Authors: Wen-Lin Su, Chou-Chin Lan, Mei-Chen Yang, Chun-Yao Huang, Yao-Kuang Wu
Categories: Original Research, COPD exacerbation, triple therapy, mortality, real-world study, retrospective cohort
Source: International Journal of Chronic Obstructive Pulmonary Disease
Doi: 10.2147/COPD.S586308
Authors: Wen-Lin Su, Chou-Chin Lan, Mei-Chen Yang, Chun-Yao Huang, Yao-Kuang Wu
Chronic obstructive pulmonary disease (COPD) exacerbations significantly accelerate disease progression and increase mortality and healthcare utilization. While triple therapy (inhaled corticosteroids/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]) is commonly prescribed to manage COPD, its long-term real-world effectiveness following hospitalization for acute exacerbation of COPD remains unclear.
This retrospective cohort study included 500 patients hospitalized for severe COPD exacerbations at a tertiary hospital (2015–2023). Patients were classified as receiving triple therapy (ICS/LABA/LAMA) during or within 7 days after the index hospitalization or not. Primary outcomes were COPD-related readmission and all-cause mortality within three years; secondary analyses were stratified by prior exacerbation frequency, baseline FEV1 % predicted, and eosinophil count. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models, with Kaplan–Meier methods for survival.
Among the study population, 329 patients (65.8%) received triple therapy. Overall, no significant differences were observed in three-year COPD-related readmission rates (adjusted hazard ratio [aHR]: 0.95, 95% confidence interval [CI]: 0.66–1.35) or all-cause mortality (aHR: 0.88, 95% CI: 0.57–1.36) between the groups. However, stratified analyses demonstrated significant benefits of triple therapy in patients with ≥2 exacerbations within one year prior to the index hospitalization (aHR for 0.14; aHR for 0.24) and showed numerically lower risks among those with baseline FEV1 ≥50% predicted (aHR for 0.57; aHR for 0.43).
Triple therapy was not associated with improved outcomes in the overall cohort but may be associated with better outcomes in selected high-risk subgroups. These findings should be interpreted with caution given the observational design and potential residual confounding. Further studies are warranted to confirm these findings and refine patient selection for triple therapy.
Chronic obstructive pulmonary disease (COPD) is a global health challenge with profound implications for patient health and healthcare systems.1 Affecting over 250 million people worldwide, COPD contributes to approximately 3.23 million deaths annually and ranks as the third leading cause of global mortality.2 The disease’s prevalence is expected to rise due to aging populations, increased tobacco use, and ongoing exposure to environmental pollutants.3 Acute exacerbations of COPD (AECOPD) represent critical events that significantly accelerate disease progression and increase healthcare utilization.4 These episodes are characterized by up to 20% of patients being readmitted to the hospital within 30 days and nearly 50% within a year of an occurrence.5 The one-year mortality rate following hospitalization for AECOPD ranges from 20% to 40%.6 This highlights the urgent need for effective management strategies to mitigate these risks.
Triple therapy, comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has emerged as an important strategy in COPD management.7 According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, escalation to LABA/LAMA/ICS is recommended for patients with persistent exacerbations despite dual-bronchodilator therapy.8 Prior randomized controlled trials have demonstrated that triple therapy can reduce exacerbation risk and improve clinical outcomes in selected patients with a high exacerbation burden. However, real-world evidence regarding the long-term effectiveness of triple therapy following hospitalization for acute exacerbation of COPD remains limited.9,10 In addition, clinical trial populations may not fully represent routine clinical practice, as patients with advanced age, multiple comorbidities, or polypharmacy are often underrepresented.11,12 Therefore, real-world studies are needed to better evaluate the effectiveness of triple therapy in broader and more representative patient populations.
Accordingly, the present retrospective cohort study aimed to evaluate the long-term impact of triple therapy on exacerbation rates and mortality among patients hospitalized for an AECOPD. By analyzing real-world data, we seek to bridge the knowledge gap between clinical trial results and everyday clinical practice. The findings might offer valuable evidence to inform personalized treatment strategies and improve patient outcomes in this high-risk population.
This retrospective cohort study analyzed patients discharged after hospitalization for a severe AECOPD between January 2015 and November 2023 at Taipei Tzu Chi Hospital, a tertiary medical center in Northern Taiwan. Eligible patients were identified from electronic medical records and were required to be aged ≥18 years, have a confirmed diagnosis of COPD before the index date based on the International Classification of Diseases (ICD) diagnostic codes, and have experienced at least one severe AECOPD requiring hospitalization (the index hospitalization) during the study period. The diagnosis of COPD was identified using ICD-9 codes 491, 492, and 496, or ICD-10 codes J41-J44. Severe AECOPD were defined as a hospitalization or emergency department visit with a primary COPD diagnosis (ICD-10-CM J44.1 or J44.0, ICD-9-CM 491.21 or 491.22) accompanied by prescription records for systemic corticosteroids and/or respiratory antibiotics during the encounter, where moderate exacerbations were defined as outpatient visits for a primary COPD diagnosis with prescriptions for systemic corticosteroids and/or respiratory antibiotics for a duration of 3–14 days.13–15 In the present study, we focused on severe AECOPD requiring hospitalization; therefore, patients who were evaluated only in the emergency department and discharged within 24 hours without admission were not classified as hospitalized AECOPD cases and were not included in the study cohort.
Exclusion criteria a prior diagnosis of another significant respiratory disease (eg., asthma, clinically significant bronchiectasis, or interstitial lung disease) or incomplete clinical data.
