Mortality and exacerbation risk according to GOLD and STAR severity stages of COPD: a 5-year multicenter prospective cohort study PDF Free Download
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Mortality and exacerbation risk
according to GOLD and STAR
severity stages of COPD: a 5-year
multicenter prospective cohort
study
Hiroaki Ogata1, Kazuya Tsubouchi1, Tomotsugu Takano1, Katsuyuki Ichiki2, Ryo Torii3,
Shohei Takata4, Noriaki Nakagaki5, Makoto Yoshida6, Yasuhiko Kitasato7, Kazunori Tobino8,
Eiji Harada9, Hiroshi Wataya10, Hiroshi Ishii11, Takashige Maeyama12, Masayuki Kawasaki13,
Masaki Fujita14, Kazuhiro Yatera15, Yoshiaki Zaizen16, Yoichi Nakanishi17 & Isamu Okamoto1
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classication, based on percent
predicted forced expiratory volume in 1 s (ppFEV1), has been widely adopted for assessment of
chronic obstructive pulmonary disease (COPD) severity. However, the STaging of Airow obstruction
by Ratio (STAR) system, based on the ratio of FEV1 to forced vital capacity, was recently proposed as
an alternative classication. This study aimed to compare the prognostic performance of the GOLD
and STAR classications for prediction of mortality and exacerbation risk in individuals with COPD.
This 5-year prospective, multicenter cohort study enrolled 370 individuals with COPD at 29 medical
centers. All-cause mortality risk across GOLD and STAR stages was evaluated with Kaplan-Meier
curves and Cox proportional hazards models. The risk of moderate to severe COPD exacerbations
across GOLD and STAR stages was examined with cumulative incidence function (CIF) curves and Fine
and Gray models. Both classication systems showed a signicant association with mortality and
exacerbation risk (P < 0.01 for trend). The GOLD classication provided a better separation of Kaplan-
Meier and CIF curves for advanced stages, whereas the STAR classication showed a clearer distinction
between stages I and II. These associations remained consistent after multivariable adjustments.
The GOLD classication was superior for prediction of prognosis in advanced COPD, whereas the
STAR classication provided better dierentiation in early-stage disease. These ndings highlight the
complementary roles of the GOLD and STAR classications in assessment of COPD severity.
Keywords Chronic obstructive pulmonary disease, Forced expiratory volume, Prognosis
1Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan. 2Kirigaoka Tsuda Hospital, Kitakyushu, Japan. 3Department of Respiratory
Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Kitakyushu, Japan.
4Department of Respiratory Medicine, NHO Fukuokahigashi Medical Center, Koga, Japan. 5Department of
Respiratory Medicine, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan. 6Department of Respiratory
Medicine, NHO Fukuoka National Hospital, Fukuoka, Japan. 7Department of Respiratory Medicine, Japan
Community Health Care Organization Kurume General Hospital, Kurume, Japan. 8Division of Respiratory Medicine,
Aso Iizuka Hospital, Iizuka, Japan. 9Department of Respiratory Medicine, Kitakyushu Municipal Medical Center,
Kitakyushu, Japan. 10Department of Respiratory Medicine, Harasanshin Hospital, Fukuoka, Japan. 11Department
of Respiratory Medicine, Fukuoka University Chikushi Hospital, Chikushino, Japan. 12Department of Respiratory
Medicine, Hamanomachi Hospital, Fukuoka, Japan. 13Department of Respiratory Medicine, NHO Omuta National
Hospital, Omuta, Japan. 14Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka,
Japan. 15Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu,
Japan. 16Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume
University School of Medicine, Kurume, Japan. 17Kitakyushu City Hospital Organization, Kitakyushu, Japan. email:
ogata.hiroaki.626@m.kyushu-u.ac.jp
OPEN
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Abbreviations
COPD chronic obstructive pulmonary disease
GOLD Global Initiative for Chronic Obstructive Lung Disease
pp percent predicted
FEV1 forced expiratory volume in 1s
STAR STaging of Airow obstruction by Ratio
FVC forced vital capacity
OS overall survival
ICS inhaled corticosteroid
LABD long-acting bronchodilator
LAMA long-acting muscarinic antagonists
LABA long-acting β2-agonists
BMI body mass index
CRP C-reactive protein
CVD cardiovascular disease
ADO age, dyspnea, and airow obstruction
mADO modied ADO
HR hazard ratio
95% CI 95% condence interval
CIF cumulative incidence function
SHR subdistribution hazard ratio
BODE BMI, airow obstruction, dyspnea, and exercise capacity
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder associated with a risk of
exacerbation and mortality, with accurate assessment of its severity being essential for optimization of treatment
strategy and the appropriate allocation of medical resources1. e Global Initiative for Chronic Obstructive
Lung Disease (GOLD) classication is based on percent predicted forced expiratory volume in 1s (ppFEV1) and
has been widely adopted for such assessment1. Several studies have shown that GOLD staging, or its dening
factor ppFEV1, is strongly associated with mortality risk2–5. However, the lack of a signicant survival dierence
between patients with COPD stage I and healthy individuals6,7 is a key limitation of this classication that has
raised concerns about its sensitivity for capturing disease severity at early stages.
e STaging of Airow obstruction by Ratio (STAR) system, based on the ratio of FEV1 to forced vital
capacity (FVC), was recently proposed as an alternative classication for COPD severity6. is system may
better reect early-stage airow limitation because it identies COPD stage I patients as having worse survival
than healthy individuals. However, few studies have directly assessed the prognostic performance of the GOLD
and STAR classications for COPD patients. Large-scale cohort studies have reported similar prediction abilities
for overall survival (OS) between the two classications6–8, whereas a single-center study suggested that GOLD
provided better separation of survival curves across stages9. It has therefore remained unclear which system
more eectively predicts COPD outcome.
