the north-east
321 (21.1) (34.0–54.0%), the distribution of maintenance
therapies was largely similar between baseline and
908 (59.8)
1-year assessments (Table 4). Approximately one-
N = 4148 quarter (24.5–27.0%) of patients in the north-
east and south-west regions received neither ICS
1530 (36.9) nor long-acting bronchodilator therapy at base-
1601 (38.6) line. At 1 year, this proportion was the highest in
the north (25.7%) (Table 4).
270 (6.5)
747 (18.0) Overall, 27.7–35.4% of patients in tertiary hospi-
tals and 28.9–36.4% of patients in secondary hos-
pitals received ICS/LABA; LAMA monotherapy
and ICS/LABA + LAMA were received by 18.3–
19.5% and 22.1–24.6% of patients in tertiary
hospitals, and 12.5–12.6% and 12.2–13.7% of
patients in secondary hospitals, respectively
(Table 4). At baseline, 25.4% of patients in sec-
ondary hospitals and 5.0% of patients in tertiary
hospitals received neither ICS nor long-acting
bronchodilators. At 1 year, this had decreased to
17.3% in secondary hospitals, while it remained
consistent in tertiary hospitals (5.3%) (Table 4).

Patients receiving pharmacological Distribution of prescribed stable COPD mainte-

maintenance therapy
Distribution of prescribed stable COPD mainte-
nance therapies by follow-up visit. Throughout
the study, inhaled corticosteroids (ICSs)/long-
acting beta-agonists (LABAs) (28.3–36.0%),
long-acting muscarinic antagonists (LAMAs)
(13.0–16.2%) and ICS/LABA + LAMA (17.5–
18.7%) were the most frequently prescribed
maintenance therapies. Overall, 1.7–4.4%
patients received methylxanthines, 16.9–19.0%
patients received mucolytics and 1.7–3.6%
patients received TCM during the study. Nota-
bly, 11.6–15.8% of patients received neither
nance therapies at baseline and 1 year according
to disease severity at baseline. Per GOLD 2017
combined assessment criteria, the proportion of
patients receiving ICS/LABA maintenance ther-
apy increased slightly with disease severity
(GOLD groups A/B/C/D: 26.2%, 25.4%, 36.0%
and 31.3%, respectively), while the proportion of
patients receiving LAMA maintenance therapy
decreased as disease severity increased (GOLD
A/B/C/D: 24.5%, 16.4%, 17.5% and 11.7%,
respectively). The proportion of patients receiv-
ing ICS/LABA + LAMA maintenance therapy
was similar across disease severity groups

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Therapeutic Advances in
Respiratory Disease Volume 17

Table 3. Distribution of prescribed COPD maintenance therapies at baseline, telephone contact follow-ups and at 1 year.

V0 TC1 TC2 TC3 V1

(N = 4653) (N = 3360) (N = 2977) (N = 2755) (N = 2358)

Mono maintenance therapya

ICS 5 (0.1) 2 (0.1) 2 (0.1) 2 (0.1) 5 (0.2)

ICS/LABA 1316 (28.3) 1036 (30.8) 961 (32.3) 911 (33.1) 848 (36.0)

LAMA 754 (16.2) 451 (13.4) 387 (13.0) 370 (13.4) 361 (15.3)

LABA 31 (0.7) 31 (0.9) 32 (1.1) 26 (0.9) 21 (0.9)

SABA 102 (2.2) 75 (2.2) 71 (2.4) 64 (2.3) 49 (2.1)

SAMA 27 (0.6) 14 (0.4) 12 (0.4) 5 (0.2) 3 (0.1)

SABA/SAMA 2 (0.0) 1 (0.0) 2 (0.1) 2 (0.1) 3 (0.1)

Methylxanthines 204 (4.4) 99 (2.9) 104 (3.5) 101 (3.7) 41 (1.7)

TCM 80 (1.7) 114 (3.4) 104 (3.5) 98 (3.6) 53 (2.2)

None of the medications described above 120 (2.6) 106 (3.2) 90 (3.0) 84 (3.0) 58 (2.5)

Combination maintenance therapya

ICS/LABA + LAMA 871 (18.7) 598 (17.8) 540 (18.1) 482 (17.5) 417 (17.7)

LABA + LAMA 55 (1.2) 35 (1.0) 28 (0.9) 32 (1.2) 27 (1.1)

Anya

Mucolytics 785 (16.9) 640 (19.0) 557 (18.7) 471 (17.1) 403 (17.1)
Neither ICS nor long-acting bronchodilatorb 681 (14.6) 504 (15.0) 460 (15.5) 436 (15.8) 273 (11.6)

COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic
antagonist; SABA, short-acting beta-agonist; SAMA, short-acting muscarinic antagonist; TC, telephone contact; TCM, traditional Chinese medicine;
V0, baseline visit; V1, visit at 1 year.
Data are presented as n (%) unless stated otherwise. All percentages were calculated based on patients with available data.
aMedications classified by drug class.
bThis class denotes prescriptions without ICS, LABA, ICS/LABA or LAMA.