Patients were categorized into two (1) Patients in the triple therapy group were those who initiated ICS/LABA/LAMA during the index hospitalization or who started ICS/LABA/LAMA within 7 days after discharge; and (2) patients in the non-triple-therapy group receiving any other inhaled regimen. Data on inhaler use before and after index hospitalization were collected, and patients were included regardless of their maintenance inhaler regimen before the index hospitalization. Patients were contacted within 7 days after discharge for an initial follow-up.
Inhaled therapy followed institutional practice aligned with GOLD LABA + LAMA as preferred initial therapy, escalation to LABA + LAMA + ICS if an ICS indication was present, particularly in patients with blood eosinophils ≥ 300 cells/µL; LABA + ICS alone was generally avoided.16,18
The patients were followed from the index date until death, loss to follow-up, or the end of the study period (November 30, 2023), whichever occurred first.
Data extraction and verification were performed by trained research staff from the Division of Pulmonary Medicine using the hospital’s electronic medical record system, with oversight by the study investigators. Demographic, clinical, and laboratory data were collected at the time of the index admission, including age, sex, smoking status, body mass index (BMI), comorbidities (neuromuscular disease [NMD], chronic lung disease, ischemic heart disease, non-terminal cancer, end-stage renal disease [ESRD], diabetes mellitus, liver disease, autoimmune disease, and hypertension), history of prior exacerbations, and markers of inflammation (eg, C-reactive protein [CRP], white blood cell count [WBC], and neutrophil–lymphocyte ratio [NLR]), bilevel positive airway pressure (BiPAP), along with clinical outcomes and length of stay. Chronic lung disease was defined as the presence of restrictive lung disease (such as pulmonary fibrosis or work-related lung diseases including silicosis or coal worker’s pneumoconiosis) or obstructive lung diseases other than COPD (including asthma, bronchiectasis, and cystic fibrosis). We extracted spirometry results obtained within six months before the index date, including both pre- and post-bronchodilator forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. None of the patients had received systemic corticosteroids within 72 hours of the index admission.
The study complies with the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Taipei Tzu Chi Hospital (IRB: 14-IRB028). Given the retrospective design and the use of de-identified medical records, the requirement for informed consent was waived by the ethics committee of IRB.
The two primary outcomes, compared between the triple therapy group and the non-triple therapy group, were (1) time to first COPD-related readmission, defined as readmission for a severe COPD exacerbation, that is, a hospital admission or emergency visit with a primary COPD diagnosis accompanied by systemic corticosteroids and/or respiratory antibiotic prescription records, and (2) overall mortality within three years of discharge.
Secondary outcomes included stratified analyses of these endpoints by prior exacerbation frequency, eosinophil count (obtained at admission during the index hospitalization), and baseline lung function (FEV1% predicted).
For the statistical comparison of patients who underwent triple therapy or not, categorical data are presented as n (%) and performed by chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were assessed for normality using the Shapiro–Wilk test, while data with normal distribution are presented as mean ± SD and performed as a t-test, otherwise, data are presented as median and interquartile range (IQR, ie., 25th-75th percentile). For the primary outcomes, Cox proportional hazard (PH) regression models were utilized to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of the effect of triple therapy for COPD-related readmission and overall mortality within three years. Covariates with p-value < 0.1 were included as adjustment variables. The cumulative incidence curve and overall survival plot were conducted by the Kaplan–Meier method and tested by Gray’s test and Log rank test. The duration was calculated from the discharge date to the date of the event (first COPD-related readmission or mortality) that occurred or to the latest follow-up date if the patient was never readmitted due to COPD or survived past three years.
Missing data for covariates were handled by complete-case analysis; variables with missing values are indicated in the tables. No imputation was performed. As this was a retrospective cohort study including all eligible patients during the study period, no formal sample size calculation or power analysis was performed. A two-tailed p-value <0.05 was considered statistically significant. All statistical analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA).
