Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
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Original Article

Volume 17, Number 9, October 2025, pages 507-517

Evaluating the Effectiveness of Triple Therapy in Chronic Obstructive Pulmonary Disease Patients: An Asian Population-Based Survey

Figure

↓  Figure 1. Study flowchart for the composite outcome. COPD: chronic obstructive pulmonary disease; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; ICSs: inhaled corticosteroids.
Figure 1.

Tables

↓  Table 1. Baseline Characteristics of Study Population
 
Variables Triple therapy (n = 16,792) LABA + LAMA (n = 4,205) Total (n = 20,997) P value
ACEI: angiotensin-converting enzyme inhibitor; ACOs: asthma-COPD overlap syndrome; ARB: angiotensin II receptor blockers; BZD: benzodiazepine; CCB: calcium channel blocker; GERD: gastroesophageal reflux disease; LABA: long-acting beta2-agonists; LAMA: long-acting muscarinic antagonists; NSAID: non-steroid anti-inflammatory drug; PPI: proton-pump inhibitor; SABA: short-acting beta-agonists; SAMA: short-acting muscarinic antagonist; SCC: systematic corticosteroid.
Age, years old, mean (SD) 67.19 (10.72) 65.77 (11.73) 66.06 (11.54) < 0.0001
Age group < 0.0001
  < 65yeras old 7,905 (47.08) 1,764 (41.95) 9,669 (46.05)
  ≥ 65 years old 8,887 (52.92) 2,441 (58.05) 11,328 (53.95)
Gender, n (%) < 0.0001
  Male 9,877 (58.79) 3,100 (73.70) 12,977 (61.80)
  Female 6,915 (41.21) 1,105 (26.30) 8,020 (38.20)
Geographic area, n (%) 0.4935
  North 9,246 (55.06) 2,129 (50.63) 11,375 (54.17)
  Middle 2,656 (15.82) 741 (17.62) 3,397 (16.18)
  South 4,513 (26.88) 1,184 (28.16) 5,697 (27.13)
  East 377 (2.24) 151 (3.59) 528 (2.52)
COPD exacerbation (moderate or severe) 0.7758
  0 13,213 (78.70) 3,325 (79.12) 16,538 (78.78)
  1 1,625 (9.74) 392 (9.28) 2,017 (9.61)
  ≥ 2 1,954 (11.56) 488 (11.60) 24,42 (11.61)
  Disease duration 207.8 (277.3) 183.9 (266) 203.1 (275.3) < 0.0001
Urbanization, n (%) 0.023
  Urban 9,583 (57.07) 2,303 (54.77) 11,886 (56.60)
  Suburban 5,257 (31.31) 1,348 (32.06) 6,605 (31.46)
  Rural 1,870 (11.13) 527 (12.53) 2,397 (11.42)
  Unknown 82 (0.49) 27 (0.64) 109 (0.52)
Insurance premium, n (%) 0.4935
  Less than minimum monthly wage 4,161 (24.77) 1,064 (25.30) 5,225 (24.88)
  More than minimum monthly wage 12,631 (75.23) 3,141 (74.70) 15,772 (75.12)
Comorbidity, n (%)
  Hypertension 5,348 (31.80) 1,504 (35.80) 6,852 (32.63) < 0.0001
  Atrial fibrillation 925 (5.50) 242 (5.80) 1,167 (5.56) 0.5327
  Ischemic stroke 884 (5.26) 243 (5.78) 1,127 (5.37) 0.1856
  Hemorrhagic stroke 93 (0.55) 28 (0.67) 121 (0.58) 0.3907
  Heart failure 1,045 (6.22) 297 (7.06) 1,342 (6.39) 0.0465
  Dyslipidemia 2,730 (16.25) 743 (17.67) 3,473 (16.54) 0.0276
  Cardiac arrhythmia 1,144 (6.81) 334 (7.84) 1,478 (7.04) 0.0104
  Peripheral vascular disease 121 (0.72) 31 (0.74) 152 (0.72) 0.9094
  Rheumatic heart disease 143 (0.85) 35 (0.83) 178 (0.85) 0.9031
  ACOs 2,248 (13.39) 267 (6.35) 2,515(11.98) < 0.0001
  Pneumonia 2,237 (13.32) 645 (15.34) 2,882 (13.73) 0.0007
  Acute bronchitis 2,647 (15.76) 689 (16.4) 3,336 (15.89) 0.324
  Influenza 335 (1.99) 89 (2.12) 424 (2.02) 0.6163
  Dementia 371 (2.21) 100 (2.38) 471 (2.24) 0.5088
  Depression 605 (3.60) 123 (2.93) 728 (4.37) 0.0317
  Parkinsonism 241 (1.44) 50 (1.19) 291 (1.39) 0.2221
  Diabetes mellitus 2,394 (14.26) 674 (16.03) 3,068 (14.61) 0.0036
  Chronic kidney disease 651 (3.88) 180 (4.28) 831 (3.96) 0.2298
  Chronic liver disease 625 (3.72) 167 (3.97) 792 (3.77) 0.4477
  Coronary artery disease 2,040 (12.15) 612 (14.55) 2,652 (12.63) < 0.0001
  GERD 2,222 (13.23) 434 (10.32) 2,656 (12.65) < 0.0001
  Malignancy 2,021 (12.04) 525 (12.49) 2,546 (12.13) 0.4244
  Sepsis 371 (2.21) 105 (2.50) 476 (2.27) 0.2624
Co-medication, n (%)
  Antiplatelet agents 262 (1.56) 78 (1.85) 340 (1.62) 0.1758
  Anticoagulants 4,900 (29.18) 1,128 (26.83) 6,028 (28.71) 0.0025
  Lipid-lowering drugs 219 (1.30) 70 (1.66) 289 (1.38) 0.0728
  PPI 729 (4.34) 152 (3.61) 881 (4.20) 0.0356
  H­2-blocker 220 (1.31) 53 (1.26) 273 (1.30) 0.799
  BZD drugs or Z-drugs 133 (0.79) 45 (1.07) 178 (0.85) 0.0786
  Antipsychotics 635 (3.78) 143 (3.40) 778 (3.71) 0.2423
  Opioids 1,629 (9.70) 377 (8.97) 2,006 (9.55) 0.1468
  Systematic corticosteroids 395 (2.35) 95 (2.26) 490 (2.33) 0.7206
  NSAID 206 (1.23) 44 (1.05) 250 (1.19) 0.3348
  CCB 267 (1.59) 92 (2.19) 359 (1.71) 0.0075
  Diuretics 621 (3.70) 162 (3.85) 783 (3.73) 0.6366
  ACEI 2,798 (16.66) 667 (15.86) 3,465 (16.50) 0.211
  ARB 352 (2.09) 110 (2.62) 20,535 (97.8) 0.0399
  Beta-blocker 408 (2.43) 80 (1.90) 488 (2.32) 0.0086
  Digoxin 25 (0.15) 7 (0.17) 32 (0.15) 0.7937
  Antiarrhythmics 3,123 (18.60) 758 (18.03) 3,881 (18.48) 0.3928
  Nitrates 1,567 (9.23) 368 (8.75) 1,935 (9.22) 0.2353
  Influenza vaccine 1,635 (9.74) 465 (11.06) 2,100 (10.00) 0.0106
  Pneumococcal vaccine 3,196 (19.03) 882 (20.98) 4,078 (19.42) 0.0044

