Abstract
Background
Although the efficacy of triple therapy in treating chronic obstructive pulmonary disease (COPD) patients with a history of exacerbation is well established in groups with frequent exacerbations, less research has been conducted on its use in group B. Here, we investigated the effects of triple therapy on COPD patients with low eosinophil counts in the context of the current management of group B.
Methods
Using data from the Korean COPD Subtype Study (KOCOSS), we selected patients with blood eosinophil count (BEC) less than 300 cells/μL as non-eosinophilic COPD groups. The study evaluated the effect of a triple therapy group (combination of inhaled corticosteroid, a long-acting β2-agonist [LABA] and a long-acting muscarinic antagonist [LAMA]) and a dual therapy group (LABA/LAMA) on moderate-to-severe exacerbations, as well as longitudinal changes in lung function over 3 years in patients categorized as Global Initiative for Chronic Obstructive Lung Disease (GOLD) B.
Results
Of the 328 non-eosinophilic COPD group B, 145 (44.2%) patients were in triple therapy and 183 (55.8%) patients were in dual therapy. Triple therapy group showed an increased risk of moderate-to-severe exacerbation in multivariate adjusted model (adjusted incidence rate ratio of annual rate, 2.04; 95% confidence interval, 1.45 to 2.84; P < 0.001). Similarly, restricted cubic spline regression analysis of annual rates of moderate-to-severe exacerbations suggested an increased risk associated with the triple therapy over dual therapy in BEC lower than 300 cells/μL. There was no significant difference in the adjusted rate of forced expiratory volume in 1 second decline between triple therapy group and dual therapy group (−10.0 [−39.8 to –19.7] mL/year vs. 22.3 [−4.4 to −49.0] mL/year, P for interaction = 0.888)
Conclusion
In conclusion, our research suggests that triple therapy was associated with a higher risk of moderate-to-severe exacerbations in non-eosinophilic COPD categorized as GOLD B compared with dual therapy.
Keywords: Pulmonary Disease, Chronic Obstructive; Bronchodilator Agents; KOCOSS Cohort; Registries
Graphical Abstract
INTRODUCTION
Pharmacological treatment with long-acting bronchodilators plays a key role in the management of chronic obstructive pulmonary disease (COPD). The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report highlighted the role of inhalers as pharmacotherapy in reducing the risk of exacerbations and the rate of decline in lung function. Further research is needed to develop a strategy for selecting patients for an appropriate inhaler.1
The GOLD 2024 report recommends triple combination therapy with inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA) in patients with a blood eosinophil count (BEC) greater than 300 cells/µL or in patients with recurrent exacerbations who were previously prescribed LABA/LAMA. Contrary to group E, a combination of LABA/LAMA is recommended for group B, which experiences one or fewer moderate exacerbations.1 This proposal is based on previous studies showing that LABA/LAMA reduces exacerbation risk,2 is as effective as ICS/LABA and has less pneumonia risk.3 Also, recent real-world studies showed ICS-containing regimens incur higher medical costs, suggesting against their initial use.4
ICS prescriptions are commonly used in the treatment of COPD patients in many countries.5,6,7 According to a study by Kim et al.,8 approximately 40% of Korean COPD patients use ICS-containing inhalers. While ICS inhalers are frequently prescribed for COPD, their role in group B, which makes up the majority of COPD patients,9 remains unclear. Considering that a previous study found no association between ICS use and acute exacerbation during a 1-year follow-up in group A patients,10 we extended our research to include patients with non-eosinophilic COPD in group B.
In this study, we used real-world data to investigate the impact of ICS treatment on groups A and B in patients with low eosinophilic COPD. We examined the effects of ICS-containing inhalers and LABA/LAMA through longitudinal changes in lung function and clinical outcomes of acute exacerbations.
