Abstract
Background
Chronic obstructive pulmonary disease (COPD) is a global health concern, characterised by exacerbations, worsening outcomes and increasing costs. Real-world studies are essential for understanding treatment regimens and long-term outcomes.
Objective
TETRIS focused on the impact of triple therapy in managing COPD.
Trial Design
TETRIS was a prospective, observational study that enrolled 1,196 patients with COPD from 134 centres who were on triple therapy for at least 2–48 weeks prior to inclusion.
Methods
The primary objectives were to quantify the proportion of patients continuously receiving triple therapy at 6, 12 and 24 months and assess time to discontinuation using Kaplan–Meier methodology. Clinical outcomes and therapy changes were evaluated overall and in subgroups by dosing regimen (once-daily [OD] vs. twice-daily [BID]) and specific single-inhaler triple therapies.
Results
Persistence with triple therapy was 92.5%, 84.4% and 38.5% at 6, 12 and 24 months, respectively. Only 10% of patients changed therapy over 24 months. At 24 months, the mean change in CAT sum score since baseline was −4.4 among patients on OD triple therapy (FF/UMEC/VI OD). The overall CAT responder rate was 50.1%. Exacerbation and hospitalisation rates remained low throughout the study. The composite endpoint of clinically important deterioration occurred in 53.6% of patients, with lower rates of 45.9% among patients receiving FF/UMEC/VI OD.
Conclusion
In this real-world cohort, 38.5% of patients remained on triple therapy at 24 months, and most patients did not require a change in their initial therapy. The steep drop at 24 months was mostly because only few patients remained under observation since the protocol permitted study completion at 18 months, and any patient who dropped out from the study was not censored but counted as patient no longer on continuous triple therapy. These findings support the effectiveness and stability of triple therapy in routine practice and highlight the value of OD single-inhaler regimens in optimising COPD management.
Registration
Keywords: chronic obstructive pulmonary disease, triple therapy, single-inhaler triple therapy, multiple-inhaler triple therapy, treatment adherence, persistence with therapy
Introduction
Globally, chronic obstructive pulmonary disease (COPD) is one of the major public health concerns associated with significant morbidity, mortality and socio-economic burden.1,2 Being the third leading cause of mortality worldwide, the burden of COPD is anticipated to grow in the coming decades due to persistent exposure to risk factors and an increasing ageing population.2,3 COPD exacerbations, defined as acute worsening of respiratory symptoms requiring additional therapy, exert a profound and prolonged negative impact on the lung function and health status of patients.4,5 Exacerbations are associated with an increased risk of further exacerbations and mortality, contributing to the greatest proportion of COPD-related healthcare costs.2,6 Consequently, COPD treatment goals aim to minimise the negative impact of current exacerbations and prevent subsequent exacerbations. 2
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend a step up to triple therapy in patients with a high symptom burden and exacerbation risk who continue to experience exacerbations despite receiving initial maintenance therapy. 2 However, these recommendations are primarily based on evidence from randomised controlled trials (RCTs) that include a highly selected patient population. Treatment recommendations from RCTs cannot necessarily be extrapolated to unselected patient populations in real-world settings. 7 RCTs are conducted based on robust protocols with control groups and randomised treatment selection. In contrast, real-world studies include broader patient populations such as older adults, smokers, or those with comorbidities, better representing the profiles typically observed in routine clinical practice. These studies also account for patient adherence and persistence shaped by daily routines. As a result, real-world studies are essential for enhancing our understanding of factors influencing treatment outcomes in patients with COPD. 8
A real-world German claims data study by Vogelmeier et al. demonstrated that single-vs. multiple-inhaler triple therapy (SITT vs. MITT) for COPD was associated with significantly higher adherence and persistence to treatment over 6–18 months following treatment initiation. 9 The real-world ELLITHE study conducted in Germany demonstrated the benefits of once-daily (OD) SITT on the health status and lung function of patients with COPD after 12 months of treatment. However, this study included 63.9% patients who were stepped up from their dual therapies and 18% patients who were switched from MITTs to OD SITT. 10 To the best of our knowledge, no prospective, non-interventional study to date has investigated the treatment journeys of patients with COPD already receiving triple therapy.
The Triple thErapy in paTients with COPD under Real lIve Setting (TETRIS) study aimed to provide a better understanding of factors influencing treatment decisions made by German physicians and the reasons behind these changes. TETRIS also aimed to provide data on the proportion of patients with COPD who continuously remain on triple therapy and compare clinical outcomes based on the subgroup stratification over a 24-month period.
Materials and methods
Study design, population and conduct
The TETRIS study was a prospective, observational study conducted between 14 January 2021 (first patient, first visit) and 5 July 2024 (last patient, last visit) across 134 centres in Germany. The study included patients with COPD with or without comorbid asthma already treated with triple therapy for at least 2–48 weeks (Supplemental Figure S1). Patients were considered eligible if they met all inclusion criteria and no exclusion criteria (Supplemental Table S1). Reporting for this study adheres to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for observational studies. 11
Data were collected in two parts during routine patient visits: Part 1 involved the cross-sectional phenotyping of patients at study enrolment/baseline (visit 1 [V1]). Part 2 involved a 24-month longitudinal follow-up period during which each patient was monitored, and all visits (i.e. V2, V3 and V4 after approximately 6 [-3/+2], 12 [-3/+5] and 24 [-6/+no limit] months, respectively) were documented. Notably, the interval between V3 and V4 was approximately 12 months (i.e. twice the duration between V1 and V2 as well as between V2 and V3).
Details of any additional visits to the treatment centre between the baseline visit and the 24-month follow-up were recorded, including safety data, exacerbations, hospital stays, treatment changes and the reasons for the treatment change. No adjustments were made for confounding factors.
Objectives and endpoints
The primary objective and endpoint were to describe the percentage of patients with diagnosed COPD with or without comorbid asthma who continuously received triple therapy for 6, 12 and 24 months following study enrolment. Continuous treatment was defined as uninterrupted use of triple therapy throughout the respective follow-up period, assessed relative to the baseline population and irrespective of patient attrition during the study. An additional primary endpoint was time to discontinuation of triple therapy. 12
A detailed list of the secondary objectives and endpoints is provided in Supplemental Table S2. SITT and MITT were evaluated separately and in combination when analysing information from the primary and secondary endpoints.
TETRIS also evaluated the composite endpoint of clinically important deterioration (CID), which is defined as a 100-mL decrease of FEV1 from baseline to 24 months, or >2-unit increase in CAT sum score from baseline, or any documented exacerbation, or all-cause mortality. Clinical studies include the St. George’s Respiratory Questionnaire (SGRQ) score or the CAT sum score to evaluate CID.13,14 In the real-world TETRIS study, we used the CAT sum score as a surrogate for SGRQ since it offers comparable sensitivity while better reflecting routine clinical practice.
TETRIS evaluated a total of 14 COPD subgroups (Supplemental Text 1) separately for all analyses related to primary and secondary endpoints. Here, we report the final results at baseline and at 6-, 12- and 24-month follow-up visits in the overall population and two subgroups stratified based on (i) dosing of triple therapy: OD (n=562) vs. twice-daily (BID, n=563) triple therapy and (ii) different SITT regimen the patients were using during the study: fluticasone furoate, umeclidinium and vilanterol administered OD (FF/UMEC/VI OD [n=562]) vs. beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide administered BID (BDP/FOR/GLY BID [n=285]) vs. budesonide, glycopyrrolate and formoterol fumarate administered BID (BUD/GLY/FOR BID [n=102]).
Power calculation
A total observation period of 24 months was chosen for this observational study to gain insights on the long-term maintenance of triple therapy. Within the primary endpoint—description of the percentage of patients with a physician’s diagnosis of COPD with or without comorbid asthma who continuously receive triple therapy for an additional 6, 12 and 24 months period after study enrolment—we focused on the percentage of patients on a continuous triple therapy regimen for 24 months. The power calculation was based on the precision of the estimate for this endpoint. A formal sample size calculation was not performed.
It was assumed that approximately 35% of all patients would continuously remain on triple therapy 24 months after study enrolment. For a sample size of 740 patients with a target width of 7%, the corresponding 95% confidence interval ranged from 31.6% to 38.7%. Since data for this planned analysis were necessary for 24 months, a sample size of approximately 1,100 patients was determined, considering a drop-out rate of about 30%.
Interim analyses
Two interim analyses were performed, and the results have been published.12,15 The first analysis collected and analysed cross-sectional data/baseline characteristics after at least 825 patients had been recruited (approximately 75% of the total study population). 12 The second analysis included 6- and 12-month data for a subset of the study population after recruitment was completed. 15
The final analysis was performed after a 24-month follow-up from study enrolment and included all patients who signed the informed consent form, met all inclusion criteria and none of the exclusion criteria and completed visit 1. This population was considered the primary analysis population for all endpoints, including safety data. Therefore, there was no difference between the safety analysis set (SAS) and full analysis set (FAS).
Statistical analysis
TETRIS was an observational study; hence, it was not powered to detect differences, and formal hypothesis testing was not conducted for any of the endpoints. Continuous measures were analysed by the number of non-missing values, mean, median, minimum, maximum, and standard deviation (SD); discrete and categorical measures were analysed by frequencies and percentages, and event/survival endpoints were analysed by event rates per patient-year and Kaplan–Meier estimates.