A total of 500 patients were included. Among them, 329 patients (65.8%) received triple therapy during or within 7 days after discharge from their index hospitalization, while 171 patients (34.2%) did not. The median age of the patients was 78 years, with a predominance of male patients (84.4%). Hypertension was observed in 52.6% of the patients. Prior severe AECOPD in the past 12 months was 0 in 65.4% of patients, 1 in 20.8%, and ≥2 in 13.8% (Table 1).Table 1Comparison of Baseline Characteristics Between Patients with and without Triple TherapyVariablesAllTriple TherapyNon-Triple TherapyP-value(N=500)(N=329)(N=171)Male, n (%)422 (84.4)271 (82.4)151 (88.3)0.083Age, years78.0 (69.0–85.0)77.0 (68.0–83.0)80.0 (72.0–88.0)<0.001BMI, kg/m2 (missing=3)23.3 (20.4–26.3)22.7 (20.4–26.0)23.9 (20.6–26.7)0.070Smoking status0.061 Current109 (21.8)82 (24.9)27 (15.8) Former202 (40.4)129 (39.2)73 (42.7) Never189 (37.8)118 (35.9)71 (41.5)Comorbidities, n (%) NMD49 (9.8)32 (9.7)17 (9.9)0.939 Chronic lung disease55 (11.0)42 (12.8)13 (7.6)0.080 Ischemic heart disease140 (28.0)98 (29.8)42 (24.6)0.217 Non-terminal cancer54 (10.8)38 (11.6)16 (9.4)0.453 ESRD7 (1.4)6 (1.8)1 (0.6)0.431 Diabetes mellitus103 (20.6)80 (24.3)23 (13.5)0.004 Liver disease9 (1.8)8 (2.4)1 (0.6)0.175 Autoimmune disease10 (2.0)7 (2.1)3 (1.8)1.000 Hypertension263 (52.6)164 (49.8)99 (57.9)0.087Laboratory measures CRP, mg/dL (missing=52)1.9 (0.5–6.8)1.6 (0.4–5.9)2.7 (0.7–8.2)0.004 WBC, 103/µL9.6 (7.1–12.8)9.7 (7.3–12.5)9.4 (7.0–13.3)0.712 Neutrophil, %77.1 (67.3–84.5)77.3 (66.7–84.1)77.0 (68.3–84.6)0.699 Lymphocyte, %13.2 (8.0–20.4)13.5 (8.0–20.5)13.0 (7.5–19.9)0.630 Monocyte, %6.1 (4.7–8.4)6.0 (4.7–8.4)6.4 (4.7–8.1)0.718 Eosinophil, %1.0 (0.1–2.4)1.0 (0.2–2.4)0.9 (0.1–2.2)0.152 Basophil, %0.2 (0.1–0.4)0.2 (0.1–0.5)0.2 (0.1–0.4)0.107 Neutrophil count, 103/µL7.0 (4.9–10.4)6.8 (5.2–10.4)7.4 (4.6–10.1)0.797 Lymphocyte count, 103/µL1.2 (0.8–1.8)1.2 (0.8–1.8)1.2 (0.8–1.7)0.556 Eosinophil count, cells/µL93.7 (12.0–221.9)97.2 (19.4–238.6)78.9 (8.6–213.7)0.100 <300405 (81.0)259 (78.7)146 (85.4)0.072 ≥30095 (19.0)70 (21.3)25 (14.6) NLR5.8 (3.3–10.6)5.8 (3.2–10.2)6.0 (3.7–11.4)0.615 <3110 (22.0)74 (22.5)36 (21.1)0.712 ≥3390 (78.0)255 (77.5)135 (78.9) Platelet, 103/µL213.0 (169.5–264.0)218.0 (176.0–267.0)204.0 (162.0–253.0)0.037 Hb, g/dL13.3 ± 2.113.5 ± 2.212.9 ± 2.00.002****Respiration FEV1, %, predicted51.0 (39.0–65.0)49.0 (37.0–62.0)57.0 (44.0–74.0)<0.001 <50223 (44.6)166 (50.5)57 (33.3)<0.001 ≥50277 (55.4)163 (49.5)114 (66.7) FVC, %, predicted74.0 (59.0–90.5)71.0 (58.0–86.0)78.0 (62.0–99.0)0.003 FEV1, L1.1 (0.8–1.5)1.0 (0.8–1.4)1.2 (0.9–1.6)<0.001 FVC, L2.1 ± 0.72.1 ± 0.72.2 ± 0.80.105 FEV1/FVC, %55.4 (46.3–63.0)53.0 (45.0–61.6)59.0 (49.0–65.0)<0.001 BiPAP, %90 (18.0)67 (20.4)23 (13.5)0.056 RCW8 (1.6)5 (1.5)3 (1.8)1.000AECOPD before the index hospitalization within 1 year****0.012 0327 (65.4)202 (61.4)125 (73.1) 1104 (20.8)72 (21.9)32 (18.7) 2+69 (13.8)55 (16.7)14 (8.2)Notes: Bold values indicate statistical significance (p < 0.05).Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BiPAP, bilevel positive airway pressure; BMI, body mass index; CRP, C-reactive protein; ESRD, end-stage renal disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Hb, hemoglobin; NMD, neuromuscular disease; NLR, neutrophil-to-lymphocyte ratio; RCW, respiratory care ward; WBC, white blood cell.
The patterns of inhaler use before and after the index hospitalization for patients receiving or not receiving triple therapy are summarized in Supplemental Table 1. Before the index hospitalization, 59.6% of patients in the triple therapy group (those who received triple therapy after hospitalization) and 7.6% in the non-triple therapy group were already on triple therapy.
Among the 329 patients who received triple therapy after the index hospitalization, 75.4% were prescribed multiple-inhaler triple therapy (MITT) and 24.6% single-inhaler triple therapy (SITT). Among the 171 patients who did not receive triple therapy, 10.5% received LAMA monotherapy, 28.7% received ICS/LABA, and 60.8% received LAMA+LABA (Supplemental Table 1).
Patients receiving triple therapy were generally younger (median: 77.0 vs. 80.0 years, p<0.001) and had higher proportion of diabetes (24.3% vs. 13.5%, p=0.004), lower CRP levels (1.6 vs. 2.7 mg/dL, p=0.004), and higher platelet and hemoglobin (Hb) levels (median: 218.0 vs. 204 103/µL, p=0.0378; 13.5 vs. 12.9, p=0.002, respectively) compared with those not receiving triple therapy. Significant differences were also observed between the triple therapy cohort and the non-triple therapy cohort in respiratory status, including pre-bronchodilator FEV1% predicted (median: 49.0% vs. 57.0%, p < 0.001) and FVC% predicted (median: 71.0% vs. 78.0%, p = 0.003), post-bronchodilator FEV1 (median: 1.0 L vs. 1.2 L, p < 0.001), and FEV1/FVC ratio (median: 53.0% vs. 59.0%, p < 0.001) (Table 1).