METHODS
Definition and stratification of the study population
We analyzed data from the Korean COPD Subtype Study (KOCOSS) cohort,11 which is the largest multicenter prospective cohort study of patients with COPD in South Korea. In this study, we extracted the KOCOSS data from a cohort of patients enrolled between 2005 and 2019.
The classification into groups A, B, and E was based on the GOLD 2024.1 Patients who had two or more moderate exacerbations or at least one exacerbation requiring hospitalization were classified as group E and excluded from the analysis.
In this study, eosinophilic COPD was defined as a BEC greater than 300 cells/μL based on the blood test taken at the beginning of enrollment.12 Additionally, we conducted a subgroup analysis to compare the clinical characteristics of groups with less than 100 cells/μL, between 100 and 300 cells/μL, and more than 300 cells/μL.
The definition of inhaler use was based on baseline data. Triple therapy groups were defined as patients prescribed ICS/LABA with LAMA, LABA/LAMA with ICS (multi-inhaler triple therapy, MITT), or ICS/LABA/LAMA (single-inhaler triple therapy, SITT). The LABA/LAMA group included patients prescribed a LABA/LAMA fixed combination or those using both LABA and LAMA, excluding ICS-containing inhaler users.
The inclusion criteria and number of patients included in the study are described in Fig. 1.
Fig. 1. Flow chart of study population selection.
KOCOSS = Korean Chronic Obstructive Pulmonary Disease Subtype Study, BD = bronchodilator, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, GOLD = Global Initiative for Chronic Obstructive Lung Disease, ICS = inhaled corticosteroid, LABA = long-acting beta agonist, LAMA = long-acting muscarinic antagonist.
Data collection
Baseline sociodemographic information included age, sex, smoking history, body mass index (BMI), and the Charlson Comorbidity Index (CCI). In terms of clinical characteristics, the modified Medical Round Council (mMRC) scale, acute exacerbations in the previous year, pulmonary function test (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], residual volume/total lung capacity [RV/TLC], and diffusing capacity of the lungs for carbon monoxide [DLCO]), and eosinophil count (calculated as the percentage of eosinophils within total white blood cells) were included. Quality of life was assessed using the COPD-specific version of St. George’s Respiratory Questionnaire (SGRQ-C) and the Chronic Obstructive Pulmonary Disease Assessment Test (CAT). Acute exacerbations were defined as recent worsening of symptoms classified as moderate, requiring treatment with steroids or antibiotics (moderate), or severe, requiring hospital admission or emergency department visits. Each acute exacerbation event was recorded using a questionnaire administered during regular visits. In addition, to reduce recall bias, exacerbation history was supplemented through linkages with healthcare insurance claims data.
Study outcomes
In this study, we evaluated the clinical outcomes of inhaler use from 2 perspectives: moderate-to-severe acute exacerbations and lung function decline. Acute exacerbation was defined as an acute worsening of respiratory symptoms requiring additional treatment.1 The clinical outcome was the occurrence of acute exacerbations of COPD and the frequency of acute exacerbations, calculated as the annualized frequency of exacerbations, to compare the differences between the inhaler regimens. We also examined longitudinal changes in spirometric data, specifically FEV1 and FVC, according to the inhaler regimen.
Statistical analysis
To compare baseline characteristics, categorical variables were compared using the χ2 test and the Fisher exact test, and continuous variables were compared using the Student’s t-test and Wilcoxon rank-sum analysis. Logistic regression analysis was used to estimate the risk of acute exacerbation (AE) of COPD. The Poisson or negative binomial regression analyses were used to compare the frequency of AE-COPD. We conducted a multilevel mixed-effects linear regression analysis to analyze longitudinal changes in lung function and COPD symptom scores. In the multivariate model, each outcome was adjusted for age, sex, BMI, total pack-years of smoking, baseline trough FEV1, history of moderate-to-severe exacerbations in the year before enrollment, and the total SGRQ score. Restricted cubic spline analysis using the R package rms was used to analyze the association between the incidence rate ratio of eosinophil count and inhaler use. STATA (Ver 17; StataCorp, College Station, TX, USA), R studio (Ver 2023; RStudio, Inc., Boston, MA, USA), and R software (Ver 4.3.2; The R Foundation for Computing, Vienna, Austria) were used for the statistical analyses.