Analyses were based on available data. Missing data were not imputed and were displayed as a separate category. Further details on the handling of missing data are presented in Supplemental Text 2.
Primary endpoint calculations
The Kaplan–Meier method is a non-parametric approach that estimates the probability of remaining on continuous triple therapy over time, accounting for both events, discontinuations of triple therapy and missing observations (drop-out patients who did not discontinue triple therapy during the observation period but ended study participation regularly before the examined timepoint or were lost to follow-up). Notably, the high number of drop-outs observed from day 660 onward had a substantial impact on the estimated survival probabilities and should be considered when interpreting the persistence rates. All statistical analyses were performed using standard survival analysis techniques, and the number of patients at risk was reported at each time point to provide transparency regarding the influence of events and drop-outs on the results. Reasons for triple therapy discontinuation were assessed through physician/patient multiple choice questionnaire.
Results
A total of 1,273 patients with COPD were screened, and baseline data were documented for 1,255 patients, of whom 1,212 met the eligibility criteria. Among the 1,212 patients, 1,196 were considered for the FAS and SAS; 16 patients were excluded from the analysis due to missing critical data. 231 patients (19.3%) discontinued the study prematurely, with the most common reasons being loss to follow-up (n=120; 10.0%), death (n=47, 3.9%) and consent withdrawal (n=23, 1.9%). Here, we provide an overview of the most relevant patient characteristics at baseline in the overall population and the two subgroups. A more detailed and comprehensive overview is available in Table 1.
Table 1.
Patient demographics and baseline characteristics in the overall population and across the two subgroups.
| Characteristic | Overall | OD triple therapy | BID triple therapy | FF/UMEC/VI OD | BDP/FOR/GLY BID | BUD/GLY/FOR BID |
|---|---|---|---|---|---|---|
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| Patient demographics at baseline | ||||||
| Age, years, mean (SD) | 66.4 (9.7) | 65.9 (9.9) | 67.0 (9.5) | 65.9 (9.9) | 66.1 (9.3) | 66.8 (9.9) |
| Sex, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| Male | 634 (53.0) | 295 (52.5) | 305 (54.2) | 295 (52.5) | 153 (53.7) | 59 (57.8) |
| Female | 562 (47.0) | 267 (47.5) | 258 (45.8) | 267 (47.5) | 132 (46.3) | 43 (42.2) |
| Smoking status, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| Lifelong non-smoker | 106 (8.9) | 56 (10.0) | 45 (8.0) | 56 (10.0) | 24 (8.4) | 8 (7.8) |
| Current smoker | 454 (38.0) | 224 (39.9) | 200 (35.5) | 224 (39.9) | 99 (34.7) | 37 (36.3) |
| Previous smoker | 636 (53.2) | 282 (50.2) | 318 (56.5) | 282 (50.2) | 162 (56.8) | 57 (55.9) |
| Comorbidities (multiple answers possible), n (%) | ||||||
| Heart disease | 419 (35.0%) | 174 (31.0) | 224 (39.8) | 174 (31.0) | 122 (42.8) | 36 (35.3) |
| None | 362 (30.3) | 190 (33.8) | 153 (27.2) | 190 (33.8) | 76 (26.7) | 28 (27.5) |
| Other respiratory, thoracic and mediastinal disorders | 354 (29.6) | 165 (29.4) | 174 (30.9) | 165 (29.4) | 85 (29.8) | 46 (45.1) |
| Metabolism and nutrition disorders | 151 (12.6) | 65 (11.6) | 71 (12.6) | 65 (11.6) | 39 (13.7) | 5 (4.9) |
| Musculoskeletal, connective tissue and bone diseases | 142 (11.9) | 60 (10.7) | 66 (11.7) | 60 (10.7) | 22 (7.7) | 15 (14.7) |
| Endocrine disorders | 140 (11.7) | 62 (11.0) | 71 (12.6) | 62 (11.0) | 40 (14.0) | 10 (9.8) |
| Vascular disease | 138 (11.5) | 70 (12.5) | 57 (10.1) | 70 (12.5) | 27 (9.5) | 5 (4.9) |
| Gastrointestinal disorders | 78 (6.5) | 42 (7.5) | 32 (5.7) | 42 (7.5) | 18 (6.3) | 4 (3.9) |
| Psychiatric illness | 77 (6.4) | 42 (7.5) | 32 (5.7) | 42 (7.5) | 12 (4.2) | 5 (4.9) |
| Surgical and medical interventions | 75 (6.3) | 43 (7.7) | 26 (4.6) | 43 (7.7) | 14 (4.6) | 5 (4.9) |
| COPD with or without asthma, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| COPD with asthma | 166 (13.9) | 56 (10.0) | 101 (17.9) | 56 (10.0) | 42 (14.7) | 11 (10.8) |
| COPD without asthma | 1030 (86.1) | 506 (90.0) | 462 (82.1) | 506 (90.0) | 243 (85.3) | 91 (89.2) |
| With currently diagnosed chronic bronchitis, n (%) | ||||||
| | 245 (20.5) | 126 (22.4) | 106 (18.8) | 126 (22.4) | 40 (14.0) | 41 (40.2) |
| Attendance in DMP, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| Yes | 702 (58.7) | 340 (60.5) | 335 (59.5) | 340 (60.5) | 163 (57.2) | 69 (67.6) |
| Patient characteristics at baseline | ||||||
| GOLD A–D, n (%) | ||||||
| Missing | 197 (16.5) | 82 (14.6) | 96 (17.1) | 82 (14.6) | 46 (16.1) | 22 (21.6) |
| GOLD A | 163 (13.6) | 82 (14.6) | 64 (11.4) | 82 (14.6) | 24 (8.4) | 11 (10.8) |
| GOLD B | 525 (43.9) | 250 (44.5) | 255 (45.3) | 250 (44.5) | 140 (49.1) | 42 (41.2) |
| GOLD C | 160 (13.4) | 93 (16.5) | 58 (10.3) | 93 (16.5) | 24 (8.4) | 12 (11.8) |
| GOLD D | 151 (12.6) | 55 (9.8) | 90 (16.0) | 55 (9.8) | 51 (17.9) | 15 (14.7) |
| GOLD 1–4, n (%) | ||||||
| Missing | 231 (19.3) | 125 (22.2) | 95 (16.9) | 125 (22.2) | 56 (19.6) | 19 (18.6) |
| GOLD 1 | 89 (7.4) | 50 (8.9) | 34 (6.0) | 50 (8.9) | 20 (7.0) | 3 (2.9) |
| GOLD 2 | 454 (38.0) | 209 (37.2) | 214 (38.0) | 209 (37.2) | 93 (32.6) | 36 (35.3) |
| GOLD 3 | 335 (28.0) | 156 (27.8) | 158 (28.1) | 156 (27.8) | 80 (28.1) | 28 (27.5) |
| GOLD 4 | 87 (7.3) | 22 (3.9) | 62 (11.0) | 22 (3.9) | 36 (12.6) | 16 (15.7) |
| Duration since COPD diagnosis (months) | ||||||
| Non-missing | 894 | 413 | 424 | 413 | 215 | 83 |
| Mean (SD) | 82.5 (65.5) | 82.5 (63.9) | 80.6 (64.3) | 82.5 (63.9) | 85.7 (65.4) | 56.9 (55.6) |
| Peripheral blood eosinophil count [cells/µl], n (%) | ||||||
| Total N | 94 | 38 | 51 | 38 | 30 | 8 |
| <100 | 22 (23.4) | 7 (18.4) | 14 (27.5) | 7 (18.4) | 11 (36.7) | 0 (0.0) |
| 100–199 | 25 (26.6) | 12 (31.6) | 11 (21.6) | 12 (31.6) | 6 (20.0) | 1 (12.5) |
| 200–299 | 18 (19.1) | 8 (21.1) | 10 (19.6) | 8 (21.1) | 4 (13.3) | 3 (37.5) |
| ≥300 | 29 (30.9) | 11 (28.9) | 16 (31.4) | 11 (28.9) | 9 (30.0) | 4 (50.0) |
| CAT sum score | ||||||
| Non-missing | 935 | 411 | 476 | 411 | 266 | 64 |
| Mean (SD) | 19.5 (7.2) | 19.1 (7.1) | 20.0 (7.2) | 19.1 (7.1) | 20.8 (7.0) | 17.7 (7.4) |
| EQ-5D-5L/VAS Done, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| Yes | 894 (74.7) | 391 (69.6) | 459 (81.5) | 391 (69.6) | 240 (84.2) | 80 (78.4) |
| EQ-5D-5L anxiety/depression, n (%) | ||||||
| N | 894 | 391 | 459 | 391 | 240 | 80 |
| I am not scared or depressed | 436 (48.8) | 192 (49.1) | 227 (49.5) | 192 (49.1) | 99 (41.3) | 52 (65.0) |
| I am little scared or depressed | 241 (27.0) | 113 (28.9) | 116 (25.3) | 113 (28.9) | 75 (31.3) | 17 (21.3) |
| I am moderately scared or depressed | 147 (16.4) | 55 (14.1) | 83 (18.1) | 55 (14.1) | 52 (21.7) | 8 (10.0) |
| I am very scared or depressed | 60 (6.7) | 29 (7.4) | 26 (5.7) | 29 (7.4) | 10 (4.2) | 2 (2.5) |
| I am extremely scared or depressed | 10 (1.1) | 2 (0.5) | 7 (1.5) | 2 (0.5) | 4 (1.7) | 1 (1.3) |
| % predicted FEV 1 | ||||||
| Non-missing | 1053 | 469 | 521 | 469 | 264 | 93 |
| Mean (SD) | 57.1 (18.7) | 59.2 (19.2) | 55.0 (18.0) | 59.2 (19.2) | 53.8 (18.1) | 55.9 (19.2) |
| % FVC | ||||||
| Non-missing | 892 | 388 | 459 | 388 | 243 | 75 |