 

↓  Table 2. The Study Outcomes of Counting Cox Model
 
Observation period (days) Event number Crude HR (95% CI) Adjusted HR (95% CI)
COPD: chronic obstructive pulmonary disease; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; HR: hazard ratio; CI: confidence interval.
Primary outcomes
  Primary outcome 1
    LABA + LAMA 2,490,676 1,534 1 (reference)
    Triple therapy 7,355,285 5,105 1.081 (1.020 - 1.145) 1.162 (1.098 - 1.230)
  Primary outcome 2
    LABA + LAMA 2,490,676 1,475 1 (reference)
    Triple therapy 7,355,285 4,982 1.097 (1.034 - 1.164) 1.171 (1.105 - 1.241)
Secondary outcomes
  All-cause mortality
    LABA + LAMA 3,676,382 779 1 (reference)
    Triple therapy 10,547,405 1,902 0.842 (0.779 - 0.910) 1.074 (0.994 - 1.161)
  Respiratory-related mortality
    LABA + LAMA 3,676,405 524 1 (reference)
    Triple therapy 10,547,405 1,292 0.846 (0.770 - 0.930) 1.089 (0.991 - 1.196)
  Moderate COPD exacerbation
    LABA + LAMA 3,146,834 494 1 (reference)
    Triple therapy 9,247,962 1,688 1.033 (0.934 - 1.143) 1.027 (0.931 - 1.134)
  Sever COPD exacerbation
    LABA + LAMA 3,572,160 88 1 (reference)
    Triple therapy 10,221,161 445 1.335 (1.059 - 1.683) 1.346 (1.078 - 1.682)
  Acute respiratory failure
    LABA + LAMA 3,628,098 95 1 (reference)
    Triple therapy 10,425,265 323 1.132 (1.061 - 1.207) 1.315 (1.047 - 1.653)
  Pneumonia
    LABA + LAMA 3,325,536 539 1 (reference)
    Triple therapy 9,563,094 1,715 1.149 (1.043 - 1.266) 1.221 (1.109 - 1.344)
  Respiratory-related admission
    LABA + LAMA 2,748,346 614 1 (reference)
    Triple therapy 7,986,776 2,163 1.189 (1.087 - 1.301) 1.264 (1.157 - 1.382)