(GOLD A/B/C/D: 19.9%, 18.1%, 17.2% and
19.3%, respectively) (Table 5), although ICS/
LABA + LAMA use rose with increasing disease
severity when severity was assessed by airflow
limitation (10.9% mild, 15.7% moderate, 21.7%
severe, 26.4% very severe). Overall, the propor-
tions of patients receiving ICS/LABA, LAMA or
ICS/LABA + LAMA (according to disease sever-
ity at baseline) were largely consistent between
baseline and 1-year assessments (Table 5).
Few patients received short-acting beta-agonists
(SABAs), short-acting muscarinic antagonists
(SAMAs), SABA/SAMA or LABA + LAMA main-
tenance therapies for stable COPD, regardless of
disease severity and severity assessment method
(airflow limitation or GOLD 2016/2017 criteria)
(Table 5). In general, more patients with group D
disease as per GOLD 2017 combined assessment
received SABA monotherapy (up to 4%) than
those with group A, B or C disease. LABA + LAMA
combination was received by 0.7–1.7% of patients
throughout the study. At baseline, methylxanthines
and TCM were used regardless of disease severity,
and this trend was similar at the 1-year follow-up.
Use of mucolytics was also similar across disease
severity groups. Overall, there was a substantial
proportion of patients who received neither ICS
nor long-acting bronchodilators (no trend across
severity groups) at baseline and 1 year (Table 5),
despite increased symptoms and risk of exacerba-
tion in patients with more severe disease.

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 T Yang, B Cai et al.

Table 4. Distribution of stable COPD maintenance medication by geographic region and hospital tier.

Region Hospital tier Total

(N = 4978)
North-east North East South- North- South- Tertiary Secondary
(N = 623) (N = 1005) (N = 1248) central west west (N = 2597) (N = 2381)
(N = 904) (N = 602) (N = 596)

V0, n (%)

 Number of patients 574 (92.1) 933 (92.8) 1196 (95.8) 869 (96.1) 583 (96.8) 498 (83.6) 2460 (94.7) 2193 (92.1) 4653 (93.5)
with available data

ICS/LABA (mono)a 195 (34.0) 247 (26.5) 318 (26.6) 231 (26.6) 211 (36.2) 114 (22.9) 682 (27.7) 634 (28.9) 1316 (28.3)

LAMA (mono)a 86 (15.0) 146 (15.6) 297 (24.8) 76 (8.7) 93 (16.0) 56 (11.2) 479 (19.5) 275 (12.5) 754 (16.2)

ICS/LABA + LAMAa 101 (17.6) 203 (21.8) 310 (25.9) 62 (7.1) 99 (17.0) 96 (19.3) 604 (24.6) 267 (12.2) 871 (18.7)

 Neither ICS nor long- 155 (27.0) 130 (13.9) 39 (3.3) 196 (22.6) 39 (6.7) 122 (24.5) 124 (5.0) 557 (25.4) 681 (14.6)
acting bronchodilatorb

V1, n (%)

 Number of patients 202 (32.4) 335 (33.3) 672 (53.8) 599 (66.3) 321 (53.3) 229 (38.4) 1123 (43.2) 1235 (51.9) 2358 (47.4)
with available data

ICS/LABA (mono)a 109 (54.0) 132 (39.4) 196 (29.2) 204 (34.1) 155 (48.3) 52 (22.7) 398 (35.4) 450 (36.4) 848 (36.0)

LAMA (mono)a 26 (12.9) 44 (13.1) 153 (22.8) 59 (9.8) 48 (15.0) 31 (13.5) 206 (18.3) 155 (12.6) 361 (15.3)

ICS/LABA + LAMAa 38 (18.8) 39 (11.6) 173 (25.7) 47 (7.8) 75 (23.4) 45 (19.7) 248 (22.1) 169 (13.7) 417 (17.7)

 Neither ICS nor long- 25 (12.4) 86 (25.7) 19 (2.8) 94 (15.7) 14 (4.4) 35 (15.3) 59 (5.3) 214 (17.3) 273 (11.6)
acting bronchodilatorb

COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic
antagonist; V0, baseline visit; V1, visit at 1 year.
All percentages were calculated based on patients with available data.
aSubjects prescribed one and only mono or combination of medications on display, with no prohibition of being prescribed mucolytic and others at

the same time.

bICS, ICS/LABA, LABA, LAMA, ICS/LABA + LAMA and LABA + LAMA not prescribed.

Table 5. Distribution of prescribed COPD maintenance therapies by disease severity at baseline and at 1 year.