The length of stay was longer in the triple therapy group (median: 8.0 vs. 7.0 days, p=0.020). However, no significant differences were found in the rate of the first COPD-related readmission within 1 year (17.6% vs. 17.0%, p=0.851) or 3 years (38.3% vs. 35.7%, p=0.565). Mortality rates were slightly lower in the triple therapy group, but the difference did not reach statistical significance (3-year 17.0% vs. 23.4%, p=0.086) (Table 2).Table 2Comparison of Outcomes Between Patients with and without Triple TherapyOutcomeAllTriple TherapyNon-Triple TherapyP-value(N=500)(N=329)(N=171)Length of stay, day8.0 (6.0–12.0)8.0 (6.0–13.0)7.0 (6.0–12.0)0.020****COPD-related readmission within242 (48.4)166 (50.5)76 (44.4)0.202 1 year87 (17.4)58 (17.6)29 (17.0)0.851 3 years187 (37.4)126 (38.3)61 (35.7)0.565AECOPD post index hospitalization/per year0.468 00.9408 (81.6)266 (80.9)142 (83.0) 11.949 (9.8)36 (10.9)13 (7.6) ≥243 (8.6)27 (8.2)16 (9.4)Mortality140 (28.0)83 (25.2)57 (33.3)0.056 1 year17 (3.4)9 (2.7)8 (4.7)0.255 3 years96 (19.2)56 (17.0)40 (23.4)0.086Follow-up duration, years2.7 (1.5–4.6)2.6 (1.5–4.4)2.7 (1.5–4.8)0.518Notes: Bold values indicate statistical significance (p < 0.05).Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; COPD, chronic obstructive pulmonary disease.
The cumulative incidence curve of the first COPD-related readmission and overall survival curve for the entire study population indicate no difference for a rise in hospital readmission (p=0.540) and increased mortality (p=0.140) over the 3-year period between the two groups (Figure 1). Figure 1(A) The cumulative incidence curve for first COPD-related readmission and (B) classified by treatment in patients with COPD and severe exacerbations post-hospitalization.The image A showing a graph of cumulative incidence with the x-axis labeled 'Years since index hospitalization discharge' and the y-axis labeled 'Cumulative Incidence'. The graph displays two curves representing 'Inhaler triple therapy Yes' and 'No', with a Gray's Test p-value of 0.540. Data points are shown for years 0 to 3, with values for 'Yes' starting at 329 and decreasing to 116 and 'No' starting at 171 and decreasing to 67. The image B showing a graph of survival probability with the x-axis labeled 'Years since index hospitalization discharge' and the y-axis labeled 'Survival Probability'. The graph displays two curves for 'Inhaler triple therapy Yes' and 'No', with a Log-Rank p-value of 0.140. Data points are shown for years 0 to 3, with values for 'Yes' starting at 329 and decreasing to 140 and 'No' starting at 171 and decreasing to 77.Two graphs showing cumulative incidence and survival probability over three years post-hospitalization.
The stratified cumulative incidence curve of first COPD-related readmission and overall survival curve found no difference between triple therapy patients and those not receiving triple therapy for hospital readmission in patients who had within 1 year prior to index hospitalization <2 exacerbations (p=0.101) or an FEV1% predicted <50% (p=0.400) (Figure 2A and C). In addition, no difference in survival rate was seen in these two subgroups with or without triple therapy (p=0.245 and 0.775, respectively) (Figure 3A and C). However, triple therapy was associated with a lower risk of hospital readmission due to COPD in the patients with ≥2 exacerbation within 1 year prior of index hospitalization (p=0.009) or FEV1% predicted ≥50% (p=0.039) (Figure 2B and D). Triple therapy was also associated with higher survival in patients with ≥2 exacerbations (p=0.009) or FEV1% predicted ≥50% (p=0.004) (Figure 3B and D). Figure 2The cumulative incidence curve for first COPD-related readmission was classified by treatment in the subgroups (A) <2 exacerbations, (B) ≥2 exacerbations, (C) FEV1% predicted <50%, (D) FEV1% predicted ≥50%.The image contains four graphs labeled A, B, C and D, each showing cumulative incidence over time. Graph A shows cumulative incidence for patients with FEV1 percent predicted less than 50 percent, with a Gray's Test p-value of 0.400. The x-axis is labeled 'Years since index hospitalization discharge' and the y-axis is labeled 'Cumulative Incidence'. Graph B shows data for patients with two or more exacerbations, with a p-value of 0.009. Graph C shows patients with less than two exacerbations, with a p-value of 0.101. Graph D shows patients with FEV1 percent predicted 50 percent or more, with a p-value of 0.039. Each graph compares inhaler triple therapy (Yes) and no therapy (No) groups, with data points and shaded areas indicating confidence intervals. The number of patients in each group is listed below the x-axis for each graph.Four cumulative incidence graphs showing COPD-related readmission by treatment and exacerbation subgroups. Figure 3The overall survival curve was classified by treatment in the subgroups (A) <2 exacerbations, (B) ≥2 exacerbations, (C) FEV1% predicted < 50%; (D) FEV1% predicted ≥50%.The image A shows a graph of survival probability over years since index hospitalization discharge, with a log-rank p-value of 0.245. The x-axis is labeled 'Years since index hospitalization discharge' and the y-axis is labeled 'Survival Probability'. The graph compares 'Yes' and 'No' groups for inhaler triple therapy, with initial values of 274 and 157, respectively. The image B shows a similar graph with a log-rank p-value of 0.009, initial values of 55 for 'Yes' and 14 for 'No'. The image C shows another graph with a log-rank p-value of 0.775, initial values of 163 for 'Yes' and 114 for 'No'. The image D shows a graph with a log-rank p-value of 0.004, initial values of 166 for 'Yes' and 57 for 'No'. Each graph includes a 'Censored' label and tracks survival probability over three years.Four survival probability graphs by years since hospitalization discharge, showing inhaler triple therapy effects.