Given this background, we aimed to evaluate and compare the prognostic performance of the GOLD and
STAR classications in a multicenter cohort of COPD patients according to a 5-year prospective study design.
Methods
Study design and population
is prospective, multicenter observational study was performed at 29 general hospitals in the Fukuoka
Tobacco-Related Lung Disease registry study group10–12. e cohort initially included 374 individuals with
COPD who were aged ≥ 20 years, consented to participate in the study between 1 September 2013 and 30 April
2016, and were followed longitudinally for 5 years. Aer exclusion of four individuals without smoking pack-
year information, the remaining 370 patients were enrolled in the study. COPD was diagnosed according to
the criteria of GOLD, with a cuto based on an FEV1/FVC ratio of < 70%1. Participants were divided into four
groups on the basis of GOLD stage: stage I (n = 57), ppFEV1 ≥ 80%; stage II (n = 137), 50% ≤ ppFEV1 < 80%;
stage III (n = 109), 30% ≤ ppFEV1 < 50%; and stage IV (n = 67), ppFEV1 < 30%1. ey were also analyzed by
assignment to four additional groups according to STAR grading: stage I (n = 87), 60% ≤ FEV1/FVC < 70%; stage
II (n = 98), 50% ≤ FEV1/FVC < 60%; stage III (n = 88), 40% ≤ FEV1/FVC < 50%; and stage IV (n = 97), FEV1/
FVC < 40%6. e distributions of patients by disease severity according to GOLD and STAR stages are shown in
Figure S1 in the Supporting Information.
Clinical evaluation and laboratory measurements
Each participant completed a self-administered questionnaire regarding their smoking habits, inhalational
treatment, and history of asthma. On the basis of smoking habits, individuals were categorized as never smokers
or current/former smokers. Given that smoking exposure levels were not normally distributed, we established
three groups: 0 pack years, 0 < pack years < 20, and ≥20 pack years. Information on the presence or absence of
prescriptions for inhaled corticosteroid (ICS) and long-acting bronchodilator (LABD) medications was collected
with regard to inhalation therapy. LABDs included long-acting muscarinic antagonists (LAMAs) and long-acting
β2-agonists (LABAs). Body mass index (BMI) was calculated as body weight/height2. Pulmonary function tests
were performed according to the guidelines of the American oracic Society/European Respiratory Society13,
with all values recorded without bronchodilator inhalation. Predicted values of FEV1 were calculated with a
reference equation provided by the Japan Respiratory Society in 201414. Blood tests were performed at the time
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of study inclusion to obtain data on C-reactive protein (CRP) concentration. Positive CRP status was dened
as a CRP level of ≥ 0.30 mg/dL15. Follow-up surveillance was conducted annually for 5 years to assess mortality.
Causes of death were evaluated and classied into six categories: respiratory disease, cardiovascular disease
(CVD), infectious disease, primary lung cancer, other malignancies, and other/unspecied causes. Respiratory
disease–related deaths included exacerbation of COPD and pneumonia, given that they oen overlapped,
making it dicult to determine denitively which was the actual cause of death. Deaths due to infectious
disease did not include pneumonia-related mortality. CVD-related deaths were dened as deaths resulting from
myocardial infarction, chronic heart failure, pulmonary hypertension, aortic disease, or other cardiovascular
events. Neoplasm-related deaths were divided into deaths from primary lung cancer and other malignancies.
Moderate or severe exacerbations of COPD were dened as exacerbation events of COPD requiring the use of
systemic steroids or antibiotics (or both), according to GOLD criteria1. Among the 303 patients with available
modied Medical Research Council scale data, the age, dyspnea, and airow obstruction (ADO) index was
calculated16, and patients were classied into four groups according to ADO quartiles: 0–3, 4, 5, and ≥ 6. A
modied ADO (mADO) index, in which the FEV1/FVC ratio was used instead of ppFEV16, was also assessed in
the same population, and patients were similarly categorized into four groups based on mADO quartiles: 0–3,
4, 5, and ≥ 6.
Statistical analysis
All statistical analysis was performed with R soware version 4.4.0 (R Foundation for Statistical Computing,
Vienna, Austria). A two-sided P value of < 0.05 was considered to indicate statistical signicance. For baseline
characteristics, heterogeneity among COPD severity stages (GOLD and STAR stages) was evaluated with
the chi-square test (or Monte Carlo simulations), one-way analysis of variance, or the Kruskal-Wallis test.
Concordance between the GOLD and STAR severity classication schemes was assessed descriptively with a
Bangdiwala plot and quantied for agreement between multiple classes with the weighted Bangdiwala B value,
which adjusts for the frequency of each severity class17,18. Kaplan-Meier curves were constructed to depict OS
for each GOLD stage group. Linear trends in the association between GOLD stages and OS were estimated
as hazard ratios (HRs) and 95% condence intervals (CIs) with both unadjusted and multivariable-adjusted
Cox proportional hazards models. Adjustments were made for age, sex, BMI, smoking exposure level, use of
an ICS, use of an LABD, history of asthma, and CRP level. Pairwise comparisons of mortality risk between
groups were performed with Bonferroni correction to account for multiple comparisons. Given that post hoc
comparisons were performed for six pairs in the four-group analysis (among GOLD stages I–IV), the 95% CIs
were adjusted to 99.17% with Bonferroni correction. A trend in the relation between the GOLD classication
and cause-specic death rates was evaluated with Cox proportional hazards models. Mortality due to respiratory
disease, the leading cause of death in the cohort, was examined across GOLD stages with multivariable-adjusted
Cox proportional hazards models, and with post hoc pairwise comparisons being conducted with the use of
Bonferroni correction. With consideration of death as a competing risk, cumulative incidence function (CIF)
curves were generated to depict the incidence of moderate or severe exacerbation across GOLD stage groups.
e association between the GOLD classication and the risk of moderate or severe exacerbation of COPD
was estimated as a subdistribution hazard ratio (SHR) with the Fine and Gray proportional subdistribution
hazards model. For multivariable adjustment, the adjustment factors were the same as those adopted in the
Cox proportional hazards analysis mentioned above. Post hoc pairwise comparisons were performed with
Bonferroni correction. In the same manner, we investigated the association between STAR stages and mortality
or exacerbation risk with application of the relevant models.