Maintenance Disease severity Baseline 1 year Disease severity Baseline 1 year Disease severity Baseline 1 year
therapya at baseline at baseline at baseline
(airflow limitation) (GOLD 2016) (GOLD 2017)

ICS/LABA Mild 117/430 76/164 A 120/494 73/192 A 198/755 112/316

(27.2) (46.3) (24.3) (38.0) (26.2) (35.4)

Moderate 498/1775 300/827 B 245/982 148/412 B 497/1960 322/915

(28.1) (36.3) (24.9) (35.9) (25.4) (35.2)

Severe 393/1444 257/781 C 164/516 95/285 C 119/331 73/189

(27.2) (32.9) (31.8) (33.3) (36.0) (38.6)

Very severe 138/575 112/367 D 685/2402 477/1354 D 502/1605 341/937

(24.0) (30.5) (28.5) (35.2) (31.3) (36.4)

ICS/LABA + Mild 47/430 18/164 A 81/494 26/192 A 150/755 57/316

LAMA (10.9) (11.0) (16.4) (13.5) (19.9) (18.0)

Moderate 278/1775 110/827 B 139/982 51/412 B 354/1960 154/915

(15.7) (13.3) (14.2) (12.4) (18.1) (16.8)

(Continued)

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Table 5. (Continued)

Maintenance Disease severity Baseline 1 year Disease severity Baseline 1 year Disease severity Baseline 1 year
therapya at baseline at baseline at baseline
(airflow limitation) (GOLD 2016) (GOLD 2017)

Severe 313/1444 162/781 C 112/516 53/285 C 57/331 27/189

(21.7) (20.7) (21.7) (18.6) (17.2) (14.3)

Very severe 152/575 100/367 D 489/2402 270/1354 D 309/1605 178/937

(26.4) (27.2) (20.4) (19.9) (19.3) (19.0)

LAMA Mild 110/430 28/164 A 143/494 44/192 A 185/755 68/316

(25.6) (17.1) (28.9) (22.9) (24.5) (21.5)

Moderate 374/1775 166/827 B 213/982 90/412 B 322/1960 152/915

(21.1) (20.1) (21.7) (21.8) (16.4) (16.6)

Severe 166/1444 109/781 C 85/516 52/285 C 58/331 33/189

(11.5) (14.0) (16.5) (18.2) (17.5) (17.5)

Very severe 53/575 25/367 D 275/2402 158/1354 D 188/1605 108/937

(9.2) (6.8) (11.4) (11.7) (11.7) (11.5)

LABA + Mild 3/430 2/164 A 4/494 2/192 A 6/755 4/316

LAMA (0.7) (1.2) (0.8) (1.0) (0.8) (1.3)

Moderate 21/1775 10/827 B 13/982 7/412 B 30/1960 14/915

(1.2) (1.2) (1.3) (1.7) (1.5) (1.5)

Severe 25/1444 9/781 C 6/516 4/285 C 4/331 2/189

(1.7) (1.2) (1.2) (1.4) (1.2) (1.1)

Very severe 5/575 6/367 D 32/2402 14/1354 D 15/1605 7/937

(0.9) (1.6) (1.3) (1.0) (0.9) (0.7)

SABA Mild 9/430 3/164 A 5/494 2/192 A 7/755 5/316

(2.1) (1.8) (1.0) (1.0) (0.9) (1.6)

Moderate 34/1775 13/827 B 17/982 7/412 B 35/1960 17/915

(1.9) (1.6) (1.7) (1.7) (1.8) (1.9)

Severe 37/1444 17/781 C 7/516 9/285 C 7/331 6/189

(2.6) (2.2) (1.4) (3.2) (2.1) (3.2)

Very severe 8/575 10/367 D 68/2402 28/1354 D 53/1605 21/937

(1.4) (2.7) (2.8) (2.1) (3.3) (2.2)

SAMA Mild 2/430 0 A 3/494 0 A 4/755 0

(0.5) (0.6) (0.5)

Moderate 17/1775 2/827 B 1/982 0 B 2/1960 0

(1.0) (0.2) (0.1) (0.1)

Severe 5/1444 1/781 C 7/516 0 C 7/331 0

(0.3) (0.1) (1.4) (2.1)

Very severe 2/575 0 D 15/2402 3/1354 D 14/1605 3/937

(0.3) (0.6) (0.2) (0.9) (0.3)

SABA/SAMA Mild 0 0 A 1/494 0 A 1/755 0

(0.2) (0.1)

Moderate 1/1775 0 B 0 0 B 1/1960 0

(0.1) (0.1)

Severe 1/1444 1/781 C 0 0 C 0 0

(0.1) (0.1)

(Continued)

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Table 5. (Continued)

Maintenance Disease severity Baseline 1 year Disease severity Baseline 1 year Disease severity Baseline 1 year
therapya at baseline at baseline at baseline
(airflow limitation) (GOLD 2016) (GOLD 2017)

Very severe 0 2/367 D 1/2402 3/1354 D 0 3/937

(0.5) (<0.1) (0.2) (0.3)

Methylxanthines Mild 29/430 4/164 A 17/494 4/192 A 25/755 4/316

(6.7) (2.4) (3.4) (2.1) (3.3) (1.3)

Moderate 72/1775 12/827 B 65/982 5/412 B 122/1960 11/915

(4.1) (1.5) (6.6) (1.2) (6.2) (1.2)

Severe 71/1444 14/781 C 12/516 3/285 C 5/331 3/189

(4.9) (1.8) (2.3) (1.1) (1.5) (1.6)