Univariate analysis identified age, BMI, NMD, smoking status, ESRD, CRP, WBC, lymphocyte, monocyte, NLR, platelet count, hemoglobin, respiratory parameters, BiPAP use, and exacerbation frequency within one year before the index hospitalization as significantly associated with readmission risk (p < 0.1) (Table 3). Variables meeting this threshold were entered into the multivariable Cox PH model. Due to strong intercorrelations among lymphocyte percentage, NLR, and respiratory parameters (Spearman’s ρ > 0.7; Supplemental Table 2), NLR and FEV1 (L) were retained to address multicollinearity in the final model.Table 3Factors Associated with COPD-Related ReadmissionVariablesCrude HRP-valueAdjusted HRP-value(95% CI)(95% CI)Inhaler triple therapy1.10 (0.81–1.49)0.5410.95 (0.66–1.35)0.764 Male vs Female1.19 (0.79–1.80)0.406 Age, years1.01 (0.99–1.03)0.0641.01 (0.99–1.02)0.461 BMI, kg/m2 (missing=3)0.94 (0.91–0.98)0.0010.96 (0.92–1.00)0.032 Smoking (vs Never) Current1.12 (0.75–1.68)0.5791.10 (0.69–1.76)0.692 Former1.47 (1.06–2.03)0.0211.39 (0.97–1.99)0.075Comorbidities NMD2.26 (1.53–3.35)<0.0012.46 (1.61–3.77)<0.001 Chronic lung disease0.96 (0.61–1.53)0.876 Ischemic heart disease1.09 (0.79–1.49)0.609 Non-terminal cancer0.78 (0.47–1.30)0.336 ESRD4.58 (2.02–10.36)<0.0015.89 (2.38–14.59)<0.001 Diabetes mellitus1.06 (0.74–1.50)0.760 Liver disease1.07 (0.34–3.34)0.913 Autoimmune diseaseNA- Hypertension1.18 (0.88–1.57)0.271Laboratory measures CRP, mg/dL (missing=52)0.97 (0.95–1.001)0.0560.97 (0.94–1.00)0.033 WBC,103/µL1.04 (1.01–1.07)0.0121.03 (0.99–1.07)0.146 Neutrophil, %1.01 (0.99–1.02)0.263 Lymphocyte, %0.98 (0.97–0.999)0.036 Monocyte, %0.94 (0.89–0.99)0.0171.00 (0.94–1.06)0.930 Eosinophil, %1.003 (0.96–1.05)0.893 Basophil, %1.02 (0.64–1.62)0.947 NLR1.01 (1.003–1.02)0.0061.01 (1.00–1.02)0.112 Platelet, 103/µL5.83 (1.52–22.29)0.0104.39 (0.71–27.17)0.111 Hb, g/dL0.92 (0.86–0.99)0.0251.00 (0.92–1.10)0.936Respiration FEV1, %, predicted0.988 (0.981–0.996)0.002 FVC, %, predicted0.992 (0.986–0.998)0.009 FEV1, L0.52 (0.37–0.73)<0.0010.59 (0.38–0.92)0.021 FVC, L0.77 (0.63–0.94)0.009 FEV1/FVC, %0.98 (0.97–0.99)0.0061.00 (0.98–1.02)0.853 BiPAP, %1.37 (0.97–1.93)0.075 RCWNA-AECOPD before the index hospitalization within 1 year (vs 0) 11.11 (0.76–1.61)0.5921.16 (0.78–1.72)0.477 2+2.45 (1.73–3.48)<0.0012.57 (1.72–3.85)**<0.001*Notes: Bold values indicate statistical significance (p < 0.05). NA means no event occurred in a subgroup. *Adjusted for covariates with p < 0.1 in the univariate analysis.Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BiPAP, bilevel positive airway pressure; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ESRD, end-stage renal disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Hb, hemoglobin; HR, hazard ratio; NMD, neuromuscular disease; NLR, neutrophil-to-lymphocyte ratio; RCW, respiratory care ward; WBC, white blood cell.
After adjusting for relevant covariates, triple therapy was not associated with a significant reduction in COPD-related readmission risk (adjusted HR: 0.95, 95% CI: 0.66–1.35, p = 0.764). NMD (adjusted HR: 2.46, 95% CI: 1.61–3.77, p < 0.001) and ESRD (adjusted HR: 5.89, 95% CI: 2.38–14.59, p < 0.001) remained independently associated with higher readmission risk (Table 3).