Stratied analysis according to the presence or absence of inhalation therapy was conducted, accounting
for dierences in usage frequency across the severity stages of the GOLD and STAR classications. In the
multivariable-adjusted Cox proportional hazards analysis, all of the aforementioned potential confounders,
with the exception of prescriptions for ICS and LABD medications, were included. When investigating the
associations of the ADO and mADO indices with all-cause mortality and exacerbation risk, Cox proportional
hazards models and Fine–Gray proportional subdistribution hazards models were used. Adjustments were made
for sex, BMI, smoking exposure level, use of an ICS, use of an LABD, history of asthma, and CRP level. Age was
not included as a covariate because it is already incorporated into both the ADO and mADO indices. Post hoc
pairwise comparisons were conducted with Bonferroni correction.
Results
Demographic and clinical characteristics stratied by GOLD stage
Table S1 in the Supporting Information summarizes the demographic and clinical characteristics of the study
cohort. e majority of subjects were male, had a history of smoking, and were prescribed LABD. Approximately
half of the cohort were users of ICS. e mean values of ppFEV1 and FEV1/FVC were 53.9% and 48.9%,
respectively.
Stratication of the study cohort according to GOLD severity stages revealed that mean BMI decreased
progressively from stages I to IV (23.2, 22.3, 21.7, and 20.3 kg/m2, respectively; P < 0.01 for heterogeneity)
(Table1). e frequency of individuals with a history of asthma was highest for stage III and lowest for stage
I (8.8%, 15.3%, 26.6%, and 14.9% for stages I–IV, respectively; P = 0.01 for heterogeneity). ICS and LABD
mediations were prescribed more frequently in stages III and IV (ICS, 65.1% and 74.6%; LABD, 96.3% and
94.0%, respectively) compared with stages I and II (ICS, 29.8% and 39.4%; LABD, 77.2% and 89.1%, respectively),
with P < 0.01 for heterogeneity in each instance. With regard to LABD prescriptions, higher disease stages
were associated with an increased preference for LAMA/LABA combination therapy over LAMA or LABA
monotherapy. Mean values of FEV1, ppFEV1, and FEV1/FVC decreased with stage progression (P < 0.01 for
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heterogeneity in each case). e proportions of males and smokers, mean age, median smoking pack-years, and
CRP level did not dier signicantly among stages.
Demographic and clinical characteristics stratied by STAR stage
Demographic and clinical characteristics according to STAR severity stages are summarized in Table2. Similar
to the results for the GOLD classication, mean values of BMI, FEV1, ppFEV1, and FEV1/FVC decreased
progressively from STAR stages I to IV (P < 0.01 for heterogeneity in each instance). Prescriptions for ICS and
LABD mediations also increased signicantly with STAR stage progression (ICS, 33.3%, 43.9%, 58.0%, and
71.1%; LABD, 81.6%, 89.8%, 92.0%, and 96.9% for stages I–IV, respectively, with P < 0.01 for heterogeneity
in each case). As the STAR stage increased, a greater proportion of patients were prescribed LAMA/LABA
combination therapy. Unlike the GOLD classication, however, no signicant dierence was apparent among
STAR stages for the frequency of individuals with a history of asthma (P = 0.33 for heterogeneity). ere were
also no statistically signicant dierences in age, sex distribution, smoking exposure, or CRP level.
A Bangdiwala plot for agreement between GOLD and STAR severity stages is shown in Figure S2 in the
Supporting Information. e agreement (weighted Bandiwala B value) between the two classication systems
was 0.85.
Association between GOLD and STAR stages and mortality
e median follow-up period was 5.0 years, and 48 participants (13.0% of the entire cohort) died during follow-
up. e all-cause mortality rate (per 1000 person-years) for GOLD stages I to IV was 11.6, 11.7, 34.7, and 87.6,
respectively. Kaplan-Meier curves (Fig.1A) revealed a signicant trend for all-cause mortality among GOLD
stages (P < 0.01 for trend). OS for stages I, II, or III was signicantly longer than that for stage IV (adjusted P
value of < 0.01 for stages I and II and of 0.02 for stage III versus stage IV). However, Kaplan-Meier curves for
stages I and II overlapped substantially. e tendency for death rate across GOLD stages was broadly consistent
regardless of prescription status for inhalation therapy, with P < 0.01 for trend in each instance (Figure S3 in the
Supporting Information). Among individuals receiving inhaler treatment, the mortality rate for stages I, II, or
III was more favorable than that for stage IV (adjusted P value of 0.04 for stage I, < 0.01 for stage II, and 0.03 for
stage III versus stage IV), although the survival curve for stage I was paradoxically below that for stage II.