| Mean (SD) | 71.6 (16.9) | 73.0 (16.8) | 70.8 (16.9) | 73.0 (16.8) | 70.0 (17.1) | 71.6 (16.6) |
| Exacerbations in last 3 years before start of current triple therapy, n (%) | ||||||
| Non-missing | 1196 | 157 | 251 | 157 | 133 | 36 |
| Mean (SD) | 0.6 (1.3) | 1.4 (0.9) | 1.8 (2.1) | 1.4 (0.9) | 1.9 (2.6) | 1.9 (1.2) |
| Hospitalisations in last 3 years before start of current triple therapy, n (%) | ||||||
| Non-missing | 1196 | 32 | 99 | 32 | 53 | 20 |
| Mean (SD) | 0.1 (0.4) | 1.2 (0.8) | 1.2 (0.5) | 1.2 (0.8) | 1.2 (0.5) | 1.4 (0.8) |
| Previous treatments | ||||||
| Previous use of triple therapy | ||||||
| Number of patients (%) | 158 (13.2) | 65 (11.6) | 83 (14.7) | 65 (11.6) | 36 (12.6) | 12 (11.8) |
| Number of days, n | 116 | 50 | 57 | 50 | 27 | 9 |
| Mean (SD) | 411.7 (724.6) | 276 (469.4) | 536 (900.3) | 276.0 (469.4) | 485.8 (832.4) | 164.3 (126.1) |
| Previous therapy before initiating triple therapy, n (%) | ||||||
| N | 1196 | 562 | 563 | 562 | 285 | 102 |
| LABA/LAMA | 729 (61.0) | 344 (61.2) | 343 (60.9) | 344 (61.2) | 175 (61.4) | 74 (72.5) |
| ICS/LABA | 334 (27.9) | 147 (26.2) | 163 (29.0) | 147 (26.2) | 82 (28.8) | 11 (10.8) |
| LAMA | 76 (6.4) | 45 (8.0) | 28 (5.0) | 45 (8.0) | 13 (4.6) | 6 (5.9) |
| Other | 57 (4.8) | 26 (4.6) | 29 (5.2) | 26 (4.6) | 15 (5.3) | 11 (10.8) |
| Reasons for starting COPD triple therapy (multiple answers possible), n (%) | ||||||
| Total | 1196 | 562 | 563 | 562 | 285 | 102 |
| Symptomatic despite previous dual therapy with ICS/LABA | 280 (23.4) | 125 (22.2) | 136 (24.2) | 125 (22.2) | 61 (21.4) | 10 (9.8) |
| Symptomatic despite previous dual therapy with LAMA/LABA | 627 (52.4) | 295 (52.5) | 291 (51.7) | 295 (52.5) | 154 (54.0) | 57 (55.9) |
| Deteriorating quality of life and/or lung function despite long-term therapy | 388 (32.4) | 170 (30.2) | 204 (36.2) | 170 (30.2) | 112 (39.3) | 49 (48.0) |
| One or more exacerbations | 181 (15.1) | 65 (11.6) | 99 (17.6) | 65 (11.6) | 55 (19.3) | 19 (18.6) |
| Exacerbation prophylaxis | 254 (21.2) | 130 (23.1) | 114 (20.2) | 130 (23.1) | 67 (23.5) | 16 (15.7) |
| Patients wish to change medication or device | 241 (20.2) | 154 (27.4) | 74 (13.1) | 154 (27.4) | 45 (15.8) | 9 (8.8) |
BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; DMP, disease management program; EQ-5D-5L VAS, EuroQoL-5 Dimension 5-Level Visual Analogue Scale; FEV1, forced expiratory volume in 1 second; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; N, total number of patients; n, number of patients; OD, once daily; SD, standard deviation.
Patient demographics at baseline
Among the 1,196 patients included the mean (SD) age in the overall population was 66.4 (9.7) years, and 53.0% of patients were male. Only 8.9% of patients were lifelong non-smokers, while 38.0% were current smokers and 53.2% were previous smokers. The mean (SD) age, gender distribution and smoking status in the two subgroups were similar to those in the overall population (Table 1).
Overall, 69.7% of patients had comorbidities, with heart diseases (35.0%) being the most common, followed by other respiratory, thoracic and mediastinal disorders (29.6%). The proportion of patients with comorbidities in the two subgroups was comparable to that observed in the overall population. In both subgroups, heart diseases followed by respiratory, thoracic and mediastinal disorders were the most common comorbidities, occurring in similar proportions in the OD and BID subgroups compared to the overall population. Among patients receiving different SITTs, a notably high proportion of heart diseases and respiratory, thoracic and mediastinal disorders was observed among those treated with BDP/FOR/GLY BID (42.8%) and BUD/GLY/FOR BID (45.1%), respectively, (Table 1).
In total, 166 (13.9%) patients had comorbid asthma, and only 8 patients were diagnosed with asthma before 40 years of age, among whom 7 were categorised as having COPD without asthma at the time of study enrolment. Among patients in the OD and BID triple therapy subgroups, five and one, respectively, were diagnosed with asthma before the age of 40 years but were categorised as having COPD without asthma at the time of study enrolment. Similarly, in the FF/UMEC/VI OD and BDP/FOR/GLY BID subgroups, five and one patient, respectively, were diagnosed with asthma before the age of 40 years and were classified as having COPD without asthma at the time of study enrolment. None of the patients in the BUD/GLY/FOR BID subgroup were diagnosed with asthma before the age of 40 years.
Overall, 20.5% of patients were diagnosed with chronic bronchitis at baseline. Similar proportions were observed in the OD (22.4%) and BID (18.8%) subgroups. Among the different SITT subgroups, the prevalence of chronic bronchitis was 40.2% in BUD/GLY/FOR BID, followed by 22.4% in FF/UMEC/VI OD and 14.0% in BDP/FOR/GLY BID subgroup (Table 1).
Patient clinical characteristics at baseline
At study start in 2021, COPD was classified in accordance with the 2020 GOLD Report, using the GOLD A–D categories to evaluate symptom burden and exacerbation risk. In the overall population, the majority was classified as COPD GOLD 2 (n=454, 38.0%) and GOLD B (n=525, 43.9%), and the average (SD) duration of COPD diagnosis was 82.5 (65.5) months. The distribution of COPD GOLD A–D and GOLD 1–4 categorisations in the two subgroups were comparable to the overall population (Table 1).
Absolute numbers of eosinophils per µL were available only for 94 patients at baseline, of whom 29 (30.9%) had an eosinophil count of ≥300/µL. Among these patients, 11 (28.9%) in the OD and16 (31.4%) in the BID subgroups, as well as 11 (28.9%) in the FF/UMEC/VI OD, 9 (30.0%) in the BDP/FOR/GLY BID and 4 (50.0%) in the BUD/GLY/FOR BID subgroups had an eosinophil count ≥300/µL (Table 1).
Baseline assessments in the overall population showed a mean (SD) COPD Assessment Test (CAT) score of 19.5 (7.2) and a mean (SD) predicted forced expiratory volume in 1 second (FEV1) of 57.1% (18.7). The corresponding findings in the two strata were comparable to those observed in the overall population. During the three years prior to initiating the current triple therapy, the mean (SD) number of exacerbations and hospitalisations due to exacerbations was low, at 0.6 (1.3) and 0.1 (0.4), respectively. However, the mean number (SD) of exacerbations in the last 3 years prior to initiating the current triple therapy was 1.8 (2.1) and 1.4 (0.9) among patients receiving BID and OD triple therapy, and 1.9 (2.6), 1.9 (1.2) and 1.4 (0.9) among patients receiving BDP/FOR/GLY BID, BUD/GLY/FOR BID and FF/UMEC/VI OD, respectively. The mean number (SD) of hospitalisations was similar across the subgroups (Table 1).
Previous COPD treatments
In total, 158 patients (13.2%) had received triple therapy at least twice prior to the study: one previous therapy and another at study start. Overall, the mean (SD) duration of prior triple therapy was 411.7 (724.6) days (based on non-missing data: n=116). Among the subgroups, the mean (SD) duration on historical triple therapy was 276.0 (469.4) in the OD and 535.5 (900.3) days in the BID subgroups. For patients on SITT therapy, this was 276.0 (469.4) in the FF/UMEC/VI OD, 485.8 (832.4) in the BDP/FOR/GLY BID and 164.3 (126.1) days in the BUD/GLY/FOR BID subgroup, respectively (Table 1).