Table 4 shows factors associated with overall mortality after the index hospitalization. In the multivariable model, higher age (aHR 1.04, 95% CI 1.01–1.06, p = 0.002) was associated with increased mortality, whereas higher BMI (aHR 0.94, 95% CI 0.89–0.99, p = 0.017) and higher hemoglobin (aHR 0.86, 95% CI 0.77–0.96, p = 0.007) were associated with lower mortality risk. The presence of NMD (aHR 3.30, 95% CI 1.98–5.49, p < 0.001) and ≥2 exacerbations in the prior year (aHR 2.01, 95% CI 1.20–3.37, p = 0.008) also predicted higher mortality. Triple therapy use was not significantly associated with mortality risk (aHR 0.88, 95% CI 0.57–1.36, p = 0.556) (Table 4).Table 4Factors Associated with Overall MortalityVariablesCrude HRP-valueAdjusted HRP-value(95% CI)(95% CI)Inhaler triple therapy0.74 (0.49–1.11)0.1410.88 (0.57–1.36)0.556Male vs Female1.87 (0.94–3.71)0.0751.30 (0.63–2.67)0.476Age, years1.06 (1.03–1.08)<0.0011.04 (1.01–1.06)0.002BMI, kg/m2 (missing=3)0.93 (0.89–0.98)0.0040.94 (0.89–0.99)**0.017Smoking (vs Never) Current0.79 (0.43–1.45)0.4421.06 (0.54–2.06)0.867 Former1.41 (0.91–2.20)0.1241.48 (0.94–2.35)0.094Comorbidities NMD3.25 (2.00–5.27)<0.0013.30 (1.98–5.49)<0.001 Chronic lung disease1.18 (0.64–2.16)0.596 Ischemic heart disease1.28 (0.84–1.96)0.249 Non-terminal cancer1.45 (0.81–2.60)0.216 ESRD2.46 (0.60–10.03)0.208 Diabetes mellitus0.75 (0.44–1.29)0.298 Liver disease0.67 (0.09–4.82)0.693 Autoimmune diseaseNA- Hypertension1.40 (0.93–2.11)0.104Laboratory measures CRP, mg/dL (missing=52)0.99 (0.96–1.03)0.626 WBC, 103/µL1.03 (0.99–1.07)0.200 Neutrophil, %1.02 (0.999–1.04)0.062 Lymphocyte, %0.97 (0.95–0.998)0.0350.99 (0.96–1.01)0.329 Monocyte, %0.93 (0.86–1.004)0.0640.95 (0.88–1.02)0.143 Eosinophil, %1.02 (0.96–1.08)0.607 Basophil, %1.45 (0.80–2.60)0.218 NLR1.01 (0.997–1.02)0.126 Platelet, 103/µL4.95 (0.69–35.31)0.111 Hb, g/dL0.79 (0.72–0.87)<0.0010.86 (0.77–0.96)**0.007Respiration FEV1, %, predicted1.000 (0.99–1.01)0.925 FVC, %, predicted1.001 (0.99–1.01)0.884 FEV1, L0.70 (0.44–1.11)0.128 FVC, L0.84 (0.64–1.10)0.206 FEV1/FVC, %0.99 (0.98–1.01)0.506 BiPAP, %1.28 (0.79–2.07)0.324 RCWNA-AECOPD before the index hospitalization within 1 year (vs 0) 11.28 (0.78–2.12)0.3261.19 (0.71–1.99)0.514 2+2.25 (1.38–3.69)0.0012.01 (1.20–3.37)**0.008*Notes: Bold values indicate statistical significance (p < 0.05). NA means no event occurred in a subgroup. *Adjusted for covariates with p < 0.1 in the univariate analysis.Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BiPAP, bilevel positive airway pressure; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ESRD, end-stage renal disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Hb, hemoglobin; HR, hazard ratio; NMD, neuromuscular disease; NLR, neutrophil-to-lymphocyte ratio; RCW, respiratory care ward; WBC, white blood cell.
Table 5 shows that, when stratified by eosinophil count, NLR, history of AECOPD, and FEV1% predicted, inhaler triple therapy was not significantly associated with COPD-related readmission or overall mortality in most subgroups. The only exception was in patients with ≥2 prior AEs, where triple therapy was linked to a substantially lower risk of both readmission (aHR 0.14, 95% CI 0.05–0.44, p = 0.001) and mortality (aHR 0.24, 95% CI 0.07–0.78, p = 0.018) (Table 5).Table 5Comparison of Inhaler Triple Therapy versus No Triple Therapy for COPD-Related Readmission and Overall Mortality, Stratified by Eosinophil Count, NLR, History of AECOPD, and FEV1% PredictedSubgroupTriple TherapyNon-Triple TherapyAdjusted HRP-valueTotalEvent%TotalEvent%(95% CI)First COPD-related readmissionEosinophil count, cells/µL <300 2288738.2%1314735.9%1.00 (0.68–1.47)0.993 ≥300652741.5%22627.3%0.80 (0.27–2.37)0.682NLR <3652640.0%331030.3%0.95 (0.42–2.15)0.902 ≥32288838.6%1204335.8%0.95 (0.63–1.41)0.782AECOPD a 012458534.7%1404129.3%1.05 (0.70–1.57)0.809 2+482960.4%131292.3%0.14 (0.05–0.44)0.001****FEV1, %, predicted <501454732.4%1022423.5%1.08 (0.64–1.84)0.767 ≥501486745.3%512956.9%0.69 (0.43–1.11)0.128Overall mortality****Eosinophil count, cells/µL <300 2574216.3%1453121.4%0.89 (0.54–1.45)0.633 ≥300701420.0%25832.0%0.85 (0.31–2.34)0.753NLR <3741114.9%36513.9%1.09 (0.28–4.26)0.898 ≥32534517.8%1343425.4%0.92 (0.57–1.49)0.743AECOPD a 012724115.1%1563119.9%1.03 (0.64–1.68)0.895 2+551527.3%14857.1%0.24 (0.07–0.78)**0.018*FEV1, %, predicted <501623119.1%1132017.7%1.22 (0.66–2.25)0.532 ≥501652515.2%571933.3%0.62 (0.33–1.17)0.138Notes: *Adjusted for covariates with p<0.1 in the univariate analysis, except the stratified variable. An AECOPD before the index hospitalization within 1 year. Bold values indicate statistical significance (p < 0.05).Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; NLR, neutrophil-to-lymphocyte ratio; FEV1, forced expiratory volume in 1 second.
This retrospective cohort study evaluated the real-world long-term outcomes of triple therapy (ICS/LABA/LAMA) in patients hospitalized for COPD exacerbations, a high-risk population that is often underrepresented in randomized controlled trials. No significant differences in three-year COPD-related readmission or all-cause mortality were observed between patients who received triple therapy and those who did not. However, stratified analyses suggested that triple therapy may be associated with lower risks of COPD-related readmission and mortality in certain subgroups. These findings should be interpreted with caution given the observational design, potential residual confounding, and non-random treatment allocation. Overall, the results suggest that the effects of triple therapy may vary across patient subgroups and highlight the need for further studies to clarify which patients may benefit most.