Cox proportional hazards analysis adjusted for multiple variables revealed that the association between OS
and GOLD stages remained signicant (P < 0.01 for trend). Compared with stage IV, multivariable-adjusted HRs
for stages I to III were all signicantly lower (HR [adjusted CI] and adjusted P of 0.13 [0.02–0.77] and 0.01, 0.12
[0.03–0.41] and < 0.01, and 0.34 [0.14–0.83] and < 0.01, respectively) (Fig.2).
Cause-specic mortality according to GOLD stage is summarized in Table S2 in the Supporting Information.
Most deaths were related to respiratory disease, the death rate for which increased with stage progression
(3.9, 3.4, 13.0, and 51.8 per 1000 person-years for stages I–IV, respectively; P < 0.01 for trend). is positive
Characteristic
Mean (SD), median [IQR], or frequency
P for heterogeneity
Stage I
(n = 57) Stage II
(n = 137) Stage III
(n = 109) Stage IV
(n = 67)
Male (%) 93.0 88.3 83.5 86.6 0.36*
Age (years) 69.9 (7.9) 72.2 (7.9) 72.8 (8.3) 70.8 (8.3) 0.10
BMI (kg/m2) 23.2 (3.3) 22.3 (3.1) 21.7 (3.5) 20.3 (4.0) < 0.01
Current or former smoker (%) 96.5 97.8 99.1 97.0 0.77*
Smoking exposure (pack-years) 45.0 [30.0, 82.5] 50.0 [35.0, 75.0] 50.0 [40.0, 70.5] 55.0 [40.0, 79.0] 0.49
History of asthma (%) 8.8 15.3 26.6 14.9 0.01*
ICS use (%) 29.8 39.4 65.1 74.6 < 0.01
LABD use (%) 77.2 89.1 96.3 94.0 < 0.01*
LAMA use (%) 26.3 17.5 13.8 6.0 0.02*
LABA use (%) 21.1 21.9 22.0 13.4 0.50
LAMA/LABA use (%) 29.8 49.6 60.6 74.6 < 0.01
FEV1 (L) 2.4 (0.4) 1.6 (0.3) 1.0 (0.2) 0.6 (0.1) < 0.01
ppFEV1 (%) 90.9 (8.6) 64.0 (8.7) 40.7 (5.5) 23.2 (4.3) < 0.01
FEV1/FVC (%) 63.1 (4.9) 54.8 (8.2) 43.1 (9.2) 34.2 (9.8) < 0.01
CRP (mg/dL) 0.1 [0.0, 0.4] 0.1 [0.0, 0.2] 0.1 [0.1, 0.4] 0.1 [0.1, 0.4] 0.36
Table 1. Demographic and clinical characteristics according to GOLD stages. Abbreviations: GOLD, Global
Initiative for Chronic Obstructive Lung Disease; SD, standard deviation; IQR, interquartile range; BMI, body
mass index; ICS, inhaled corticosteroid; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic
antagonist; LABA, long-acting β2-agonist; FEV1, forced expiratory volume in 1s; ppFEV1, percent predicted
FEV1; FVC, forced vital capacity; CRP, C-reactive protein. Age, BMI, FEV1, ppFEV1, and FEV1/FVC are
presented as mean (SD), whereas smoking exposure and CRP level are presented as median [IQR] because of a
skewed distribution. Other variables are given as percentages. *Monte Carlo simulations were used instead of
the chi-square test when expected frequencies were < 5 subjects.
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trend in the association of the GOLD classication with respiratory disease–related death remained apparent
aer multivariable adjustment (P < 0.01 for trend). e multivariable-adjusted HRs for stages II and III were
signicantly lower than that for stage IV (HR [adjusted CI] and adjusted P of 0.08 [0.01–0.66] and 0.10, and 0.25
[0.06–0.99] and 0.048 for stages II and III, respectively) (Figure S4 in the Supporting Information).
Regarding the STAR classication, all-cause mortality rate (per 1000 person-years) was 13.1, 21.6, 32.5, and
54.9 for stages I to IV, respectively. As was the case for the GOLD classication system, there was a signicant
trend for OS according to STAR stages (P < 0.01 for trend). Of note, and in contrast to the results for GOLD
stages, the survival curve for STAR stage I was mostly higher than that for stage II, although the dierence was
not statistically signicant. Bonferroni-adjusted P values for all-cause death rates relative to stage IV were 0.02
for stage I, 0.11 for stage II, and 0.84 for stage III (Fig.1B). A similar trend in death rates was observed across
STAR stages regardless of prescription status for inhalation therapy (P < 0.01 for trend among individuals with
inhalation therapy, and P = 0.02 for trend among those without), although no statistically signicant dierences
were observed between stages I, II, or III and stage IV (Figure S5 in the Supporting Information).
e positive linear association between STAR stages and all-cause mortality was robust aer adjustment
for possible confounders (P < 0.01 for trend). Although multivariable-adjusted HRs for stages I to III were not
signicantly decreased compared with stage IV, a gradual progression of HRs was apparent (Fig.2).
e incidence of respiratory disease–related death, which accounted for most mortality, also increased
signicantly with STAR stage progression (P < 0.01 for trend) (Table S3 in the Supporting Information). is
positive trend also remained signicant aer multivariable adjustment (P < 0.01 for trend). However, the HRs
for stages I, II, and III were not signicantly dierent from that for stage IV (Figure S4 in the Supporting
Information).