Very severe 26/575 6/367 D 107/2402 29/1354 D 52/1605 23/937

(4.5) (1.6) (4.5) (2.1) (3.2) (2.5)

TCM Mild 11/430 2/164 A 9/494 4/192 A 14/755 6/316

(2.6) (1.2) (1.8) (2.1) (1.9) (1.9)

Moderate 27/1775 17/827 B 15/982 6/412 B 38/1960 18/915

(1.5) (2.1) (1.5) (1.5) (1.9) (2.0)

Severe 23/1444 19/781 C 7/516 5/285 C 2/331 3/189

(1.6) (2.4) (1.4) (1.8) (0.6) (1.6)

Very severe 12/575 9/367 D 44/2402 34/1354 D 26/1605 26/937

(2.1) (2.5) (1.8) (2.5) (1.6) (2.8)

Anya

Mucolytic Mild 70/430 22/164 A 92/494 43/192 A 147/755 67/316

(16.3) (13.4) (18.6) (22.4) (19.5) (21.2)

Moderate 312/1775 155/827 B 184/982 64/412 B 374/1960 161/915

(17.6) (18.7) (18.7) (15.5) (19.1) (17.6)

Severe 255/1444 142/781 C 91/516 64/285 C 47/331 41/189

(17.7) (18.2) (17.6) (22.5) (14.2) (21.7)

Very severe 96/575 67/367 D 380/2402 222/1354 D 217/1605 134/937

(16.7) (18.3) (15.8) (16.4) (13.5) (14.3)

 Neither ICS Mild 79/430 18/164 A 53/494 14/192 A 75/755 20/316

nor long-acting (18.4) (11.0) (10.7) (7.3) (9.9) (6.3)
bronchodilatorb

Moderate 232/1775 84/827 B 156/982 44/412 B 321/1960 111/915

(13.1) (10.2) (15.9) (10.7) (16.4) (12.1)

Severe 227/1444 91/781 C 57/516 25/285 C 41/331 19/189

(15.7) (11.7) (11.0) (8.8) (12.4) (10.1)

Very severe 92/575 43/367 D 391/2402 173/1354 D 244/1605 123/937

(16.0) (11.7) (16.3) (12.8) (15.2) (13.1)

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA,
long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta-agonist; SAMA, short-acting muscarinic antagonist;
TCM, traditional Chinese medicine.
Data are presented as n/N (%) unless stated otherwise. All percentages were calculated based on patients with available data.
aMedications classified by drug class.
bThis class denotes prescriptions without ICS, LABA, ICS/LABA or LAMA.

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Therapeutic Advances in
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Table 6. Distribution of prescribed nonpharmacological therapies at baseline, telephone contact follow-ups

and at 1 year.

V0 TC1 TC2 TC3 V1

(N = 3342) (N = 2822) (N = 2681) (N = 2558) (N = 2441)

COPD health education 2976 (89.0) 2677 (94.9) 2561 (95.5) 2437 (95.3) 2334 (95.6)

Smoking cessation 1298 (38.8) 692 (24.5) 571 (21.3) 512 (20.0) 453 (18.6)

Quit 562 (16.8) 111 (3.9) 48 (1.8) 36 (1.4) 39 (1.6)

Reduction 466 (13.9) 368 (13.0) 320 (11.9) 273 (10.7) 233 (9.5)

No change 270 (8.1) 213 (7.5) 203 (7.6) 203 (7.9) 181 (7.4)

Exercise of respiratory function 1567 (46.9) 1417 (50.2) 1391 (51.9) 1354 (52.9) 1358 (55.6)

Lip reduction breathing 1228 (36.7) 1154 (40.9) 1143 (42.6) 1109 (43.4) 1020 (41.8)

Abdominal breathing 930 (27.8) 841 (29.8) 828 (30.9) 828 (32.4) 852 (34.9)

Other 121 (3.6) 108 (3.8) 128 (4.8) 123 (4.8) 152 (6.2)

Vaccination (related to COPD)a 391 (11.7) 107 (3.8) 113 (4.2) 134 (5.2) 196 (8.0)

Pneumonia 226 (6.8) 46 (1.6) 47 (1.8) 42 (1.6) 70 (2.9)

Influenza 243 (7.3) 75 (2.7) 91 (3.4) 114 (4.5) 157 (6.4)

Other 2 (0.1) 0 0 0 2 (0.1)

COPD, chronic obstructive pulmonary disease; TC, telephone contact; V0, baseline visit; V1, visit at 1 year.
Data are presented as n (%). All percentages were calculated based on the number of subjects with nondrug treatments
at each visit.
aA positive vaccination status was recorded if the patient received vaccination at any point since the last follow-up

(including the TC follow-up).