The most common reasons for initiating the current triple therapy in the overall population were being symptomatic despite the previous LABA/LAMA dual therapy (n=627; 52.4%) and deteriorating quality of life and/or lung function despite long-term therapy (n=388; 32.4%). Similar findings were observed in the two subgroups (Table 1).
Primary outcomes
The proportion of patients who continuously received triple therapy for 6, 12 and 24 months after study enrolment was 92.5%, 84.4% and 38.5%, respectively, in the overall population. Notably, continuous treatment was defined over the entire study period based on the initial baseline population, irrespective of the number of patients remaining in the study at each time point. Comparable findings were observed in the OD (93.4%, 85.6% and 40.6%) and BID (91.5%, 84.9% and 37.7%) subgroups and among the SITT therapies: FF/UMEC/VI OD (93.4%, 85.6% and 40.6%), BDP/FOR/GLY BID (91.2%, 84.2% and 36.1%) and BUD/GLY/FOR BID (92.2%, 84.3% and 45.1%) for 6, 12 and 24 months, respectively.
The Kaplan–Meier curve (Figure 1(a)) illustrates time to triple therapy discontinuation. Drop-outs (censoring) and therapy discontinuations (events) occurred throughout the 24-month period with the most pronounced decline in persistence beyond month 27 (day 840). The steep decline in persistence estimates at day 840 is mainly attributed to the fact that only 10 patients remained under observation at this timepoint. The number of patients at risk (Figure 1(b)) exhibits a noticeably steeper decline starting from day 660, which is due to the study protocol that allows regular completion at 18 months. The primary reasons for the discontinuation of triple therapy, as noted in the physicians’ report, included patient preference (∼40%–65%), lack of efficacy (∼27%–31%), deterioration in quality of life or lung function (6%–12%) and adverse events (2%–7%).
Figure 1.
Time to Stop of Triple Therapy (Kaplan–Meier analysis). BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FAS, full analysis set; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; OD, once daily.
Secondary outcomes
Changes in therapy across visits
Overall, 82.6% of patients had no change in their COPD symptoms at the 24-month visit since the last visit. Over the 24-month study period, a total of 120 patients (10%) experienced a change in their COPD maintenance therapy. Most patients demonstrated high persistence to triple therapy, with 94.5% maintaining treatment at the 6-month visit, 96.3% at the 12-month visit and 95.7% at the 24-month visit. Persistence was assessed based on each patient’s individual duration of study participation; therefore, patients who did not complete the full 24-month follow-up could still be classified as persistent with triple therapy. Similar findings were observed in the OD (99.8%, 99.8% and 99.8%) and BID (94.5, 96.6% and 96.3%) subgroups and among the SITT subgroups: FF/UMEC/VI OD (99.8%, 99.8% and 99.8%), BDP/FOR/GLY BID (98.8%, 99.1% and 98.6%) and BUD/GLY/FOR BID (100%, 100% and 100%) at 6, 12 and 24 months, respectively.
Overall, the proportion of patients with at least one switch from triple therapy to dual therapy (LAMA/LABA: 2.2%; ICS/LABA: 1.5%) after 6, 12 and 24 months of treatment was very low. While none of the patients on OD triple therapy switched, 2.1% and 1.8% of patients on BID triple therapy had at least one switch from their current triple therapy to LAMA/LABA and ICS/LABA, respectively. Among the different SITT subgroups, none of the patients on FF/UMEC/VI OD, BDP/FOR/GLY BID or BUD/GLY/FOR BID switched from their current triple therapy to LAMA/LABA or ICS/LABA. Re-escalation (i.e. change from triple to dual therapy and back to triple therapy) was rare and occurred only in 0.8% (from triple to LAMA/LABA and back) and 0.3% (from triple to ICS/LABA and back) of patients in the overall population. None of the patients in the FF/UMEC/VI OD, BDP/FOR/GLY BID or BUD/GLY/FOR BID subgroups had a re-escalation; only 0.9% (from triple to LAMA/LABA and back) and 0.2% (from triple to ICS/LABA and back) of patients on BID triple therapy required a re-escalation.
Changes in treatable traits across visits
A change in CAT sum score from baseline was observed in >50% of the OD subgroup and >56% of the BID subgroup. Additionally, changes were observed in >50% of the FF/UMEC/VI OD, >63% of the BDP/FOR/GLY BID and >34% of the BUD/GLY/FOR BID subgroups (Table 2). Changes in CAT sum scores from baseline to follow-up visits are depicted in Figure 2(a). A mean ± SD improvement of −2.75 ± 7.91 points was observed in the overall population. The corresponding values among patients on FF/UMEC/VI OD, BDP/FOR/GLY BID, and BUD/GLY/FOR BID were −4.36 ± 7.28, −3.39 ± 8.32 and −0.35 ± 7.78, respectively, at 24 months. The CAT responder rates, defined as a clinically meaningful improvement with a reduction of at least 2 points from baseline, were observed in 50.1% of the overall population. Specifically, responder rates in the subgroups were 57.8% for OD and 45.7% for BID; within SITTs the rates were 57.8% for FF/UMEC/VI OD, 51.8% for BDP/FOR/GLY BID, and 42.3% for BUD/GLY/FOR BID, at 24 months (Figure 2(b)).
Table 2.
Treatment outcomes in the overall population and two subgroups across the study duration.
| Characteristic | Overall | OD triple therapy | BID triple therapy | FF/UMEC/VI OD | BDP/FOR/GLY BID | BUD/GLY/FOR BID |
|---|---|---|---|---|---|---|
| Patient population, N | ||||||
| Baseline | 1196 | 562 | 563 | 562 | 285 | 102 |
| Month 6 | 1088 | 510 | 509 | 510 | 250 | 94 |
| Month 12 | 1016 | 481 | 472 | 481 | 231 | 83 |
| Month 24 | 927 | 437 | 434 | 437 | 208 | 76 |
| % predicted FEV 1 , mean (SD) | ||||||
| Month 6 | 59.5 (20.2) | 62.9 (18.9) | 56.7 (20.6) | 62.9 (18.9) | 56.6 (20.8) | 53.5 (18.9) |
| Month 12 | 59.3 (20.4) | 62.9 (19.6) | 55.5 (20.4) | 62.9 (19.6) | 53.1 (18.6) | 56.5 (19.1) |
| Month 24 | 59.1 (21.2) | 62.2 (20.4) | 56.2 (20.9) | 62.2 (20.4) | 56.1 (19.3) | 53.6 (22.0) |
| Change of smoking status – yes, % | ||||||
| Month 6 | 1.7 | 0.5 | 0.8 | 0.6 | 0.6 | 0.2 |
| Month 12 | 1.8 | 0.7 | 0.8 | 0.9 | 0.5 | 0.1 |
| Month 24 | 1.5 | 0.4 | 0.9 | 0.5 | 0.4 | 0.4 |
| Changes in CAT score from baseline, n (%) | ||||||
| Month 6 | 647 (59.5) | 287 (56.3) | 322 (63.3) | 287 (56.3) | 183 (73.2) | 42 (44.7) |
| Month 12 | 544 (53.5) | 246 (51.1) | 271 (57.4) | 246 (51.1) | 146 (63.2) | 31 (37.3) |
| Month 24 | 485 (52.3) | 219 (50.1) | 244 (56.2) | 219 (50.1) | 137 (65.9) | 26 (34.2) |
| CAT sum score of 11–19, % | ||||||
| Baseline | 37.8 | 39.2 | 36.3 | 39.2 | 35.3 | 37.5 |
| Month 6 | 48.5 | 53.3 | 45.3 | 53.3 | 48.6 | 50.0 |
| Month 12 | 44.9 | 48.8 | 41.0 | 48.8 | 37.7 | 38.7 |
| Month 24 | 40.8 | 44.3 | 37.3 | 44.3 | 37.2 | 34.6 |
| EQ-5D VAS per visit, mean (SD) | ||||||
| Baseline | 59.6 (17.9) | 62.6 (16.8) | 57.2 (18.4) | 62.6 (16.8) | 56.7 (19.0) | 58.3 (17.8) |
| Month 6 | 61.5 (19.5) | 63.8 (19.3) | 59.4 (19.7) | 63.8 (19.3) | 59.0 (20.0) | 61.9 (20.3) |
| Month 12 | 62.6 (20.2) | 66.1 (19.4) | 59.8 (20.5) | 66.1 (19.4) | 59.4 (21.3) | 62.0 (20.2) |
| Month 24 | 63.8 (19.4) | 68.6 (18.4) | 60.4 (19.2) | 68.6 (18.4) | 61.3 (20.1) | 61.1 (20.2) |
| Any moderate/severe exacerbation in the 24 months prior to study enrolment or 3 months prior to each subsequent on-study visit – no, % | ||||||
| Baseline | 94.9 | 96.8 | 94.1 | 96.8 | 94.7 | 91.2 |
| Month 6 | 94.4 | 96.5 | 93.5 | 96.5 | 94.0 | 90.4 |
| Month 12 | 91.5 | 93.8 | 90.9 | 93.8 | 90.0 | 90.4 |
| Month 24 | 93.2 | 95.0 | 92.4 | 95.0 | 93.8 | 94.7 |
| Clinically important deterioration (CID), n (%) (Decrease [=100 mL] of FEV1 from baseline or increase [>2 units] of CAT from baseline or any documented exacerbation or all cause mortality) | ||||||
| No | 555 (46.4) | 304 (54.1) | 235 (41.7) | 304 (54.1) | 120 (42.1) | 48 (47.1) |
| Yes | 641 (53.6) | 258 (45.9) | 328 (58.3) | 258 (45.9) | 165 (57.9) | 54 (52.9) |
%, percentage of patients; BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; CAT, COPD assessment test; CID, Clinically important deterioration; COPD, chronic obstructive pulmonary disease; EQ-5D VAS, EuroQoL-5 Dimension Visual Analogue Scale; FEV1, forced expiratory volume in 1 second; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; OD, once daily; SD, standard deviation; V1, visit 1 at baseline; V2, visit 2 at 6 months; V4, visit 4 at 24 months.