 

↓  Table 3. The Study Outcomes of Conventional Cox Model
 
Observation period (days) Event number Crude HR (95% CI) Adjusted HR (95% CI)
The multivariable models were adjusted for baseline characteristics, comorbidities, and concomitant medications. COPD: chronic obstructive pulmonary disease; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; HR: hazard ratio; CI: confidence interval.
Primary outcomes
  Primary outcome 1
    LABA + LAMA 2,490,676 1,534 1 (reference)
    Triple therapy 7,355,285 5,105 0.978 (0.930 - 1.030) 1.004 (0.954 - 1.056)
  Primary outcome 2
    LABA + LAMA 2,490,676 1,475 1 (reference)
    Triple therapy 7,355,285 4,982 0.988 (0.938 - 1.041) 1.013 (0.961 - 1.067)
Secondary outcomes
  All-cause mortality
    LABA + LAMA 3,676,382 779 1 (reference)
    Triple therapy 10,547,405 1,902 0.989 (0.916 - 1.068) 1.110 (1.011 - 1.219)
  Respiratory-related mortality
    LABA + LAMA 3,676,405 524 1 (reference)
    Triple therapy 10,547,405 1,292 1.032 (0.936 - 1.137) 1.179 (1.046 - 1.329)
  Moderate COPD exacerbation
    LABA + LAMA 3,146,834 494 1 (reference)
    Triple therapy 9,247,962 1,688 1.159 (1.058 - 1.271) 1.134 (1.034 - 1.244)
  Sever COPD exacerbation
    LABA + LAMA 3,572,160 88 1 (reference)
    Triple therapy 10,221,161 445 0.333 (0.300 - 0.371) 0.323 (0.291 - 0.361)
  Acute respiratory failure
    LABA + LAMA 3,628,098 95 1 (reference)
    Triple therapy 10,425,265 323 1.313 (1.041 - 1.658) 1.406 (1.112 - 1.780)
  Pneumonia
    LABA + LAMA 3,325,536 539 1 (reference)
    Triple therapy 9,563,094 1,715 1.007 (0.919 - 1.105) 1.040 (0.948 - 1.141)
  Respiratory-related admission
    LABA + LAMA 2,748,346 614 1 (reference)
    Triple therapy 7,986,776 2,163 1.168 (1.072 - 1.273) 1.200 (1.101 - 1.308)

 

↓  Table 4. Sensitivity Analysis of Population Excluding Asthma-COPD Overlap Patients
 
Observation period (days) Event number Crude HR (95% CI) Adjusted HR (95% CI)
The multivariable models were adjusted for baseline characteristics, comorbidities, and concomitant medications. COPD: chronic obstructive pulmonary disease; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; HR: hazard ratio; CI: confidence interval.
Primary outcomes
  Primary outcome 1
    LABA + LAMA 2,442,682 1,490 1 (reference)
    Triple therapy 6,333,410 4,473 1.117 (1.053 - 1.185) 1.174 (1.107 - 1.246)
  Primary outcome 2
    LABA + LAMA 2,442,682 1,434 1 (reference)
    Triple therapy 6,333,410 4,359 1.130 (1.064 - 1.200) 1.187 (1.117 - 1.261)
Secondary outcomes
  All-cause mortality
    LABA + LAMA 3,616,963 868 1 (reference)
    Triple therapy 9,158,924 1,988 0.905 (0.835 - 0.980) 1.017 (0.938 - 1.102)
  Respiratory-related mortality
    LABA + LAMA 3,616,986 590 1 (reference)
    Triple therapy 9,158,924 1,352 0.902 (0.819 - 0.994) 1.027 (0.932 - 1.132)
  Moderate COPD exacerbation
    LABA + LAMA 3,068,886 491 1 (reference)
    Triple therapy 7,999,751 1,493 1.031 (0.930 - 1.143) 1.064 (0.959 - 1.180)
  Sever COPD exacerbation
    LABA + LAMA 3,521,047 89 1 (reference)
    Triple therapy 8,863,890 387 1.312 (1.039 - 1.657) 1.370 (1.084 - 1.732)
  Acute respiratory failure
    LABA + LAMA 3,201,942 81 1 (reference)
    Triple therapy 8,157,867 259 1.227 (0.955 - 1.577) 1.375 (1.066 - 1.772)
  Pneumonia
    LABA + LAMA 3,303,350 492 1 (reference)
    Triple therapy 8,449,309 1,283 1.064 (0.959 - 1.181) 1.162 (1.046 - 1.291)
  Respiratory-related admission
    LABA + LAMA 3,201,942 569 1 (reference)
    Triple therapy 8,157,867 1,681 1.122 (1.020 - 1.235) 1.216 (1.104 - 1.338)