Ethics statement
The KOCOSS study protocols were approved by the Institutional Review Board (IRB) of each of the 54 participating hospitals, including the IRB of the authors’ hospital (IRB No. VHS-2023-07-005 & IRB No. KHH1010338). Written informed consent was obtained from all patients at the time of enrollment, and patient information was anonymized to protect their privacy.
RESULTS
Of the 3,476 patients registered in the KOCOSS, 328 GOLD B patients with a BEC < 300 cells/μL were analyzed. Fig. 1 depicts the patient selection flow, and Supplementary Fig. 1 shows a histogram of eosinophil count distribution in the study population. The median eosinophil count in the study population was 166.4 cells/μL. Of the 328 patients, 145 (44.2%) were administered triple therapy (ICS/LABA/LAMA), and 183 (55.8%) were treated with dual therapy (LABA/LAMA).
Demographic and clinical characteristics of the study population
Table 1 compares the characteristics of the patient groups based on inhaler therapy. The triple therapy group exhibited significantly higher mMRC dyspnea scale and total SGRQ scores. Additionally, a greater proportion of patients in this group had a history of moderate exacerbations in previous years. Furthermore, the triple therapy group demonstrated a significantly lower FEV1 FVC and higher RV/TLC.
Table 1. Baseline characteristics of the study population.
| Characteristics | Overall (N = 328) | Triple group (n = 145) | Dual group (n = 183) | P value | |
|---|---|---|---|---|---|
| Mean age, yr | 69.5 ± 7.4 | 69.3 ± 7.4 | 69.7 ± 7.4 | 0.792 | |
| Sex | 0.207 | ||||
| Male | 311 (94.8%) | 140 (96.6%) | 171 (93.4%) | ||
| Smoking | 0.198 | ||||
| Ex-smoker | 229 (69.8%) | 105 (72.4%) | 124 (67.8%) | ||
| Current smoker | 79 (24.1%) | 35 (24.1%) | 44 (24.0%) | ||
| Pack-years | 42.6 ± 26.7 | 43.8 ± 27.3 | 41.6 ± 26.3 | 0.560 | |
| BMI, kg/m2 | 22.9 ± 3.3 | 22.6 ± 3.2 | 23.1 ± 3.3 | 0.226 | |
| mMRC dyspnea scale score | 1.6 ± 0.9 | 1.8 ± 0.9 | 1.4 ± 0.9 | < 0.001*** | |
| CAT total score | 17.5 ± 6.8 | 17.9 ± 6.8 | 17.1 ± 6.7 | 0.223 | |
| SGRQ total score | 40.2 ± 20.2 | 42.7 ± 20.6 | 38.1 ± 19.7 | 0.0269* | |
| Total CCI score | 0.3 ± 0.6 | 0.3 ± 0.6 | 0.3 ± 0.6 | 0.811 | |
| History of moderate exacerbation | 54 (16.5%) | 33 (22.8%) | 21 (11.5%) | 0.0062** | |
| Frequency of moderate exacerbation in previous year | 0.2 ± 0.4 | 0.2 ± 0.4 | 0.2 ± 0.4 | 0.696 | |
| PDE4 inhibitor | 33 (10.1%) | 14 (9.7%) | 19 (10.4%) | 0.828 | |
| Pre BD FEV1, absolute, L | 1.4 ± 0.5 | 1.3 ± 0.4 | 1.6 ± 0.6 | < 0.001*** | |
| Pre BD FEV1, % predicted | 50.4 ± 17.3 | 44.8 ± 14.5 | 54.9 ± 18.1 | < 0.001*** | |
| Pre BD FVC, absolute, L | 3.1 ± 0.8 | 3.0 ± 0.8 | 3.2 ± 0.8 | 0.004** | |
| Pre BD FVC, % predicted | 76.5 ± 17.2 | 72.6 ± 16.5 | 79.6 ± 17.1 | < 0.001*** | |
| DLCO, % predicted | 60.7 ± 19.4 | 59.8 ± 20.1 | 61.4 ± 18.8 | 0.426 | |