Figure 2.
Mean Change in CAT Sum Score and CAT Responder Rates. BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; MCID, minimal clinically important difference; OD, once daily.
Another clinical outcome evaluated was the change in FEV1 at 24 months compared to baseline. Both overall and within the subgroups, FEV1 remained stable, with a mean (SD) change of 1.31% (13.17) from baseline in the overall population at 24 months. The subgroups demonstrated similar trends, reflecting consistent stability in lung function across the groups (Figure 3).
Figure 3.
FEV1 by Treatment Group and Visit Month. BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FEV1, forced expiratory volume in 1 second; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; OD, once daily.
The mean (SD) number of exacerbations since the last visit was low in both dosing regimen subgroups. At 6 months it was 0.06 (0.26) for OD and 0.09 (0.44) for BID; at 24 months it was 0.09 (0.36) and 0.14 (0.43), respectively. The mean (SD) number of hospitalisations due to exacerbations since the last visit was 0.005 (0.07) for OD and 0.025 (0.17) for BID at 6 months, and 0.014 (0.13) and 0.030 (0.20), respectively, at 24 months. Across the SITT subgroups, both the mean number of exacerbations (Figure 4) and hospitalisations due to exacerbations since the last visit remained consistently low, particularly among patients on FF/UMEC/VI OD (Figure 5).
Figure 4.
Mean Number of Exacerbations Since Last Visit. BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; OD, once daily.
Figure 5.
Mean Number of Hospitalisations due to Exacerbations Since Last Visit. BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; OD, once daily.
Overall, CID was observed in 53.6% of patients. The proportion of patients experiencing a CID was 45.9% in OD and 58.3% in the BID subgroup and 45.9%, 57.9% and 52.9% in the FF/UMEC/VI OD, BDP/FOR/GLY BID and BUD/GLY/FOR BID subgroups, respectively (Table 2). At 24 months, patients in the OD triple therapy (i.e. FF/UMEC/VI OD) subgroup had a meaningful improvement in the CAT score (>−2.0).
Adverse events and safety
Safety analyses were performed using SAS. Considering that TETRIS was an observational study, only adverse drug reactions (ADRs), serious ADRs (SADRs) and serious adverse events (SAEs) were documented which also included the reported adverse events that led to the discontinuation of triple therapy. A total of 217 SAEs (91.6% of all documented events), 28 ADRs (11.8%), and 8 SADRs (3.4%) were documented during the 24-month observation period (Table 3). When evaluated specifically for pneumonia, 33 (2.8%) patients experienced infections and infestations among whom 20 (1.7%) and 1 (0.1%) were affected by pneumonia and aspiration pneumonia, respectively. Cardiac disorders were noted in 21 (1.8%) patients, with cardiac failure (n=10, 0.8%) and atrial fibrillation (n=6, 0.5%) being the most common (Table 4). The proportion of patients who experienced an ADR was low with 0.5% for OD (i.e. FF/UMEC/VI OD), 2.1% for BID, 1.1% for BDP/FOR/GLY BID and 2.0% for BUD/GLY/FOR BID. SADR occurred in 0.4% of patients in all the subgroups except for the BDP/FOR/GLY BID subgroup, where the rate was 1.0%. The proportion of patients experiencing an SAE was 9.4% among patients on OD triple therapy (i.e. FF/UMEC/VI OD) and 15.8% among patients on BDP/FOR/GLY BID. Consistent with the overall population, SAEs accounted for >90% of all events across the two subgroups. A total of 5 ADRs were documented in the OD subgroup and 17 ADRs in the BID subgroup; SADR counts were 4 and 3 in the OD and BID subgroups, respectively. Within the SITT class, ADR counts were 5 for FF/UMEC/VI OD, 8 for BDP/FOR/GLY BID, and 2 for BUD/GLY/FOR BID; SADR counts were 4, 2, and 1, respectively (Table 3). The proportion of patients experiencing pneumonia and cardiovascular events in the two subgroups was consistent with those observed in the overall population (Table 4).
Table 3.
Number of ADRs, SADRs, and SAEs (patient- and event-based).
| | Overall (N=1196) | OD triple therapy (N=562) | BID triple therapy (N=563) | FF/UMEC/VI OD (N=562) | BDP/FOR/GLY BID (N=285) | BUD/GLY/FOR BID (N=102) |
|---|---|---|---|---|---|---|
| Patient-based, n (%) | ||||||
| Patients with any event | 154 (12.9) | 54 (9.6) | 89 (15.8) | 54 (9.6) | 47 (16.5) | 16 (15.7) |
| Patients with any ADR | 20 (1.7) | 3 (0.5) | 12 (2.1) | 3 (0.5) | 3 (1.1) | 2 (2.0) |
| Patients with any SAE | 142 (11.9) | 53 (9.4) | 82 (14.6) | 53 (9.4) | 45 (15.8) | 15 (14.7) |
| Patients with any SADR | 5 (0.4) | 2 (0.4) | 2 (0.4) | 2 (0.4) | 1 (0.4) | 1 (1.0) |
| Event-based, m (%) | ||||||
| All events | 237 (100.0) | 76 (100.0) | 140 (100.0) | 76 (100.0) | 82 (100.0) | 19 (100.0) |
| All ADRs | 28 (11.8) | 5 (6.6) | 17 (12.1) | 5 (6.6) | 8 (9.8) | 2 (10.5) |
| All SAEs | 217 (91.6) | 75 (98.7) | 126 (90.0) | 75 (98.7) | 76 (92.7) | 18 (94.7) |
| All SADRs | 8 (3.4) | 4 (5.3) | 3 (2.1) | 4 (5.3) | 2 (2.4) | 1 (5.3) |
%, percentage of patients; ADR, adverse drug reaction; BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; m, number of events; n, number of patients; OD, once daily; SADR, serious adverse drug reaction; SAE, serious adverse event.
Table 4.
Safety profile with a focus on pneumonia and cardiovascular events.
| Patients | Overall | OD triple therapy | BID triple therapy | FF/UMEC/VI OD | BDP/FOR/GLY BID | BUD/GLY/FOR BID |
|---|---|---|---|---|---|---|
| Any event, n (%) | 154 (12.9) | 54 (4.5) | 78 (6.5) | 54 (4.5) | 47 (3.9) | 16 (1.3) |
| Cardiac disorders, n (%) | 21 (1.8) | 10 (0.8) | 8 (0.7) | 10 (0.8) | 6 (0.5) | 1 (0.1) |
| Cardiac failure | 10 (0.8) | 4 (0.3) | 4 (0.3) | 4 (0.3) | 4 (0.3) | 1 (0.1) |
| Atrial fibrillation | 6 (0.5) | 3 (0.3) | 3 (0.3) | 3 (0.3) | 3 (0.3) | 0 (0.0) |
| Infections and infestations, n (%) | 33 (2.8) | 12 (1.0) | 15 (1.3) | 12 (1.0) | 9 (0.8) | 5 (0.4) |
| Pneumonia | 20 (1.7) | 6 (0.5) | 10 (0.8) | 6 (0.5) | 5 (0.4) | 4 (0.3) |
BDP/FOR/GLY, beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide; BID, twice daily; BUD/GLY/FOR, budesonide, glycopyrrolate, and formoterol fumarate; FF/UMEC/VI, fluticasone furoate, umeclidinium, and vilanterol; n, number of patients; OD, once daily.