Patients receiving nonpharmacological similar across disease severity categories at base-

treatment
COPD health education was the most common
nonpharmacological treatment at each study visit
(89.0–95.6%), followed by lip reduction breath-
ing (36.7–43.4%) and abdominal breathing
(27.8–34.9%). At baseline, quitting smoking
(16.8%) was the fourth most common nonphar-
macological treatment, replaced by smoking
reduction in subsequent follow-up visits (9.5–
13.0%). Smoking cessation treatment (including
quitting, reduction and no change) was provided
in only 38.8%, 24.5%, 21.3%, 20.0% and 18.6%
of patients at V0, TC1–3 and V1, respectively. At
each visit, 1.6–6.8% of patients received vaccina-
tion for pneumonia, while 2.7–7.3% of patients
received vaccination for influenza (Table 6).
line (airflow limitation: 96.1–96.9%, GOLD
2016: 93.5–97.7%, GOLD 2017: 94.3–98.0%)
(Table 7). The proportion of patients with main-
tenance treatment expenses was also similar
across disease severity categories (airflow limita-
tion: 95.4–96.9%, GOLD 2016: 92.5–97.2%,
GOLD 2017: 93.5–97.7%) (Table 7). The
median total direct cost and median treatment
expenses, however, increased with worsening dis-
ease severity, and this trend was consistent regard-
less of the method of disease severity classification.
The proportion of total direct COPD costs that
were attributed to COPD maintenance treatment
expenses reduced as disease severity increased
(Table 7).

Discussion
Direct costs associated with COPD REAL is the first nationwide study to collect pro-
Over the course of the study, the proportion of spective longitudinal real-world data on the man-
patients incurring any direct COPD cost was agement and clinical outcomes of a large cohort

10 journals.sagepub.com/home/tar
 T Yang, B Cai et al.

Table 7. COPD costs by baseline COPD severity classified by airflow limitation, GOLD 2016 and GOLD 2017.

Total direct COPD costs COPD maintenance treatment expenses Proportion of

total direct COPD
Patients with any RMB, median (Q1, Patients with RMB, median (Q1, costs attributed to
direct costs, n/N Q3) any treatment Q3) COPD maintenance
(%) expenses, n/N treatment expenses
(%) (%)

Severity of airflow limitation (GOLD stage)

Mild 440/458 (96.1) 1251 (350, 3043) 437/458 (95.4) 1049 (308, 2545) 83.85

Moderate 1827/1886 (96.9) 1981 (625, 4301) 1811/1886 (96.0) 1600 (516, 3128) 80.77

Severe 1510/1558 (96.9) 2694 (854, 5997) 1504/1558 (96.5) 1868 (648, 3869) 69.34

Very severe 597/616 (96.9) 4073 (1514, 8706) 597/616 (96.9) 2556 (899, 4799) 62.75

GOLD 2016

A 501/526 (93.5) 1601 (510, 3704) 496/536 (92.5) 1500 (487, 3273) 93.69

B 1010/1034 (97.7) 1573 (492, 3437) 1003/1034 (97.0) 1415 (421, 2950) 89.96

C 539/563 (95.7) 2453 (863, 5148) 533/563 (94.7) 1873 (712, 3663) 76.36

D 2502/2566 (97.5) 2991 (926, 6960) 2495/2566 (97.2) 1933 (650, 3779) 64.63

GOLD 2017

A 771/818 (94.3) 1885 (600, 4002) 765/818 (93.5) 1709 (553, 3544) 90.66

B 2027/2083 (97.3) 2010 (599, 4474) 2018/2083 (96.9) 1703 (511, 3531) 84.73

C 349/363 (96.1) 2192 (720, 4958) 344/363 (94.8) 1565 (635, 3244) 71.40
D 1678/1712 (98.0) 3122 (1084, 7501) 1672/1712 (97.7) 1864 (652, 3550) 59.71

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; RMB, renminbi.
Data are presented in RMB unless stated otherwise. All values were calculated based on patients with available data.

of Chinese outpatients with stable COPD. Here,
we report treatment patterns among patients from
six different geographic regions treated in second-
ary or tertiary hospitals, as well as treatment pat-
terns by COPD severity. In addition, we report
rates of nonpharmacological treatment and costs
relating to treatment, to provide a deeper under-
standing of current COPD management across
China.
Overall, a substantial proportion of patients
enrolled in the REAL study had high disease
severity; similar findings have been reported in
three other multicentre, observational studies of
patients with COPD in China.10,13,18 Final out-
comes of the REAL study showed that a substan-
tial proportion of patients with severe disease
experienced exacerbations.16 Supporting this,
other multicentre, observational studies of
patients with COPD in China showed that there
is a positive correlation between disease severity
and annual exacerbation rate.18,19 These data
highlight the ongoing gap between the goals of
COPD treatment1 and real-world clinical out-
comes of patients with COPD in China.
In the REAL study, which included a large,
nationally representative sample of patients with
COPD in China, ICS/LABA, LAMA and ICS/
LABA + LAMA were the most frequently pre-
scribed maintenance medications for stable
COPD. These treatment patterns are similar to
two previous observational studies in China,
which reported that LAMA (34.8% and 39.1%),
ICS/LABA (9.9% and 14.4%) and ICS/
LABA + LAMA (39.4% and 39.0%) were the top