| RV/TLC, % | 46.7 ± 14.1 | 49.8 ± 14.2 | 43.8 ± 13.4 | < 0.001*** | |
| FeNO, (PPB) unit | 31.5 ± 18.9 (n = 34) | 24.8 ± 13.0 (n = 16) | 37.4 ± 21.5 (n = 18) | 0.0337* | |
| Eosinophil count, cells/μL | 138.9 ± 72.2 | 132.8 ± 71.9 | 143.7 ± 72.3 | 0.219 | |
| GOLD grade | < 0.001*** | ||||
| I | 18 (5.5%) | 1 (0.7%) | 17 (9.3%) | ||
| II | 146 (44.5%) | 50 (34.5%) | 96 (52.5%) | ||
| III | 125 (38.1%) | 68 (46.9%) | 57 (31.1%) | ||
| IV | 39 (11.9%) | 26 (17.9%) | 13 (7.1%) | ||
Values are presented as mean ± standard deviation or number (%).
BMI = body mass index, mMRC = modified Medical Research Council, CAT = Chronic Obstructive Pulmonary Disease Assessment Test, SGRQ = St. George’s Respiratory Questionnaire, CCI = Charlson Comorbidity Index, BD = bronchodilator, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, DLCO = diffusing capacity of the lungs for carbon monoxide, RV/TLC = residual volume/total lung capacity, FeNO = fractional exhaled nitric oxide, GOLD = Global Initiative for Chronic Obstructive Lung Disease.
*P < 0.05, **P < 0.01, ***P < 0.001.
The relative risk of AE COPD in each group
Table 2 presents the relative risk of acute exacerbation within 1 year. Triple therapy was associated with a significant increase in the incidence rate ratio (IRR) of acute exacerbations in the multivariate-adjusted models. The crude IRR of moderate to severe exacerbation in the ICS group was 2.43 (95% confidence interval [CI], 1.76 to 3.37; P < 0.001), and the adjusted IRR (adjusted for age, sex, BMI, total pack-years of smoking, previous moderate exacerbation, trough FEV1, and total SGRQ score) was 2.04 (95% CI, 1.45 to 2.84; P < 0.001). The rate ratio of moderate exacerbation (crude IRR, 2.32; 95% CI, 1.63 to 3.29; P < 0.001 and adjusted IRR, 1.95; 95% CI, 1.36 to 2.81; P < 0.001) and severe exacerbation (crude IRR, 3.42; 95% CI, 1.82 to 6.40; P < 0.001 and adjusted IRR, 2.78; 95% CI, 1.47 to 5.27; P < 0.001) also increased in the triple therapy group. Supplementary Table 1 shows the increased risk of an acute exacerbation event with an increased odds ratio (OR) for moderate to severe exacerbations (crude OR, 2.93; 95% CI, 1.86 to 4.61; P < 0.001 and adjusted OR, 2.22; 95% CI, 1.37 to 3.59; P < 0.001), moderate exacerbations (crude OR, 2.57; 95% CI, 1.64 to 4.02; P < 0.001 and adjusted OR, 2.97; 95% CI, 1.30 to 3.38; P = 0.002), and severe exacerbations (crude OR, 3.01; 95% CI, 2.02 to 7.93; P < 0.001 and adjusted OR, 2.10; 95% CI, 1.46 to 6.04; P = 0.003) in the triple therapy group. Table 3 and Supplementary Table 2 present the relative risk of annualized exacerbation rates during the 3-year follow-up of the 260 enrolled patients. The multivariate-adjusted risk of a moderate-to-severe exacerbation of triple therapy was significantly higher in the triple therapy group (IRR, 1.92; 95% CI, 1.43 to 2.57; P < 0.001 and OR, 2.60; 95% CI, 1.27 to 5.35; P = 0.009).