Discussion
To the best of our knowledge, the TETRIS study is the first prospective study to provide data on the number of patients with COPD who remained continuously on triple therapy, reasons for treatment changes, and long-term outcomes following triple therapy over a 24-month follow-up period in a real-world setting in Germany. The baseline demographics and a 12-months interim analysis of patients included in the TETRIS study have been published.12,15
The TETRIS cohort included a well-balanced mix of males and females and >90% of the patients had a history of smoking. These findings are similar to those of two real-world studies conducted in Germany: the DACCORD study (males: 59.7%) and the TriOptimize study (males: 55.1%).16,17 The almost equal gender distribution in these studies suggests that COPD, which was previously considered to affect men, is now becoming increasingly prevalent in women probably due to the increasing consumption of tobacco in women. 18 With the majority of patients having a history of smoking (TETRIS: 91.1%; DACCORD: 80%; TriOptimize: 86.6%), smoking continues to be the leading and most important modifiable risk factor for COPD in Germany.19–21
Comorbidities are commonly noted in patients with COPD, with cardiovascular diseases being prevalent in 20%–70% of patients. 22 Consistent with these findings, 69.7% of patients in the TETRIS study had comorbidities, with cardiac diseases (35.0%) being the most common. Similar to the TETRIS cohort, comorbidities were observed in 78.3% and 76.9% of patients in the DACCORD and TriOptimize studies, respectively, with cardiovascular disease and arterial hypertension being the most common (51.9% and 49.4%, respectively).16,17
Notably, the TETRIS cohort included a relatively low proportion of patients with comorbid or historical asthma (13.9% and 2.6%, respectively). This allows for a clearer assessment of triple therapy outcomes in a predominantly COPD-only population, thereby minimising confounding by asthma–COPD overlap. Compared to other large studies such as IMPACT and ECLIPSE, which included higher proportions of patients with asthma features, the TETRIS results may be more representative of typical COPD patients encountered in routine practice.23,24 Chronic bronchitis is a common phenotype observed in patients with COPD, with smoking serving as the main risk factor. The prevalence of chronic bronchitis in patients with COPD has been reported to be 14%–74%. 25 In line with these findings, in our study, 20.5% of all patients were diagnosed with chronic bronchitis at baseline.
The GOLD COPD classification system is primarily designed to guide initial pharmacotherapy decisions, and its relevance may diminish in patients already receiving long-term maintenance therapy. 26 In TETRIS, the fact that patients had been diagnosed for an average of 6.9 years at study entry limits the interpretability of GOLD categorisation as a baseline indicator of untreated disease severity. Most patients were classified as GOLD B and GOLD 2, with a mean baseline CAT score of 19.5, reflecting a moderate symptom burden. Interestingly, the mean number of exacerbations and hospitalisations in the 3 years prior to initiating triple therapy was low, suggesting that GOLD classification in this context may reflect disease control under treatment rather than initial risk. This contrasts with studies like DACCORD and COSYCONET, where GOLD grouping was applied before therapy initiation, allowing clearer alignment between GOLD status and treatment escalation.27,28 In TETRIS, the majority of patients (61.0%) were previously on LAMA/LABA dual therapy and were stepped up to triple therapy in line with GOLD recommendations, 2 but the observational nature of the study and incomplete records may have influenced categorisation.
TETRIS primarily evaluated the proportion of patients who continuously remained on triple therapy: 92.5%, 84.4% and 38.5% of patients remained on triple therapy for 6, 12 and 24 months after study enrolment, respectively. These results show prominent higher persistence rates than those in the German claims data study by Vogelmeier et al. (2024), in which adherence and persistence of patients to triple therapy at 6, 12 and 18 months after treatment initiation were evaluated based on prescription refill pattern. Adherence was defined as the proportion of days covered, and persistence was defined as time until discontinuation of therapy. At 6, 12 and 18 months, persistence rates for SITTs were 31.1%, 18.7% and 13.2%, respectively, and those for MITTs were 8.8%, 3.4% and 1.8%, respectively. The highest persistence was found in patients on FF/UMEC/VI OD, with 16.5% at 18 months. 9
To robustly assess time to discontinuation, the study employed Kaplan–Meier methodology to estimate the time to stop triple therapy and analysed the numbers of patients at risk. The Kaplan–Meier curve illustrates a gradual decline in the numbers of patients almost along the entire period (Figure 1(a)), while the patients-at-risk curve reveals a steep decline after day 660. Notably, the sharp decline at the end of the curve is driven by the accumulation of patients who completed the study before reaching the full 24-month period, as permitted by the study protocol allowing study completion by 18 months (Figure 1(b)). This leads to an underestimation of the true proportion of patients remaining on therapy at 24 months. This methodological limitation is important to consider when interpreting long-term persistence rates, as the apparent decline may overstate the rate of true discontinuation in the final months of follow-up. Therefore, the use of Kaplan–Meier analysis in TETRIS provides a robust estimate of time to discontinuation but may underestimate persistence at later time points due to censoring. An additional explanation for the observed decline in persistence beyond 12 months could be the reduced intensity of patient contact over time. Despite the observational nature of the study, the initial 12-month period likely involved more frequent clinical interactions, which may have supported adherence and persistence. As patient follow-up became less intensive after the first year, this reduced engagement may have contributed to increased discontinuation or loss to follow-up, independent of therapy effectiveness.
Another important observation underlining high persistence rates is the low frequency of therapy changes of only 10% over the 24-month period, which may reflect a high degree of stability in disease among patients. Maintaining consistent therapy can support better adherence, reduce confusion related to inhaler technique and minimise disruptions in disease management. This aligns with the findings of Singh et al. (2024), who proposed disease stability as a realistic and valuable treatment goal in COPD, emphasising the importance of sustained symptom control and reduced exacerbation risk. 29 The low rate of switching may also reflect appropriate initial therapy selection and patient satisfaction, contributing to long-term disease control. While proactive therapy reviews remain essential, the stability observed in TETRIS may be viewed as a positive indicator of effective prescribing and sustained clinical benefit.
Treatable traits are clinically relevant, identifiable, measurable and modifiable disease characteristics. 30 The treatable traits strategy represents a new paradigm for precision medicine in COPD management.30,31 In this approach, patients undergo comprehensive evaluation for pre-defined treatable problems, guiding a personalised treatment plan. 30 Airflow limitation, eosinophilic airway inflammation, cachexia, reduced mobility and smoking are key treatable traits in COPD. 32 The second secondary outcome of TETRIS was to identify and monitor traits such as airflow limitation, peripheral blood eosinophil count, smoking status, and clinical parameters that, when modified, may improve outcomes. Smoking cessation improves COPD symptoms and reduces exacerbation frequency. 2 The proportion of current smokers declined slightly from 38.0% at baseline to 36.5% at 24 months, indicating that only 1.5% of patients successfully quit smoking. This aligns with the finding of other studies that reported 1%–3% of patients quit smoking spontaneously without interventions.33–35
Despite recommendations from the GOLD 2025 guidelines and accumulating clinical evidence supporting eosinophils as a relevant biomarker for guiding ICS use in COPD,2,36 the TETRIS study highlights the reality of a low eosinophil sampling rate in routine practice. Only 7.9% of patients had a documented baseline blood eosinophil count, with numbers declining further over time (5.0% at the 6-month, 5.4% at the 12-month, and 4.2% at the 24-month follow-up visit). This may reflect limited consultation time, logistical barriers and reduced patient contact after 12 months and aligns well with the observations made by Greulich et al. 2021. 37 The lack of data limits assessment of eosinophil-guided ICS use and highlights the gap between guidelines and real-world practice.
Clinical outcomes, including change of FEV1, change in CAT score, mean number of moderate and/or severe exacerbations and CID, were systematically assessed across all visits and treatment subgroups. Lung function parameters remained stable over 24 months, with patients on OD triple therapy (FF/UMEC/VI) showing the greatest improvement in CAT score and FEV1 from baseline and lowest number of exacerbations in this observational study. These findings are consistent with those of real-world studies, such as Wedzicha et al., which demonstrated that patients stepping up to FF/UMEC/VI OD from dual therapy had significantly lower rates of exacerbations than those on BUD/GLY/FOR BID. 38 Feldman et al. further confirmed these findings in an independent academic cohort, showing favourable effectiveness and safety of SITTs, particularly FF/UMEC/VI OD. 39
Notably, the increase in exacerbation rates observed between visit 2 and visit 3 in the TETRIS study population may probably reflect seasonal variation, as these visits likely occurred during the autumn or winter months, when respiratory infections are generally more prevalent and exacerbation risk is higher. 40 Supporting this assumption, the exacerbation rate declined again between visit 3 and visit 4, which covered the second year of observation. The overall lower number of exacerbations in the last 12 months compared to the first 12 months may also reflect the benefits of persistent triple therapy in maintaining disease stability and reducing exacerbation risk.
CID is a multicomponent endpoint for evaluating worsening of disease in patients with COPD.13,14 Clinical studies have used different definitions to evaluate this composite endpoint that mainly differs based on the inclusion of SGRQ or CAT sum score.13,14 In TETRIS, CID was defined as a decrease of >100 mL in FEV1 from baseline to 24 months, or >2-unit increase in CAT sum score from baseline, or any documented exacerbation, or all-cause mortality. Overall, 53.6% of patients in TETRIS experienced a CID. However, among the observed subgroups, the proportion of patients experiencing a CID was lower (45.9%) in the OD (i.e. FF/UMEC/VI) than in the BID triple therapy subgroups. Previous analysis on CID rate for FF/UMEC/VI has been conducted in the clinical trials FULFIL and IMPACT post-hoc analysis.13,14 In FULFIL, 51% of patients on FF/UMEC/VI OD experienced any CID defined as moderate/severe exacerbation and/or ≥2-unit deterioration in CAT score from baseline and/or ≥100 mL deterioration in FEV1 [CAT-containing CID] from baseline. 14 Observed differences in CID rates between TETRIS and the clinical studies may arise from differences in the underlying study populations, including COPD severity and disease and treatment history, factors that were much broader in real-world studies.