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Therapeutic Advances in
Respiratory Disease
three pharmacological treatments used.10,13 A
real-world prospective longitudinal study that
was carried out in 12 hospitals in China from
2016 to 2021 also reported similar proportions of
patients with COPD who received LAMA
(24.3%), ICS/LABA (10.4%) and ICS/
LABA + LAMA (35.3%).20
ICS/LABA was prescribed at a similar rate across
disease severity groups, while LAMA monother-
apy use decreased as disease severity increased.
As the mean time from diagnosis in the REAL
study was 3.8 years, this latter trend may be
explained by nature of patients with a higher
baseline disease severity having already had their
treatment escalated beyond LAMA. Of note,
LAMA monotherapy was consistently preferred
over LABA monotherapy, which is consistent
with GOLD strategy document.1 On the other
hand, it appears that physicians in China more
often escalated treatment to ICS/LABA rather
than the preferred LABA + LAMA combination.1
In line with findings from Zeng et al.,13
LABA + LAMA use throughout the REAL study
was consistently low (⩽1.7% regardless of disease
severity), although it is worth noting that fixed-
dose combination LABA/LAMA therapy was not
available in China at the time of the study (LABA/
LAMA therapy was included in the medical
insurance catalogue in China at the end of
2019).21 LABA/LAMA therapy has been shown
to improve lung function and reduce exacerba-
tion rates without an increase in adverse
effects,21,22 but among patients with severe stable
COPD treated with fixed-dose combination
LABA/LAMA therapy, correct use was only
reported in approximately 60%.23 In the REAL
study, ICS/LABA + LAMA use was higher in
patients with more severe disease, although not
when disease severity was categorized according
to GOLD 2017. This suggests that the physi-
cian’s decision to step-up to triple therapy was
driven by severity of lung function rather than
acute exacerbation risk. On the other hand, Cui
et al.10 and Zeng et al.13 reported a trend for
increased use of ICS/LABA + LAMA with
increasing disease severity as per GOLD 2017
combined assessment. Their studies enrolled
patients from one and two geographic regions in
China, respectively, whereas the REAL study
enrolled patients from six different regions and
found discrepancies in treatment use between the
regions, which could account for the differences
12
Volume 17
observed in prescription patterns between these
studies.
At baseline, the proportion of patients who
received LAMA or ICS/LABA + LAMA was the
highest in the east region (24.8% or 25.9%,
respectively) compared with other regions (8.7–
16.0% or 7.1–21.8%, respectively); there were
more patients at tertiary hospitals who received
LAMA (19.5%) or ICS/LABA + LAMA (24.6%)
compared with those at secondary hospitals
(12.5% or 12.2%, respectively). This may be
explained by the relative proportion of patients
residing in the urban or rural areas across differ-
ent geographic regions or hospital tiers. The east
region has the highest proportion of patients from
urban areas (62.0%) compared with other regions
(35.4–60.6%). Most patients at tertiary hospitals
were from urban areas (64.7%), whereas the
majority of patients at secondary hospitals reside
in rural areas (55.5%). A previous study has
shown that patients from rural areas were less
likely to seek medical advice and reported lower
medication use compared with patients from
urban areas.24 In the study by Zeng et al.,13 in
which patients were recruited from two provinces
in the south-central/south region of China, there
were more patients who received LAMA (39.1%)
or ICS/LABA + LAMA (39.0%), compared with
ICS/LABA (14.4%). In our study, however, there
were less patients in the south-central region who
received LAMA (8.7%) or ICS/LABA + LAMA
(7.1%), compared with ICS/LABA (26.6%) at
baseline. A community-based survey of approxi-
mately 25,000 participants across 10 regions in
China revealed that Sichuan (south-west region)
had the highest prevalence of COPD, but the
lowest reported use of any COPD medication
(10.3%).24 While we did not observe this in this
study, the south-west region had one of the high-
est proportions of patients who received neither
ICS nor long-acting bronchodilators.
Overall, up to 15.8% of patients at each visit
received neither ICS nor long-acting bronchodi-
lators, although this was as high as 15.2–16.3% in
patients with the most severe disease and reached
>25% in some regions. A large observational
study of COPD treatment patterns in Germany
(N = 250,723) reported that 65.4% of patients
were not prescribed inhaled maintenance treat-
ment.12 This sizable difference in inhaled therapy
prescription between the studies may be due to
journals.sagepub.com/home/tar