Table 2. Comparison of 1-year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD.
| Variables | Triple group | Dual group | P value | ||
|---|---|---|---|---|---|
| Moderate-to-severe exacerbation | |||||
| Rate | 2.00 | 0.89 | |||
| Crude IRR (95% CI) | 2.43 (1.76 to 3.37) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 2.04 (1.45 to 2.84) | (ref) | < 0.001*** | ||
| Moderate exacerbation | |||||
| Rate | 1.68 | 0.79 | |||
| Crude IRR (95% CI) | 2.32 (1.63 to 3.29) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 1.95 (1.36 to 2.81) | (ref) | < 0.001*** | ||
| Severe exacerbation | |||||
| Rate | 0.32 | 0.10 | |||
| Crude IRR (95% CI) | 3.42 (1.82 to 6.40) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 2.78 (1.47 to 5.27) | (ref) | < 0.001*** | ||
COPD = chronic obstructive pulmonary disease, IRR = incidence rate ratio, CI = confidence interval.
aAdjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation, baseline trough fored expiratory volume in a second, and total St George’s Respiratory Questionnaire score.
***P < 0.001.
Table 3. Comparison of 3-year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD (n = 260).
| Variables | Triple group | Dual group | P value | ||
|---|---|---|---|---|---|
| Moderate-to-severe exacerbation | |||||
| Rate | 2.04 | 0.91 | |||
| Crude IRR (95% CI) | 2.37 (1.77 to 3.17) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 1.92 (1.43 to 2.57) | (ref) | < 0.001*** | ||
| Moderate exacerbation | |||||
| Rate | 1.13 | 0.5 | |||
| Crude IRR (95% CI) | 2.33 (1.70 to 3.19) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 1.98 (1.43 to 2.74) | (ref) | < 0.001*** | ||
| Severe exacerbation | |||||
| Rate | 0.3 | 0.12 | |||
| Crude IRR (95% CI) | 2.66 (1.61 to 4.42) | (ref) | < 0.001*** | ||
| Adjusted IRR (95% CI)a | 1.93 (1.16 to 3.22) | (ref) | 0.0114* | ||
COPD = chronic obstructive pulmonary disease, IRR = incidence rate ratio, CI = confidence interval.
aAdjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation, baseline trough forced expiratory volume in a second, and total St George’s Respiratory Questionnaire score.
*P < 0.05, ***P < 0.001.
Supplementary Table 3 includes IRRs for 1-year acute exacerbations in the subgroup with BEC < 100 cells/μL, (n = 114) and Supplementary Table 4 includes the subgroup analysis with BEC between 100 and 300 cells/μL, n = 214) with the increased moderate-to-severe exacerbation risk in the triple group as in the Table 2.
Fig. 2 shows a visual representation of the results shown in Table 2 based on a restricted cubic spline model of the incidence rate ratio of moderate-to-severe exacerbations according to inhaler therapy at different levels of BEC. This figure is based on an analysis of 429 patients, including 101 GOLD B patients with a BEC ≥ 300 cells/μL. This figure shows a significantly higher rate of moderate-to-severe exacerbations in triple therapy in the eosinophil range lower than 300 cells/μL. At the BEC above 400 cells/μL, the exacerbation risk of triple therapy versus dual therapy was not statistically significantly higher (IRR, 2.13; 95% CI, 1.45 to 3.12 at a BEC 100 cells/μL, IRR, 2.07; 95% CI, 1.41 to 3.02 at a BEC 200 cells/μL, IRR, 1.61; 95% CI, 1.04 to 2.51 at a BEC 300 cells/μL, and IRR, 1.41; 95% CI, 0.81 to 2.48 at a BEC 400 cells/μL).