Association between GOLD and STAR stages and exacerbation risk
During the follow-up period, 91 individuals (24.6% of the cohort) experienced moderate to severe exacerbations
of COPD. Similar to the case for OS, CIF curves revealed a positive trend for the cumulative incidence of
exacerbations among GOLD stages (P < 0.01 for trend; adjusted P < 0.01 for stages I, II, or III versus stage IV),
although the CIF curves for stages I and II were closely aligned (Fig.3A). e results remained unchanged aer
multivariable adjustment, with the multivariable-adjusted SHRs for stages I, II, and III being signicantly lower
than that for stage IV (SHR [adjusted CI] and adjusted P of 0.11 [0.02–0.51] and < 0.01, 0.13 [0.05–0.35] and
< 0.01, and 0.40 [0.20–0.79] and < 0.01 for stages I–III, respectively; P < 0.01 for trend) (Fig.4).
e CIF curves for STAR stages also revealed a positive trend (P < 0.01 for trend), with the CIF curve for stage
II being distinctly separated from that for stage I and positioned higher (Fig.3B). Multivariable-adjusted SHRs
also increased gradually with STAR stage progression (P < 0.01 for trend), although only the SHR for stage I was
signicantly lower than that for stage IV (SHR [adjusted CI] of 0.26 [0.08–0.85]) (Fig.4).
Characteristic
Mean (SD), median [IQR], or frequency
P for heterogeneity
Stage I
(n = 87) Stage II
(n = 98) Stage III
(n = 88) Stage IV
(n = 97)
Male (%) 90.8 83.7 88.6 86.6 0.51*
Age (years) 70.8 (8.2) 72.9 (7.6) 72.3 (7.4) 70.9 (9.0) 0.19
BMI (kg/m2) 23.0 (3.5) 22.3 (3.5) 21.4 (3.2) 21.0 (3.6) < 0.01
Current or former smoker (%) 98.9 98.0 97.7 96.9 0.92*
Smoking exposure (pack-years) 50.0 [34.5, 82.8] 50.0 [30.0, 73.8] 50.0 [39.0, 60.0] 52.0 [40.0, 80.0] 0.51
History of asthma (%) 11.5 17.3 19.3 21.6 0.33*
ICS use (%) 33.3 43.9 58.0 71.1 < 0.01
LABD use (%) 81.6 89.8 92.0 96.9 < 0.01*
LAMA use (%) 20.7 20.4 14.8 7.2 0.04
LABA use (%) 31.0 16.3 19.3 15.5 0.04
LAMA/LABA use (%) 29.9 53.1 58.0 74.2 < 0.01
FEV1 (L) 2.1 (0.6) 1.5 (0.5) 1.2 (0.4) 0.8 (0.3) < 0.01
ppFEV1 (%) 79.0 (17.6) 60.8 (15.9) 45.8 (14.1) 31.7 (11.0) < 0.01
FEV1/FVC (%) 65.0 (2.8) 55.2 (2.9) 44.7 (3.0) 31.9 (5.1) < 0.01
CRP (mg/dL) 0.1 [0.0, 0.3] 0.1 [0.0, 0.3] 0.1 [0.1, 0.2] 0.1 [0.1, 0.4] 0.23
Table 2. Demographic and clinical characteristics according to STAR stages. Abbreviations: STAR, STaging
of Airow obstruction by Ratio; SD, standard deviation; IQR, interquartile range; BMI, body mass index; ICS,
inhaled corticosteroid; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; LABA,
long-acting β2-agonist; FEV1, forced expiratory volume in 1s; ppFEV1, percent predicted FEV1; FVC, forced
vital capacity; CRP, C-reactive protein. Age, BMI, FEV1, ppFEV1, and FEV1/FVC are presented as mean (SD),
whereas smoking exposure and CRP level are presented as median [IQR] because of a skewed distribution.
Other variables are given as percentages. *Monte Carlo simulations were used instead of the chi-square test
when expected frequencies were < 5 subjects.
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Fig. 2. Multivariable-adjusted HRs for all-cause mortality across GOLD and STAR stages. Adjustments were
made for age, sex, body mass index, smoking exposure, use of inhaled corticosteroids, use of long-acting
bronchodilators, history of asthma, and C-reactive protein level. As a result of a nonnormal distribution,
smoking exposure was categorized into three groups: 0 pack-years, 0 < pack-years < 20, and ≥20 pack-years.
C-reactive protein levels were dichotomized as ≥ 0.30 or < 0.30 mg/dL on the basis of their nonnormal
distribution. Abbreviations: HR, hazard ratio; CI, condence interval; GOLD, Global Initiative for Chronic
Obstructive Lung Disease; STAR, STaging of Airow obstruction by Ratio.
Fig. 1. Kaplan-Meier curves of survival probability according to GOLD (A) or STAR (B) severity stages.
Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; STAR, STaging of Airow
obstruction by Ratio.
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Association of ADO and mADO indices with morbidity and mortality
In subjects with available ADO and mADO index data (n = 303), Kaplan–Meier curves, multivariable-adjusted
HRs for all-cause mortality, CIF curves, and multivariable-adjusted SHRs for moderate to severe exacerbations
of COPD stratied by quartiles of each index are presented in Figures S6–S9 of the Supporting Information,
respectively. When stratied by ADO index quartiles, the Kaplan–Meier survival curves and forest plots of
multivariable-adjusted HRs for all-cause mortality appeared similar to those based on the GOLD classication
(Figs.1A and 2), with limited separation between stages I and II. Conversely, the CIF curves and forest plots of
Fig. 4. Multivariable-adjusted SHRs for moderate to severe COPD exacerbations across GOLD and
STAR stages. Adjustments were made for age, sex, body mass index, smoking exposure, use of inhaled
corticosteroids, use of long-acting bronchodilators, history of asthma, and C-reactive protein level. As a result
of a nonnormal distribution, smoking exposure levels were categorized into three groups: 0 pack-years, 0 <
pack-years < 20, and ≥20 pack-years. C-reactive protein levels were dichotomized as ≥ 0.30 or < 0.30 mg/dL on
the basis of their nonnormal distribution. Abbreviations: COPD, chronic obstructive pulmonary disease; SHR,
subdistribution hazard ratio; CI, 95% condence interval; GOLD, Global Initiative for Chronic Obstructive
Lung Disease; STAR, STaging of Airow obstruction by Ratio.