Notably, eosinophil-based stratification did not demonstrate clear associations with outcomes in our cohort. The lack of a clear association between eosinophil-based stratification and outcomes in our study may have several explanations. First, eosinophil counts were measured during AECOPD, which may not accurately reflect the patient’s baseline inflammatory phenotype. Second, prior or early exposure to systemic corticosteroids may have suppressed eosinophil levels, thereby attenuating potential associations. Third, the relatively small sample size in the higher eosinophil subgroup (eg, ≥300 cells/μL) may have limited statistical power to detect meaningful differences. Therefore, these findings should be interpreted with caution.
Three major randomized controlled studies have investigated the efficacy of triple therapy in patients with COPD.16,18,19 The ETHOS trial was a 52-week Phase 3 study that evaluated triple therapy using two doses of ICS in patients with moderate-to-very severe COPD (N=8509) who had at least one exacerbation within the prior year.18 They compared the ICS/LABA/LAMA therapy (budesonide/formoterol/glycopyrrolate) to a “control” group who received one of 2 dual therapies (ie, glycopyrrolate/formoterol or budesonide/formoterol). The triple therapy assessed two different ICS doses (ie, 320 µg of 160 µg of budesonide). The study found that the triple therapy resulted in a 13% to 25% lower rate (p values ≤0.003) of moderate to severe COPD exacerbations compared with the dual therapies.
The IMPACT trial was a randomized controlled study involving 10,355 patients with COPD that compared 52 weeks of once daily dosing of the ICS/LABA/LAMA combination of fluticasone furoate/vilanterol/umeclidinium with either the ICS/LABA combination fluticasone/vilanterol or LABA/LAMA combination of vilanterol/umeclidinium.16 The primary outcome was the rate of moderate or severe COPD exacerbations. Similar to the ETHOS study, they found that the triple combination resulted in a 15% to 25% reduction in the rate of moderate or severe exacerbation per year compared with the dual therapy (p values < 0.001). They also found that the triple therapy resulted in a lower rate of hospitalization due to COPD than the vilanterol/umeclidinium dual therapy.
The 52-week TRIBUTE trial investigated the efficacy of the triple ICS/LABA/LAMA therapy beclomethasone dipropionate, formoterol fumarate, and glycopyrronium compared with the dual-bronchodilator therapy indacaterol plus glycopyrronium in terms of the rate of moderate-to-severe COPD exacerbations in symptomatic COPD patients (N=1532) that.19 Included patients had severe or very severe airflow limitations and a history of exacerbations despite maintenance therapy. The triple therapy was associated with a significant reduction in the rate of moderate-to-severe exacerbations compared with the dual therapy (p=0.043).
A meta-analysis reported no increased risk of pneumonia with triple therapy compared with dual therapy.20 In contrast, other studies have suggested a potential increase in pneumonia risk despite clinical benefits.21,22 However, pneumonia outcomes were not assessed in the present study, and therefore the relevance of these findings to our cohort remains uncertain.
The mortality benefit of triple therapy observed in the three large clinical studies differs from our findings. Although the absolute risk difference of 6.4% may be clinically relevant in this high-risk population, the present study was not powered to detect modest differences in mortality, and the confidence intervals remain wide. Therefore, these findings should be interpreted with caution and considered hypothesis-generating rather than conclusive evidence of a mortality benefit. Another possible explanation is the distribution of ICS-naïve and ICS-exposed patients in our study. In the IMPACT and ETHOS studies, the proportion of ICS-naïve patients was 33% and 20%, respectively. In contrast, our study included a higher proportion of ICS-naïve subjects (43%). Subgroup analyses of ICS-naïve patients in the IMPACT and ETHOS trials found no significant difference in exacerbation risk or mortality between triple and dual therapies, suggesting that the observed benefits of triple therapy were primarily driven by patients with prior ICS exposure.20 This may explain why we did not observe a significant mortality difference in our study, since a large proportion of our study population consisted of ICS-naïve patients. Additionally, variations in primary outcomes may have played a role, as prior trials focused on reducing moderate-to-severe exacerbations, whereas our study specifically examined severe exacerbations requiring hospitalization.
Our findings suggest that COPD patients may not be a homogeneous group with respect to treatment response. However, given the relatively small subgroup sizes and multiple comparisons, these observations should be interpreted with caution and considered exploratory and hypothesis-generating. Further studies are needed to clarify whether specific patient subgroups derive differential benefit from triple therapy. Although certain subgroups appeared to show more favorable outcomes, these observations remain uncertain and may reflect underlying differences in disease severity or inflammatory patterns.23 This is consistent with prior studies, including systematic reviews and meta-analyses, which suggest that the effectiveness of triple therapy may vary according to exacerbation history, disease severity, and blood eosinophil levels.20 Overall, the triple therapy’s effectiveness was influenced by exacerbation history, disease severity, and blood eosinophil levels, suggesting its use should be tailored to specific patient characteristics. Notably, the observed association in patients with FEV1 ≥50% appears inconsistent with current GOLD recommendations, which generally support escalation to triple therapy in patients with more severe airflow limitation. One possible explanation is that FEV1 alone may not fully reflect exacerbation risk or underlying inflammatory burden. Patients with relatively preserved lung function may still experience frequent exacerbations or have distinct inflammatory phenotypes that respond to ICS-containing therapy. In addition, treatment decisions in real-world practice may be influenced by clinical factors beyond spirometric severity. Therefore, this observation should be interpreted with caution and considered exploratory.