With regards to safety, the proportion of patients experiencing an ADR and SAE was 0.5% and 9.4%, respectively, among those on FF/UMEC/VI OD, and the proportion of patients experiencing a cardiac disorder or pneumonia was 0.1% and 0.4%, respectively, in the BUD/GLY/FOR BID subgroup. In the user cohort study by Feldman et al., the incidence of first hospitalisation for pneumonia was similar among patients on BUD/GLY/FOR BID and FF/UMEC/VI OD. 39 All ICS inhalers indicated for COPD management are associated with an increased risk of pneumonia; however, the increased incidence observed among patients on fluticasone-compared to budesonide-containing inhaled medications could be attributed to an intraclass difference between these two ICSs. 41
Strengths and limitations
To the best of our knowledge, this real-world study, observes for the first time different clinical outcomes in patients receiving different triple therapies for COPD, over a period of 24 months.
However, this study had a few limitations. It is well known and acknowledged that the observational nature of study design may have limited data availability for collected variables and variables may not have been comprehensively recorded for all patients, potentially leading to a bias due to missing data. Including patients who were on triple therapy for at least 2 weeks may have limited the sample to those who were adherent to treatment and did not experience significant AEs after triple therapy initiation, restricting the generalisability of data collected. Non-interventional studies and studies without a control group can only describe correlations but cannot establish causality. Unplanned inclusion of patients with pure asthma (FEV1 normalised under treatment) is a further real-life bias. Moreover, a formal sample size calculation was not conducted and consequently, the study may be underpowered for certain analyses, and the findings should be interpreted with caution.
Conclusion
In this large, prospective, real-world study conducted across Germany, the TETRIS cohort demonstrated high persistence with SITT-therapies: continuous use was observed in 92.5% at 6 months, 84.4% at 12 months and 38.5% at 24 months, demonstrating substantial short- and medium-term durability while highlighting the challenges of long-term maintenance in routine practice. The observed decline at 24 months was substantially influenced by both, true discontinuations and drop-outs, reflecting real-world complexities such as wide visit windows, loss to follow-up or death. Therapy changes were infrequent, with only 10% of patients requiring modification of their COPD maintenance regimen over 2 years, suggesting a high degree of stability in disease with an appropriate initial therapy selection. Notably, in patients receiving OD SITT with FF/UMEC/VI the greatest improvements in patient-reported outcomes (CAT score), lung function (FEV1) and the lowest rates of exacerbations and hospitalisations were observed, supporting its robust effectiveness and safety in routine care.
Overall, the TETRIS study underscores that in a real-world setting, triple therapy is associated with low rates of exacerbations and hospitalisations and without new safety concerns. These findings support the role of SITT as an effective and practical option for long-term COPD management in clinical practice.
Supplemental material
Supplemental material for A multicentre, observational prospective study to characterise the use of inhaled triple therapy for COPD: TETRIS final results after a 24-month follow-up period by Claus F. Vogelmeier, Jing Claussen, Kai-Michael Beeh, Peter Kardos, Henrik Watz, Bernd Westermayer and Gernot Rohde in Therapeutic Advances in Respiratory Disease.
Supplemental material for A multicentre, observational prospective study to characterise the use of inhaled triple therapy for COPD: TETRIS final results after a 24-month follow-up period by Claus F. Vogelmeier, Jing Claussen, Kai-Michael Beeh, Peter Kardos, Henrik Watz, Bernd Westermayer and Gernot Rohde in Therapeutic Advances in Respiratory Disease.
Acknowledgments
In memoriam of Professor Tobias Welte, the authors would like to thank him as the principal investigator of the TETRIS study for providing significant contributions toward the conceptualisation of this study. The authors would like to acknowledge Ulrich Elsasser and Dr Klaus Hechenbichler for statistical support. The authors would also want to thank all participating study centres for their contribution to the TETRIS study. Medical writing support (including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors’ comments for each draft, assembling tables and figures and referencing) was provided by Dr Vidya V. Murthy, an employee of GSK, and funded by GSK.
Author contributions: Claus F. Vogelmeier: conceptualisation; formal analysis; methodology; writing – review & editing. Jing Claussen: conceptualisation; methodology; formal analysis; visualisation; methodology; writing – review & editing. Kai-Michael Beeh: conceptualisation; investigation; methodology; writing – review & editing. Peter Kardos: investigation; methodology; writing – review & editing. Henrik Watz: conceptualisation; methodology; writing – review & editing. Bernd Westermayer: formal analysis, methodology, writing – review & editing. Gernot Rohde: investigation; methodology; writing – review & editing.
Funding: The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was funded by GSK (study number 214468). GSK-affiliated authors were involved in the study conception and design, data analysis, data interpretation and the decision to submit the article for publication. GSK funded the article processing charges and open-access fee.
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.F. Vogelmeier received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols and Novartis and has received lecturing and personal fees from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Aerogen and Nuvaira. K-M. Beeh and/or the institution he represents have in the past 5 years received compensation for services on advisory boards or consulting activities from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Elpen, GSK, Mundipharma, Novartis, Pohl Boskamp, Sanofi and Teva; compensation for speaker activities in scientific meetings supported by AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Elpen, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Sanofi and Teva; and compensation for the design and performance of clinical trials from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Parexel, Pearl Therapeutics, Teva and Sterna. P. Kardos received honoraria for participating in zoom meetings by GSK and Sanofi; he also received honoraria for participation in advisory boards and lectures and travel costs from the following companies: AstraZeneca, Bionorica, Chiesi, Engelhard, GSK, Jansen, Klosterfrau, Novartis, MSD and Schwabe. His institution received honoraria for clinical trial participation from Bellus, the ERS NEuroCOUGH Initiative and MSD. H. Watz and/or his institution received honoraria for consulting services, speaker activities and clinical study conduct from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, BMS, Chiesi, GSK, Novartis, Roche, Sanofi and Takeda. J. Claussen and B. Westermayer are employees of GSK and hold financial equities in GSK. G. Rohde reports receiving personal fees from AstraZeneca, Atriva, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis and Pfizer for consultancy during advisory board meetings and personal fees from AstraZeneca, Berlin-Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for speaker activities.
Conference presentation: A summary of the final analysis of this study has been presented as an Oral Presentation (#OA3290) at the European Respiratory Society (ERS) Congress | 27 September – 1 October 2025 | Amsterdam, Netherlands; DOI: 10.1183/13993003.congress-2025.OA3290 (September 2025). A summary of the interim analysis of this study has been presented as a Poster (#PA4795) at the European Respiratory Society (ERS) Congress | 7–11 September 2024 | Vienna, Austria.
Supplemental material: Supplemental material for this article is available online.
ORCID iDs
Jing Claussen https://orcid.org/0000-0002-8703-0020
Kai-Michael Beeh https://orcid.org/0000-0001-9067-118X
Ethical considerations
The study was approved by the ethics committee of the Hannover Medical School (IRB: Ethikkommission der Medizinischen Hochschule, Hannover [MHH], Approval Number/ID: 9285_BO_S_2020) and is designed and conducted in accordance with the Declaration of Helsinki and the International Society for Pharmacoepidemiology’s Guidelines for Good Pharmacoepidemiology Practices of 2015. The study is being conducted in accordance with the codex of the ‘freiwillige Selbstkontrolle der Arzneimittelindustrie’ (FSA Codex, German voluntary self-control of pharmaceutical industry).
Consent to participate
All patients provided written informed consent before study initiation.
Data Availability Statement
Please refer to the GSK weblink to access GSK’s data-sharing policies and, as applicable, seek anonymised subject-level data via the link https://www.gsk-studyregister.com/en/.
References
- 1.Choi JY, Rhee CK. Diagnosis and treatment of early chronic obstructive lung disease (COPD). J Clin Med 2020; 9: 3426. 10.3390/jcm9113426 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.GOLD . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2025 Report). https://goldcopd.org/wp-content/uploads/2024/11/GOLD-2025-Report-v1.0-15Nov2024_WMV.pdf (2025), accessed 5 July 2025.