Fig. 2. Adjusted incidence rate ratio of moderate-to-severe exacerbations according to triple therapy versus dual therapy at different eosinophil levels in group B COPD patients. Adjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation, baseline trough forced expiratory volume in a second, and total St George’s Respiratory Questionnaire score.
COPD = chronic obstructive pulmonary disease, IRR = incidence rate ratio, CI = confidence interval.
Lung function decline and longitudinal change of symptom score
Table 4 presents the annual rate of decline in lung function and changes in total CAT and SGRQ scores for triple and dual therapies. The multivariate-adjusted FEV1 decline rate was −10.0 mL/year (95% CI, −39.8 to −19.7; P < 0.509) in the triple therapy group and 22.3 mL/year (95% CI, −4.4 to 49.0; P = 0.101) in the dual therapy group, with a P value for interaction of 0.888 (Supplementary Fig. 2). There were no significant differences in the adjusted FVC, total CAT score, or total SGRQ score between the dual- and triple-therapy groups.
Table 4. Longitudinal changes in lung function and symptom scores in the triple and dual group.
| Variables | Triple group | P value | Dual group | P value | P-for interaction | |
|---|---|---|---|---|---|---|
| FEV1, mL | ||||||
| Crude | −12.4 (−30.6 to 5.8) | 0.183 | 5.92 (−10.9 to 22.8) | 0.491 | < 0.001*** | |
| Adjusteda | −10.0 (−39.8 to 19.7) | 0.509 | 22.3 (−4.4 to 49.0) | 0.101 | 0.888 | |
| FVC, mL | ||||||
| Crude | −35.2 (−65.6 to −4.8) | 0.023 | −22.5 (−50.5 to 5.6) | 0.116 | < 0.001*** | |
| Adjustedb | −34.7 (−65.7 to −4.6) | 0.024 | −16.8 (−44.4 to 10.8) | 0.232 | 0.692 | |
| Total CAT score | ||||||
| Crude | −0.19 (−0.71 to 0.32) | 0.458 | −0.97 (−1.44 to −0.50) | < 0.001*** | 0.113 | |
| Adjustedc | −0.18 (−0.71 to 0.35) | 0.505 | −1.11 (−1.59 to −0.63) | < 0.001*** | 0.528 | |
| Total SGRQ score | ||||||
| Crude | −0.03 (−1.28 to 1.34) | 0.960 | −1.57 (−2.76 to −0.38) | 0.010* | 0.001** | |
| Adjustedd | 0.08 (−1.94 to 2.10) | 0.935 | −2.05 (−3.86 to −0.25) | 0.025* | 0.269 | |
Values are presented as an annual decline rate (95% confidence interval).
FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, CAT = Chronic Obstructive Pulmonary Disease Assessment Test, SGRQ = St. George’s Respiratory Questionnaire.
aAdjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation and baseline trough FEV1 (mL).
bAdjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation and baseline trough FVC (mL).
cAdjusted for adjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation, and baseline total CAT score.
dAdjusted for adjusted for age, sex, body mass index, total pack-year of smoking, previous experience of moderate exacerbation, and baseline total SGRQ score.
*P < 0.05, **P < 0.01, ***P < 0.001.
DISCUSSION
GOLD 2024 initially emphasized the use of LABA/LAMA in patients with established COPD, particularly in groups B and E.1 Drawing on real-world COPD data, our study discovered an elevated risk of acute exacerbations in group B in non-eosinophilic COPD with triple inhaler therapy. These results robustly support the GOLD 2024 recommendations for LABA/LAMA.