Similarly, a meta-analysis of 60 randomized controlled trials found that triple therapy was associated with a reduced risk of all-cause mortality in COPD patients; however, predictors of this association included medication factors and patient characteristics, among which eosinophil counts of ≥200/ìL.23 For example, previous studies have reported potential benefits of triple therapy in patients with frequent exacerbations (≥2) and higher eosinophil counts (≥300 cells/µL).21 However, these findings, including ours, should be interpreted cautiously and require further validation. Overall, the available evidence highlights the need for individualized treatment strategies while emphasizing the uncertainty of subgroup-specific effects.
In our cohort, 84% of patients were male. This marked male predominance is consistent with previous hospital-based studies of severe COPD and AECOPD in Asian populations, where men constitute 60–90% of hospitalized cases, largely reflecting higher smoking rates and occupational exposures among older men.24,25 However, contemporary global data indicate that the burden of COPD among women is increasing.26 Therefore, our findings are most generalizable to predominantly male, smoking-related COPD populations in East Asia, and caution is warranted when extrapolating these results to female patients or settings with a more balanced sex distribution.
It is also important to acknowledge that the GOLD recommendations for inhaled pharmacologic therapy evolved during the study period. Earlier GOLD reports allowed relatively broad use of ICS/LABA and triple therapy in high-risk patients, whereas more recent updates (from 2017 onwards) have prioritized LABA/LAMA combinations as first-line maintenance therapy and reserved ICS-containing regimens, including triple therapy, for selected patients with frequent exacerbations and/or elevated blood eosinophil counts.27–29 These evolving recommendations, together with the increasing availability of single-inhaler triple combinations, may have contributed to temporal changes in prescribing patterns and to the concentration of more severe or exacerbation-prone patients in the triple-therapy group, further limiting causal interpretation of our observational findings.29
The strengths of this research include its substantial sample size of 500 COPD patients, comprehensive data collection spanning from 2015 to 2023, and detailed analysis of multiple clinical parameters including baseline characteristics, respiratory functions, and long-term outcomes. In addition, the findings reflect the use of treatment in a real-world setting.
However, several limitations should be acknowledged. First, the observational nature of this study precludes definitive conclusions regarding causal relationships between triple therapy and patient outcomes. Second, potential selection bias may exist due to differences in baseline characteristics between groups; patients who received triple therapy differed in age, comorbidities, baseline lung function, inflammatory profiles, and prior inhaler use compared with those who did not. In addition, the comparator group was heterogeneous, comprising LAMA monotherapy, LABA/LAMA, and LABA/ICS regimens, which have different expected effects on exacerbation risk and mortality. This heterogeneity may have diluted treatment effects and limited direct comparability between groups. As a result, the observed associations should be interpreted with caution, as the choice of comparator may have influenced the estimated treatment effects. Third, given the retrospective design, treatment decisions were made according to clinical judgment and evolving GOLD recommendations rather than through randomized allocation, which may have introduced bias. Temporal changes in guideline recommendations and prescribing patterns during the study period may have further influenced treatment allocation. Fourth, patients receiving triple therapy may differ systematically from those receiving other regimens due to clinical decision-making, introducing potential confounding by indication. Although multivariable Cox regression was applied to adjust for measured covariates, residual confounding cannot be excluded. Fifth, the limited sample size and heterogeneity of treatment regimens in the comparator group restricted the use of more advanced statistical techniques, such as propensity score matching or inverse probability weighting, as these approaches may have resulted in substantial loss of sample size or unstable estimates. In addition, the heterogeneity of the comparator group, including LAMA monotherapy, LABA/LAMA, and LABA/ICS regimens, may have further limited comparability and influenced the estimated treatment effects. Although multivariable adjustment was performed, it may not have fully accounted for residual confounding. Sixth, the sample size may have been insufficient to detect small or moderate differences in outcomes, particularly in subgroup analyses, which may have limited statistical power. As a result, negative findings should be interpreted with caution. Seventh, data on other pharmacologic interventions (eg, phosphodiesterase inhibitors, theophylline, long-term macrolide therapy) and non-pharmacologic measures (eg, pulmonary rehabilitation) were not systematically collected, potentially leading to unmeasured confounding. Eighth, relevant cardiovascular comorbidities, including arrhythmias, heart failure, and valvular heart disease, were not captured in the dataset and may have influenced outcomes. In addition, although Gray’s test was used to compare cumulative incidence functions, competing-risk regression models (eg, Fine–Gray models) were not applied in multivariable analyses. Therefore, the potential impact of competing risks, particularly mortality, may not have been fully accounted for. Further, both single-inhaler and multiple-inhaler triple therapy were included in this study, and differences in adherence between these approaches may have influenced outcomes. Finally, although subgroup analyses were performed, the mechanisms underlying the observed associations in patients with multiple prior exacerbations remain unclear, and these findings should be interpreted with caution. Therefore, the results of this study should be considered associative rather than causal or comparative effectiveness evidence.
In this retrospective cohort study, triple therapy (ICS/LABA/LAMA) showed no significant impact on overall COPD exacerbation-related hospital readmission rates or mortality within three years following the indexed hospitalization for COPD exacerbations. However, stratified analyses suggested possible benefits in selected high-risk subgroups; however, these findings require cautious interpretation and further validation. These findings underscore the importance of personalized treatment approaches in managing COPD, where triple therapy may be most beneficial for targeted populations rather than as a universal strategy. Further prospective studies are warranted to validate these subgroup-specific effects and guide clinical decision-making in real-world settings.