- 3.WHO . Chronic obstructive pulmonary disease (COPD), 2025. https://www.who.int/news-room/factsheets/detail/chronic-obstructive-pulmonarydisease-(copd (accessed 5 July 2025. [Google Scholar]
- 4.Vogelmeier CF, Roman-Rodríguez M, Singh D, et al. Goals of COPD treatment: Focus on symptoms and exacerbations. Respir Med 2020; 166: 105938. 10.1016/j.rmed.2020.105938 [DOI] [PubMed] [Google Scholar]
- 5.Pavord ID, Jones PW, Burgel PR, et al. Exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2016; 11: 21–30. 10.2147/COPD.S85978 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Halpin DM, Miravitlles M, Metzdorf N, et al. Impact and prevention of severe exacerbations of COPD: a review of the evidence. Int J Chron Obstruct Pulmon Dis 2017; 12: 2891–2908. 10.2147/COPD.S139470 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Herland K, Akselsen JP, Skjønsberg OH, et al. How representative are clinical study patients with asthma or COPD for a larger ‘‘real life’’ population of patients with obstructive lung disease? Respir Med 2005; 99: 11–19. 10.1016/j.rmed.2004.03.026 [DOI] [PubMed] [Google Scholar]
- 8.Heffler E, Paoletti G, Giorgis V, et al. Real-life studies of biologics used in asthma patients: key differences and similarities to trials. Expert Rev Clin Immunol 2019; 15: 951–958. 10.1080/1744666X.2019.1653758 [DOI] [PubMed] [Google Scholar]
- 9.Vogelmeier CF, Beeh KM, Schultze M, et al. Evaluation of adherence and persistence to triple therapy in patients with COPD: A German claims data study. Int J Chron Obstruct Pulmon Dis 2024; 19: 1835–1848. 10.2147/copd.s460903 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Beeh KM, Scheithe K, Schmutzler H, et al. Real-world effectiveness of fluticasone furoate/umeclidinium/vilanterol once-daily single-inhaler triple therapy for symptomatic COPD: The ELLITHE non-interventional trial. Int J Chron Obstruct Pulmon Dis 2024; 19: 205–216. 10.2147/COPD.S427770 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61: 344–349. 10.1016/j.jclinepi.2007.11.008 [DOI] [PubMed] [Google Scholar]
- 12.Vogelmeier CF, Beeh KM, Kardos P, et al. Baseline patient demographics for TETRIS: a prospective, noninterventional study to characterize the use of triple therapy for COPD in Germany. Ther Adv Respir Dis 2024; 18: 17534666241287621. 10.1177/17534666241287621 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Han MK, Criner GJ, Dransfield MT, et al. Prognostic value of clinically important deterioration in COPD: IMPACT trial analysis. ERJ Open Res 2021; 7: 00663–02020. 10.1183/23120541.00663-2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Naya I, Compton C, Ismaila AS, et al. Preventing clinically important deterioration with single-inhaler triple therapy in COPD. ERJ Open Res 2018; 4: 00047–02018. 10.1183/23120541.00047-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rohde G, Vogelmeier CF, Beeh KM, et al. TETRIS - Prospective study to observe clinical outcomes of triple therapy in COPD patients: Up to 12 months interim analysis. Respir Med 2026; 251: 108597. 10.1016/j.rmed.2025.108597 [DOI] [PubMed] [Google Scholar]
- 16.Worth H, Buhl R, Criee CP, et al. The ‘real-life’ COPD patient in Germany: the DACCORD study. Respir Med 2016; 111: 64–71. 10.1016/j.rmed.2015.12.010 [DOI] [PubMed] [Google Scholar]
- 17.Gessner C, Trinkmann F, Bahari JS, et al. Effectiveness of extrafine single inhaler triple therapy in chronic obstructive pulmonary disease (COPD) in Germany – The TriOptimize Study. Int J Chron Obstruct Pulmon Dis 2022; 17: 3019–3031. 10.2147/COPD.S382405 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Aryal S, Diaz-Guzman E, Mannino DM. COPD and gender differences: an update. Transl Res 2013; 162(4): 208–218. 10.1016/j.trsl.2013.04.003 [DOI] [PubMed] [Google Scholar]
- 19.Kauhl B, Maier W, Schweikart J, et al. Who is where at risk for chronic obstructive pulmonary disease? A spatial epidemiological analysis of health insurance claims for COPD in Northeastern Germany. PLoS One 2018; 13: e0190865. 10.1371/journal.pone.0190865 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Steppuhn H, Kuhnert R, Scheidt-Nave C. 12-month prevalence of known chronic obstructive pulmonary disease (COPD) in Germany. J Health Monit 2017; 2: 43–50. 10.17886/RKI-GBE-2017-065 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Adeloye D, Song P, Zhu Y, et al. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med 2022; 10: 447–458. 10.1016/S2213-2600(21)00511-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Agustí A, Celli BR, Criner GJ, et al. Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD executive summary. Eur Respir J 2023; 61: 2300239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018; 378: 1671–1680. 10.1056/NEJMoa1713901 [DOI] [PubMed] [Google Scholar]
- 24.Bateman ED, Reddel HK, van Zyl-Smit RN, et al. The asthma-COPD overlap syndrome: towards a revised taxonomy of chronic airways diseases? Lancet Respir Med 2015; 3(9): 719–728. 10.1016/S2213-2600(15)00254-4 [DOI] [PubMed] [Google Scholar]
- 25.Kim V, Criner GJ. The chronic bronchitis phenotype in COPD: Features and implications. Curr Opin Pulm Med 2015; 21: 133–141. 10.1097/MCP.0000000000000145 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yawn BP, Mintz ML, Doherty DE. GOLD in practice: Chronic obstructive pulmonary disease treatment and management in the primary care setting. Int J Chron Obstruct Pulmon Dis 2021; 16: 289–299. 10.2147/COPD.S222664 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Worth H, Buhl R, Criée CP, et al. GOLD 2017 treatment pathways in 'real life': An analysis of the DACCORD observational study. Respir Med 2017; 131: 77–84. 10.1016/j.rmed.2017.08.008 [DOI] [PubMed] [Google Scholar]
- 28.Lutter JI, Jörres RA, Trudzinski FC, et al. Treatment of COPD groups GOLD A and B with inhaled corticosteroids in the COSYCONET cohort - determinants and consequences. Int J Chron Obstruct Pulmon Dis 2021; 16: 987–998. 10.2147/copd.s304532 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Singh D, Han MK, Bhatt SP, et al. Is disease stability an attainable COPD treatment goal? Am J Respir Crit Care Med 2024; 211: 452–463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.McDonald VM, Fingleton J, Agusti A, et al. Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report. Eur Respir J 2019; 53: 1802058. 10.1183/13993003.02058-2018 [DOI] [PubMed] [Google Scholar]
- 31.Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016; 47: 410–419. 10.1183/13993003.01359-2015 [DOI] [PubMed] [Google Scholar]
- 32.Sin DD. Contemporary Concise Review 2019: Chronic obstructive pulmonary disease. Respirology 2020; 25: 449–454. 10.1111/resp.13782 [DOI] [PubMed] [Google Scholar]
- 33.Nielsen AO, Lange P, Hilberg O, et al. COPD and smoking status - it does matter: characteristics and prognosis of COPD according to smoking status. Chronic Obstr Pulm Dis 2024; 11(1): 56–67. 10.15326/jcopdf.2023.0433 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Thabane M, COPD Working Group . Smoking cessation for patients with chronic obstructive pulmonary disease (COPD): an evidence-based analysis. Ont Health Technol Assess Ser 2012; 12(4): 1–50. [PMC free article] [PubMed] [Google Scholar]
- 35.Principe R, Zagà V, Martucci P, et al. Smoking cessation in the management of Chronic Obstructive Pulmonary Disease (COPD): narrative review and recommendations. Ann Ist Super Sanita 2024; 60(1): 14–28. [DOI] [PubMed] [Google Scholar]
- 36.Lea S, Higham A, Beech A, et al. How inhaled corticosteroids target inflammation in COPD. Eur Respir Rev 2023; 32: 230084. 10.1183/16000617.0084-2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Greulich T, Töpfer V, Hennig M, et al. COPD in Germany: Use of Diagnostic Measures Including Blood Eosinophil Counts in Daily Practice. Pneumologie 2021; 75: 344–352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Wedzicha JA, Noorduyn SG, Di Boscio V, et al. Comparative effectiveness of FF/UMEC/VI and BUD/GLY/FORM in patients with COPD stepping up from dual therapy. Adv Ther 2025; 42: 4432–4446. 10.1007/s12325-025-03295-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Feldman WB, Suissa S, Kesselheimet AS, et al. al. Comparative effectiveness and safety of single inhaler triple therapies for chronic obstructive pulmonary disease: new user cohort study. BMJ 2024; 387: e080409. 10.1136/bmj-2024-080409 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Criner GJ, Lipson DA, Tombs L, et al. Effects of seasonality and treatment on COPD clinical outcomes: IMPACT post hoc analysis. ERJ Open Res 2024; 11: 00583–02024. 10.1183/23120541.00583-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Lodise TP, Li J, Gandhi HN, et al. Intraclass difference in pneumonia risk with fluticasone and budesonide in COPD: A systematic review of evidence from direct-comparison studies. Int J Chron Obstruct Pulmon Dis 2020; 15: 2889–2900. 10.2147/COPD.S269637 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material for A multicentre, observational prospective study to characterise the use of inhaled triple therapy for COPD: TETRIS final results after a 24-month follow-up period by Claus F. Vogelmeier, Jing Claussen, Kai-Michael Beeh, Peter Kardos, Henrik Watz, Bernd Westermayer and Gernot Rohde in Therapeutic Advances in Respiratory Disease.
Supplemental material for A multicentre, observational prospective study to characterise the use of inhaled triple therapy for COPD: TETRIS final results after a 24-month follow-up period by Claus F. Vogelmeier, Jing Claussen, Kai-Michael Beeh, Peter Kardos, Henrik Watz, Bernd Westermayer and Gernot Rohde in Therapeutic Advances in Respiratory Disease.
Data Availability Statement
Please refer to the GSK weblink to access GSK’s data-sharing policies and, as applicable, seek anonymised subject-level data via the link https://www.gsk-studyregister.com/en/.