(1) differences in time of data collection relative
to COPD diagnosis; in the REAL study, mean
time from diagnosis at study initiation was
3.8 years, whereas in the German study, data
were collected from the date of first recorded
COPD diagnosis and many patients were newly
diagnosed and (2) differences in the hospital tiers
included in the study; in the REAL study, patients
were treated at secondary and tertiary hospitals,
whereas in the German study, data were collected
from medical records of patients treated in pri-
mary and secondary care.12 We additionally
observed a fivefold increase in the number of
patients in secondary compared with tertiary hos-
pitals that did not receive ICS or long-acting
bronchodilators. These apparent differences in
COPD management practices may result from
disparities in the quantity and quality of respira-
tory services between hospital tiers in China.18,25,26
Hospital tier has been previously reported as a
risk factor for acute exacerbation.18 Moreover, a
lack of formal gatekeeping in the hospital care
system in China means that patients can access
the system at any level and may not be referred to
a more appropriate hospital tier if required.18,27
Tertiary hospitals in China, however, are respon-
sible for treating more uncommon and complex
respiratory illnesses than secondary hospitals,
which may limit their capacity to accommodate
patients with common chronic diseases such as
COPD.18 Tertiary hospitals in China are also
often located far away from rural areas. In this
study, we showed that the majority of tertiary
hospitals were located in urban versus rural areas
(64.7% versus 35.3%), and others have shown
that patients prefer to access a local hospital when
they have an acute exacerbation.28 In the REAL
study, there were more patients with severe dis-
ease in secondary versus tertiary hospitals, and
together with our data on treatment patterns, this
indicates that many patients may not have
received adequate treatment. Vogelmeier et al.12
reported that just over half the patients with one
moderate baseline exacerbation and over one-
third (36.9%) of patients with one severe baseline
or multiple baseline exacerbations were not pre-
scribed inhaled maintenance treatment at diagno-
sis, underscoring the importance of timely and
appropriate prescription of pharmacological
treatment in patients with stable COPD.
In addition to pharmacological treatment, non-
pharmacological treatment in the form of educa-
tion and self-management should be a major
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T Yang, B Cai et al.
component of the long-term management of
chronic diseases such as COPD.1 Others have
previously reported the benefits of nonpharmaco-
logical management, such as smoking interven-
tion, pulmonary rehabilitation, breathing
exercises and education programmes in reducing
symptoms and mortality, as well as improving
lung function and health-related quality of life in
patients with COPD.29–36 In this study, COPD
education was provided to almost all patients, but
optimal self-management behaviour was evident
in a much smaller proportion. Moreover, COPD
knowledge was poor. We observed low uptake of
respiratory function exercises, which are an
important part of nonpharmacological treatment
for COPD and contribute to pulmonary rehabili-
tation.1,37 REAL included the two most common
breathing exercises that have been shown to
reduce breathing frequency, improving chest wall
tidal volume and exercise capacity in patients
with COPD.31,37,38 We also found low levels of
vaccination, with only 2.7–7.3% receiving influ-
enza vaccination at each visit over the 12-month
follow-up period. This was consistent with a 2022
cross-sectional study (1.7–10.9%) that recruited
patients with COPD from eight hospitals across
different tiers in China (tertiary, secondary or
community hospitals).18 The same study also
showed that influenza vaccination in the previous
year and pneumococcal vaccination in the previ-
ous 5 years were associated with reduced risk of
acute exacerbation.18 Other studies have also
reported that influenza vaccination can effectively
reduce the risk of acute exacerbation.39–41 In addi-
tion, influenza vaccination is recommended
annually for all patients with COPD,1 and thus,
these data suggest an insufficient rate of vaccina-
tion in a vulnerable population. A recent study
reported that patients treated for COPD in com-
munity hospitals had higher vaccination rates
than those treated in secondary or tertiary hospi-
tals, and that this might be due to physicians hav-
ing more time to educate patients about the
importance and benefits of vaccination.18 Cultural
factors (such as the traditional Chinese concept
of visiting the hospital only when one is sick) may
result in Chinese patients placing less importance
on vaccination, which in turn may contribute to
low vaccination rates.18 As influenza vaccination
is not included in the national immunization pro-
gramme in China, patients are required to pay
themselves and this may contribute to the low
uptake of vaccinations.42 Economically developed
regions in China (e.g. Beijing) have started to
13
Therapeutic Advances in
Respiratory Disease
offer free influenza vaccinations to individuals
aged >60 years, and this has improved vaccina-
tion rates among eligible patients in the region.42
Of note, Zeng et al.13 also reported underpre-
scription of nonpharmacological therapies among
patients with COPD in China. Current evidence
suggests low levels of COPD knowledge among
clinicians, including respiratory physicians43;
therefore, the quality of COPD-related health
education provided to patients in routine clinical
visits should be further investigated.
Overall, we observed substantial variations in the
use of pharmacological and nonpharmacological
treatments for stable COPD across regions and
hospital tiers in China, plus notable discrepancies
between the real-world treatment patterns among
patients with stable COPD in China and treat-
ment guidelines for clinical practice.1 These dis-
crepancies may be due to several reasons. First,
dual bronchodilation and triple therapy (which
are recommended by the GOLD guidelines for
the treatment of COPD) were not included in the
medical insurance catalogue in China until recent
years.21 Second, tertiary hospitals are less acces-
sible to patients living in rural areas in China.
These patients tend to seek treatment at second-
ary hospitals, which should have the necessary
skills and resources to treat COPD exacerba-
tions.28 Third, the lack of COPD knowledge
among Chinese patients16 may prevent them from
seeking appropriate treatment and rehabilitation
guidance. Finally, Chinese patients may prefer to
combine TCM with pharmacological treatment,
as shown in a recent survey on treatment prefer-
ence among patients with COPD in China,44 and
this could be due to TCM being more affordable,
especially to patients living in rural areas.28
The REAL study additionally collected data on
COPD-related costs, including those incurred
from treatment. We found that patients with
COPD have a high burden of COPD-related
direct costs, particularly as a result of mainte-
nance treatment, with costs increasing as disease
severity increased. Maintenance treatment costs,
however, represented a lower proportion of over-
all direct costs in patients with higher disease
severity (59.7–76.4%) versus those with milder
disease (80.8–93.7%). As reported in the final
outcomes of the REAL study, patients with more
severe disease experienced a higher rate of exacer-
bations.16 This may have contributed to the dis-
proportionate increase in additional direct costs
14
Volume 17
for patients with higher disease severity. These
data further support the importance of appropri-
ate and timely management of stable COPD.
This study has several limitations. First, because
step-up and step-down of treatment could be per-
formed following improvement/worsening of dis-
ease severity, but the grouping of treatments
prescribed at TC1–3 and V1 are presented by dis-
ease severity at baseline, we are unable to evaluate
the association between treatment sequence and
change in disease severity. As such, it is possible
that the apparent association between treatment
use and disease severity throughout the study
does not accurately reflect real-world clinical
practice. Given that the overall distribution of
disease severity and treatment patterns (by dis-
ease severity) remained largely consistent across
all follow-up assessments, however, we are confi-
dent that these data provide a good estimate of
the current state of COPD management across
China. Second, even though patients were classi-
fied by GOLD A/B/C/D groups throughout the
study, these assessments can only be considered
an indicator for actual disease severity. As per the
GOLD strategy document,8,17 A/B/C/D groups
are used to guide initial pharmacological treat-
ment in clinical practice; in the REAL study,
however, patients were not necessarily newly
treated patients with COPD. Third, baseline data
on maintenance medications were collected ret-
rospectively and included both initial and follow-
up treatments; therefore, nonadherence to the
GOLD recommendations cannot be precisely
estimated. Finally, implementation of the national
hierarchical medical system allowed some patients
to obtain their prescription medications from a
community hospital, potentially influencing the
reporting of treatment patterns as these prescrip-
tions would not be recorded at the secondary or
tertiary hospitals included in this study.
Conclusion
The majority of patients in the REAL study had
moderate-to-severe disease, suggesting that this
level of disease may be prevalent among patients
with COPD who attend regular outpatient visits
in secondary or tertiary hospitals in China. The
most common treatment regimens prescribed to
patients with stable COPD in this study were
ICS/LABA, LAMA and ICS/LABA + LAMA,
and our results indicate that lung function may be
the primary indicator for treatment escalation in
journals.sagepub.com/home/tar
 T Yang, B Cai et al.