Fig. 3. Cumulative incidence function curves for the probability of moderate to severe COPD exacerbations
according to GOLD (A) or STAR (B) severity stages. Abbreviations: COPD, chronic obstructive pulmonary
disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; STAR, STaging of Airow obstruction
by Ratio.
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multivariable-adjusted SHRs for COPD exacerbations showed more visually apparent dierences in prognosis
between stages I and II compared to the GOLD classication (Figs.3A and 4). However, no signicant dierences
were found between the highest (ADO index ≥ 6) and second-highest (ADO index = 5) quartile groups (crude
analysis: adjusted P = 0.29; multivariable-adjusted analysis: adjusted P = 0.89). e survival and morbidity
patterns observed using mADO index quartiles resembled those of the STAR classication (Figs.1B, 2 and 3B,
and 4), particularly in that clear visual dierences were observed between the lowest (mADO index = 0–3) and
third-highest (mADO index = 4) quartile groups. However, in contrast to the STAR classication, the distinction
between the second-highest (mADO index = 5) and third-highest (mADO index = 4) quartile groups was less
pronounced.
Discussion
Our study has revealed signicant associations of both GOLD and STAR classications with mortality and the
incidence of moderate to severe exacerbations in individuals with COPD. In the case of the GOLD classication,
signicant dierences in all-cause mortality rate and the cumulative incidence of exacerbations were apparent
for stage IV versus stages II and III as well as stage I. In contrast, the STAR classication provided a clearer
distinction between stages I and II, as reected in both the Kaplan-Meier and CIF curves. As far as we are aware,
our study is the rst to prospectively evaluate dierences in prognostic performance between the GOLD and
STAR classications in COPD patients.
Few previous studies have statistically evaluated and compared the prognostic characteristics of the GOLD
and STAR classications for COPD. Large-scale cohort studies—namely the COPDGene Study and the combined
Pittsburgh cohort—as well as population-based research, specically the Rotterdam Study and the National
Health and Nutrition Examination Survey, have reported descriptively similar prognostic performance for the
GOLD and STAR classications, although statistical analysis was not performed6–8. On the other hand, a single-
center study in Japan indicated that the GOLD classication delineated survival curves more distinctly across
stages, which enhanced its prognostic reliability, compared with the STAR classication9. Which staging system
is superior has therefore remained unresolved. In addition, in these previous studies, excluding the COPDGene
Study and Pittsburgh cohort, subjects with COPD were classied into three groups (stage I, stage II, and stages
III–IV) because of the relatively small number of participants with COPD of GOLD or STAR stage III or IV. It
was therefore dicult to assess dierences in prognostic value between GOLD or STAR stages III and IV. In the
present study, the GOLD classication showed more pronounced dierences in prognosis between stage IV and
stages II and III, whereas the STAR classication demonstrated better separation between stages I and II. ese
ndings highlight the importance of selective utilization of the GOLD and STAR classications to improve the
prediction of survival outcome in COPD.
We identied positive trends across stages for both the GOLD and STAR systems with relation to the risk
of moderate to severe COPD exacerbations, mirroring the trends apparent for mortality. ese results are
consistent with previous studies of the GOLD system19,20. In contrast, only one previous study has examined the
association between STAR stages and exacerbation risk6, and its results were consistent with ours. Given that
exacerbation events are well-established surrogate markers for mortality in COPD1,21, it has been reasonable to
assume that STAR stages, like GOLD stages, are also associated with exacerbation risk.
We found that the STAR classication provided clearer distinctions in prognosis between stage I and stage
II, whereas the GOLD classication more eectively distinguished the prognosis of more advanced stages. With
regard to pulmonary function in individuals with COPD, ppFEV1 tends to decline slowly during the early stages
as a result of lung hyperination, whereas FVC increases, leading to a noticeable reduction in the FEV1/FVC
ratio22,23. In contrast, as the disease progresses, an accelerated decline in FVC occurs as a result of increasing
residual volume, leading to a slower decline in FEV1/FVC, whereas ppFEV1 decreases markedly together with
FVC24. STAR, the FEV1/FVC-based classication, may therefore more sensitively reect prognostic gradients
in early-stage COPD, whereas GOLD, the ppFEV1-based classication, may more eectively capture these
gradients in advanced-stage COPD.
e strengths of our study include a relatively balanced distribution of a large number of participants
across GOLD and STAR stages I to IV and an extended follow-up period, which together provided a robust
framework for evaluation of long-term prognosis. However, there are also several potential limitations of our
study. First, both ppFEV1 and FEV1/FVC values were based on a single measurement, which may have led to
misclassication of GOLD and STAR stages and attenuated the observed associations, potentially biasing the
results toward the null hypothesis. Second, it was possible that some participants had asthma-COPD overlap,
given that lung function was measured without bronchodilator administration and data on type 2 inammation
biomarkers (such as blood eosinophil count) were unavailable. However, asthma was adequately dierentiated
by respiratory specialists during cohort enrollment, and a history of asthma was included as a covariate in the
multivariable adjustment model. is limitation is therefore not likely to have altered the study conclusions.