Compared with the clinical characteristics of patients treated with dual inhalers, the triple therapy group had worse lung function, high CAT and SGRQ scores, and a high proportion of patients with a history of moderate exacerbations. The findings of severe airway obstruction, dyspnea, and symptoms in COPD patients on ICS were also described in previous real-world studies from South Korea13 and Germany.4 Herein, we found consistent results when analyzing subgroups of eosinophil counts below 300 cells/μL.
In the restricted cubic spline analysis in this study, the relative risk between the triple and dual groups was similar to that in a study using a UK primary database,14 with a decreasing risk of exacerbation in the triple group as eosinophil count increased. These findings suggest that the risk of ICS administration may differ according to eosinophil count in group B patients. In this study, most patients from the cohort had a low blood eosinophil count, with a median of 133.1 cells/μL and a mean of 139.0 cells/μL. Other studies have also reported a prevalence of eosinophilic COPD ranging from 15% to 20%, which indicates a relatively small proportion of patients with COPD.15,16,17
The clinical benefit of ICS in COPD is indisputable in cases with a high risk of exacerbation.18 However, there is debate regarding the benefit of ICS in patients with low-risk COPD concerning exacerbations. Our findings corroborate those of previous studies that have examined claims data and identified a correlation between the use of ICS and an elevated risk of acute exacerbations.19,20 Miravitlles et al.21 conducted a pooled analysis of six randomized controlled trials and found no evidence of a survival benefit of ICS in low exacerbation risk patients. Furthermore, a recent study from Taiwan's National Health Insurance Research Database by Liao et al.22 demonstrated that patients receiving triple therapy were associated with an increased mortality rate. In contrast to our study, which examined GOLD B, a recent study of GOLD A patients in the KOCOSS cohort reported no significant difference in the OR of acute exacerbations with the use versus non-use of ICS.10 One of the study’s findings was that there were fewer exacerbation events in the LABA/LAMA group, although this finding was not statistically significant.10
A previous meta-analysis indicated that FEV1 decline was not affected by ICS use as a marker of airflow obstruction.23 However, this analysis did not stratify the data according to eosinophil count. In contrast to the findings of this study, the decline in FEV1 in our study population was numerically greater in the triple therapy group but not significantly different from that in the dual therapy group when adjusted for multivariate analysis (P = 0.888).
Previous studies on longitudinal changes in quality of life and symptom scores in real-world cohorts of COPD patients did not include the effect of long-acting bronchodilators on SGRQ score change.24,25,26 Although both the Hokkaido COPD Cohort Study25 and the COSYCONET cohort study24 identified an association between changes in FEV1 and SGRQ scores, our study population did not reveal a statistically significant annual reduction in FEV1 in the study population. This observation may also explain the lack of a significant decrease in the SGRQ scores in this study, regardless of the use of long-acting bronchodilators. Despite the known association between a longitudinal increase in CAT scores and acute exacerbations,26 our study found no difference in the annual rate of CAT score changes between the triple group, which experienced more frequent acute exacerbations, and the dual group.
Although recommendations have been made to withdraw ICS,27 a considerable number of patients with COPD continue to receive ICS prescriptions. Several studies have reported prescription rates of ICS, including regimens, among COPD patients ranging from 40% to 65%.5,6,7,28,29,30 Additionally, an analysis of KOCOSS has highlighted the excessive use of ICS among COPD patients in South Korea, discrepant with the GOLD statement.8 Also, another study by Lee et al.29 analyzed patients treated with multiple inhaler triple therapy (MITT) using the South Korean National Health Insurance database (2014–2018) and reported that they experienced approximately 2 acute exacerbations per year. Before starting MITT, approximately 37% of the patients used ICS/LABA, 19% used LAMA, and 5.8% used LABA/LAMA.31 These findings also suggest that a significant proportion of patients were exposed to ICS prior to the use of triple therapy. There is also concern about excluding ICS from inhaler treatment, with reports of decreased lung function and worsening symptoms when stepping down from triple inhaler to single inhaler.31 Additionally, the study indicated a relative increase in the frequency of acute exacerbations in the ICS/LABA withdrawn group compared to the LAMA withdrawn group.31 Given the recent emergence of SITT prescribing in clinical practice, further studies on withdrawal are necessary to draw definitive conclusions.