patients with COPD in China. In terms of non- Wenhua Jian: Conceptualization; Data cura-
pharmacological management, rates of respira- tion; Formal analysis; Writing – original draft;
tory function training, smoking intervention and Writing – review & editing.
vaccination administration require improvement.
Chen Wang: Conceptualization; Data curation;
Overall, our results indicate that there may be
Formal analysis; Writing – original draft; Writing
inconsistencies between treatment guidelines and
– review & editing.
current clinical practice across China, reflecting a
need to improve the long-term management of
Acknowledgements
stable COPD nationwide, although particularly
The authors acknowledge Alice Carruthers BSc
in secondary hospitals. We hope that better
(Hons), PhD of Nucleus Global Asia Pacific for
adherence to current treatment guidelines may
editorial assistance and AstraZeneca China for
improve disease-related outcomes and the finan-
the funding in accordance with Good Publication
cial burden on patients.
Practice (GPP3) guidelines.

Funding
Declarations
The authors disclosed receipt of the following
financial support for the research, authorship
Ethics approval and consent to participate
and/or publication of this article: This work was
The ethics committee of the China–Japan
supported by AstraZeneca China. The funder
Friendship Hospital (leading study site) approved
collaborated with researchers in the design and
the study protocol and informed consent form
planned statistical analyses.
prior to study initiation (approval no. 2016-97).
The study was approved by ethics committees
Competing interests
at individual study centres and was designed
The authors declared no potential conflicts of
and conducted in accordance with the
interest with respect to the research, authorship
Declaration of Helsinki, International Conference
and/or publication of this article.
on Harmonization Good Clinical Practices, Good
Pharmacoepidemiology Practices. All patients in
Availability of data and materials
this study provided written informed consent
The data sets used and/or analysed during this
prior to study initiation.
study are available from the corresponding author
on reasonable request.
Consent for publication
Not applicable.
ORCID iD
Author contributions Chen Wang https://orcid.org/0000-0001-
Ting Yang: Conceptualization; Data curation; 7857-5435
Formal analysis; Writing – original draft; Writing
– review & editing. Supplemental material
Baiqiang Cai: Conceptualization; Data cura- Supplemental material for this article is available
tion; Formal analysis; Writing – original draft; online.
Writing – review & editing.
Bin Cao: Conceptualization; Data curation;
Formal analysis; Writing – original draft; Writing
– review & editing. References
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