ird, as a consequence of the study design, the frequency of inhaler prescriptions was uneven across stages—
the earlier the stage, the lower the frequency—regardless of whether the system adopted was GOLD or
STAR. is situation might have improved the prognosis of patients with advanced-stage COPD, potentially
attenuating the associations observed in the present study. However, the OS trends across both GOLD and
STAR stages remained broadly consistent regardless of inhaler prescription status, suggesting that the impact
of this limitation on the study results was likely minimal. Fourth, given that the study was not a randomized
controlled trial, residual confounding cannot be entirely ruled out. However, the consistency of results aer
multivariable adjustment is suggestive of a minimal impact on the ndings. Fih, the limited number of deaths
from nonrespiratory causes, including CVD and lung cancer, may have restricted the ability to fully assess
prognostic dierences among GOLD or STAR stages for cause-specic mortality beyond respiratory disease–
related deaths. Sixth, we categorized all users of LAMA, LABA, and LAMA/LABA therapies into a single group
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of LABD users. is approach may have obscured dierences in treatment eects, as LAMA/LABA combination
therapy has been shown to be more eective than monotherapy in reducing exacerbations25,26. However, in
both the GOLD and STAR classications, the proportion of patients receiving LAMA/LABA increased with
the advancing disease stage; the true eect of LABD may have been underestimated in our analysis due to the
fact that all LABD therapies were grouped together. erefore, the overall impact of this potential limitation on
our ndings is likely to be minor. Lastly, due to the lack of data on 6-minute walk distance, we were unable to
assess the BMI, airow obstruction, dyspnea, and exercise capacity (BODE) index for each patient. Instead of
the BODE index, we investigated the associations of the ADO and mADO indices with morbidity and mortality
in COPD, which demonstrated a certain degree of similarity to the GOLD and STAR stages, respectively. We are
currently planning further research to explore the prognostic value of various markers, including but not limited
to the ADO and mADO indices.
Conclusions
In conclusion, our study suggests that the GOLD classication is more eective for prediction of prognosis in
advanced-stage COPD, whereas the STAR classication provides valuable insights into early-stage disease. ese
ndings underscore the complementary roles of the GOLD and STAR classication systems in COPD prognosis.
Further research is warranted to explore how these systems can be integrated or selectively applied to improve
prognostic accuracy and inform treatment strategies.
Data availability
e datasets used and/or analyzed during the current study are available from the corresponding author upon
reasonable request.
Received: 23 April 2025; Accepted: 30 May 2025
References
1. Agustí, A. et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am. J. Respir Crit.
Care Med. 207, 819–837 (2023).
2. Tejero, E. et al. Classication of airow limitation based on z-score underestimates mortality in patients with chronic obstructive
pulmonary disease. Am. J. Respir Crit. Care Med. 196, 298–305 (2017).
3. Cadham, C. J. et al. e prevalence and mortality risks of prism and COPD in the united states from NHANES 2007–2012. Respir
Res. 25, 1–11 (2024).
4. Hansen, E. F., Phanareth, K., Laursen, L. C., Kok-Jensen, A. & Dirksen, A. Reversible and irreversible airow obstruction as
predictor of overall mortality in asthma and chronic obstructive pulmonary disease. Am. J. Respir Crit. Care Med. 159, 1267–1271
(1999).
5. Oga, T., Nishimura, K., Tsukino, M., Sato, S. & Hajiro, T. Analysis of the factors related to mortality in chronic obstructive
pulmonary disease: role of exercise capacity and health status. Am. J. Respir Crit. Care Med. 167, 544–549 (2003).
6. Bhatt, S. P. et al. FEV1/FVC severity stages for chronic obstructive pulmonary disease. Am. J. Respir Crit. Care Med. 208, 676–684
(2023).
7. Bertels, X., Riemann, S., Vauterin, D., Lahousse, L. & Brusselle, G. G. All-cause mortality of staging of airow obstruction by ratio-
categorized patients with chronic obstructive pulmonary disease among the general population. Am. J. Respir Crit. Care Med. 210,
1374–1376 (2024).
8. Backman, H., Vaneteren, L. E. G. W., Mannino, D. M. & Ekström, M. Severity of airow obstruction based on FEV1/FVC vs
FEV1% predicted in the general U.S. Population. Am. J. Respir Crit. Care Med. 210, 1308–1316 (2024).
9. Nishimura, K., Kusunose, M., Shibayama, A. & Nakayasu, K. Comparison of disease severity classications of chronic obstructive
pulmonary disease: GOLD vs. STAR in clinical practice. Diagnostics 14, 1–11 (2024).
10. Ogata-Suetsugu, S. et al. Characteristics of tobacco-related lung diseases in fukuoka prefecture, japan: a prospective, multi-
institutional, observational study. Respir Investig. 58, 74–80 (2020).
11. Tsubouchi, K. et al. Survival and acute exacerbation for patients with idiopathic pulmonary brosis (IPF) or non-IPF idiopathic
interstitial pneumonias: 5-year follow-up analysis of a prospective multi-institutional patient registry. BMJ Open. Respir Res. 10,
e001864 (2023).
12. Takano, T. et al. Update of prognosis and characteristics of chronic obstructive pulmonary disease in a real-world setting: a 5-year
follow-up analysis of a multi-institutional registry. BMC Pulm Med. 24, 556 (2024).
13. Graham, B. L. et al. Standardization of spirometry 2019 update. An ocial american thoracic society and european respiratory
society technical statement. Am. J. Respir Crit. Care Med. 200, E70–E88 (2019).
14. Kubota, M. et al. Reference values for spirometry, including vital capacity, in japanese adults calculated with the LMS method and
compared with previous values. Respir Investig. 52, 242–250 (2014).