Our analysis of group B with blood eosinophil counts < 300 cells/μL showed a statistically significant increase in acute exacerbations in patients who received triple therapy. In this study, we conducted a comprehensive comparison of triple and dual therapies on COPD patients with COPD, including factors such as exacerbation and lung function decline, which are crucial in disease progression. Furthermore, our study is valuable in reflecting real-world clinical settings in contrast to strictly controlled trials.
This study has some limitations. First, the analysis was stratified by drug use without a washout period. Blinding was not possible due to the nature of the study design. Second, the period of lung function decline analysis was relatively short (only 3 years). Finally, the patients were classified based on their eosinophil counts obtained from a single blood test performed at the time of cohort enrollment. Although variability in blood eosinophil counts has been reported in patients with COPD,32 this limitation is not a significant drawback of this study design, as post hoc analysis of the IMPACT trial suggested that a single measurement can accurately predict eosinophil counts.33
In conclusion, this study demonstrated that the use of triple therapy in patients with GOLD B COPD and low eosinophil counts may be associated with an elevated risk of acute exacerbations, thereby necessitating a cautious prescription approach.
ACKNOWLEDGMENTS
The authors thank Dr. Young Lee of the Veterans Medical Research Institute for assistance with statistical analysis.
Footnotes
Funding: This study was supported by the Research Program funded Korea National Institute of Health (Fund CODE 2016ER670100, 2016ER670101, 2016ER670102, 2018ER67100, 2018ER67101, 2018ER67102, 2021ER120500, 2021ER120501, 2021ER120502 and 2024ER120500).
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Kim Y, Kim HJ.
- Data curation: Song JH.
- Formal analysis: Song JH.
- Funding acquisition: Kim Y, Kim HJ.
- Investigation: Song JH, Park S, Jang JG, Kim Y, Ra SW, Lee CY, Kim DK, Yoon HY, Yoo KH, Kim HJ.
- Methodology: Song JH, Kim Y, Yoo KH.
- Software: Song JH, Kim Y.
- Supervision: Yoo KH, Kim HJ.
- Validation: Park S, Jang JG, Kim Y, Ra SW, Lee CY, Kim DK, Yoon HY, Yoo KH.
- Visualization: Song JH.
- Writing - original draft: Song JH, Kim HJ.
- Writing - review & editing: Song JH, Park S, Jang JG, Kim Y, Ra SW, Lee CY, Kim DK, Yoon HY, Yoo KH, Kim HJ.
SUPPLEMENTARY MATERIALS
Comparison of 1 year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD
Comparison of 3-year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD (N = 260)
Comparison of 1-year exacerbation risk in triple versus dual groups in group B with blood eosinophil count lower than 100 cells/μL (N = 114)
Comparison of 1-year exacerbation risk in triple vs. dual groups in group B with blood eosinophil count between 100 cells/μL and 300cells/μL (N = 214)
Distribution of blood eosinophil count in the study population.
Longitudinal change in FEV1 in the LABA/LAMA group and in the ICS/LABA/LAMA group.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Comparison of 1 year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD
Comparison of 3-year exacerbation risk in triple versus dual groups in group B non-eosinophilic COPD (N = 260)
Comparison of 1-year exacerbation risk in triple versus dual groups in group B with blood eosinophil count lower than 100 cells/μL (N = 114)
Comparison of 1-year exacerbation risk in triple vs. dual groups in group B with blood eosinophil count between 100 cells/μL and 300cells/μL (N = 214)
Distribution of blood eosinophil count in the study population.
Longitudinal change in FEV1 in the LABA/LAMA group and in the ICS/LABA/LAMA group.