15. Shine, B., de Beer, F. C. & Pepys, M. B. Solid phase radioimmunoassays for human C-reactive protein. Clin. Chim. Acta. 117, 13–23
(1981).
16. Puhan, M. A. et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated
BODE index and the ADO index. Lancet 374, 704–711 (2009).
17. Bangdiwala, S. I., Haedo, A. S., Natal, M. L. & Villaveces, A. e agreement chart as an alternative to the receiver-operating
characteristic curve for diagnostic tests. J. Clin. Epidemiol. 61, 866–874 (2008).
18. Bangdiwala, S. I. & Shankar, V. e agreement chart. BMC Med. Res. Methodol. 13, 97 (2013).
19. Han, M. K. et al. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS
cohort. Lancet Respir Med. 5, 619–626 (2017).
20. Hurst, J. R. et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl. J. Med. 363, 1128–1138 (2010).
21. Soler-Cataluña, J. J. et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. orax
60, 925–931 (2005).
22. Deesomchok, A. et al. Lung hyperination and its reversibility in patients with airway obstruction of varying severity. COPD J.
Chronic Obstr. Pulm Dis. 7, 428–437 (2010).
23. Gagnon, P. et al. Walking exercise response to bronchodilation in mild COPD: a randomized trial. Respir Med. 106, 1695–1705
(2012).
24. Culver, B. H. Obstructive? Restrictive? Or a ventilatory impairment? Chest 140, 568–569 (2011).
Scientic Reports | (2025) 15:19097 9
| https://doi.org/10.1038/s41598-025-05033-w
www.nature.com/scientificreports/
25. Wedzicha, J. A. et al. Tiotropium/olodaterol decreases exacerbation rates compared with tiotropium in a range of patients with
COPD: pooled analysis of the TONADO®/DYNAGITO® trials. Adv. er. 37, 4266–4279 (2020).
26. Sion, K. Y. J., Huisman, E. L., Punekar, Y. S., Naya, I. & Ismaila, A. S. A network meta-analysis of long-acting muscarinic antagonist
(LAMA) and long-acting β2-agonist (LABA) combinations in COPD. Pulm er. 3, 297–316 (2017).
Acknowledgements
We thank the study patients, their families, and all of the investigators participating in the Fukuoka Tobacco-Re-
lated Lung Disease (FOLD) registry group, as well as Clinical Research Support Center Kyushu for their ocial
work on the study.
Author contributions
H.O., K. Tsubouchi, T.T., and I.O. contributed to the literature search, gure preparation, study design, data
collection, data analysis, data interpretation, and writing of the manuscript. Y.N. contributed to the literature
search, study design, data collection, and data interpretation. K.I., R.T., S.T., N.N., M.Y., Y.K., K. Tobino, E.H.,
H.W., H.I., T.M., M.K., M.F., K.Y., and Y.Z. contributed to the literature search, data collection, and data inter-
pretation. All authors approved the nal version of the manuscript. H.O. accepts full responsibility for the work
and conduct of the study, had access to the data, and controlled the decision to publish.
Funding
is study was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology of
Japan; by the Broad-Area, Network-Based Project to Drive Clinical Research at Kyushu University Hospital; by
a grant to the Diuse Lung Diseases Research Group from the Ministry of Health, Labor, and Welfare of Japan;
and by a grant from the Clinical Research Promotion Foundation 2024 of Japan.
Declarations
Ethics approval and consent to participate
is prospective, multicenter observational study was approved by the Institutional Review Board of Kyushu
University (#25–135, 23 August 2013; #555-00, 27 August 2013) and by the institutional review boards of all
participating hospitals. Written informed consent was obtained from all participants. All study procedures
were performed according to the ethical standards in the Declaration of Helsinki.
Competing interests
K.Tsubouchi has received grants from Nippon Boehringer Ingelheim. S.T. has received personal fees from
AstraZeneca, Boehringer Ingelheim Japan, Novartis Pharma, Sano, Bristol-Meyers Squibb, GlaxoSmithKline,
Teijin Pharma, and Kyorin Pharmaceutical. K.Y. has received grants and personal fees from Chugai
Pharmaceutical Co, Eli Lilly Japan K.K., TAIHO Phamaceutical Co., Ltd., Daiichi Sankyo Company, Limited.,
Shionogi & Co., Ltd., Insmed Incorporated., Nippon Boehringer Ingelheim Co. Ltd., Takeda Pharmaceutical
Company Limited., and GlaxoSmithKline K.K.; grants from Sumitomo Pharma Co., Ltd., Kyowa Kirin Co.,
Ltd., FUJIFILM Toyama Chemical Co., Ltd., and TEIJIN HEALTHCARE LIMITED.; and personal fees from
Sano K.K., KYORIN Pharmaceutical Co.,Ltd., Novartis Pharma K.K., Teijin Home Healthcare Limited.,
Asahi Kasei Pharma Corporation., AstraZeneca K.K., ONO PHARMACEUTICAL CO., LTD., MSD K.K,
TOA EIYO LTD., and Meiji Seika Pharma Co., Ltd. Y.Z. has received personal fees from Nippon Boehringer
Ingelheim Co. Ltd. I.O. has received grants and personal fees from Daiichi Sankyo, Chugai Pharma, Eli Lilly
Japan, AstraZeneca, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, and Ono Pharmaceutical; grants
from Bristol-Myers Squibb and MSD Oncology; and personal fees from Takeda Pharmaceutical and Novartis
Pharma. All other authors declare that they have no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at h t t p s : / / d o i . o r g / 1
0 . 1 0 3 8 / s 4 1 5 9 8 - 0 2 5 - 0 5 0 3 3 - w .
Correspondence and requests for materials should be addressed to H.O.
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