www.nature.com/npjpcrm ARTICLE OPEN Clinical characteristics and factors associated with triple therapy use in newly diagnosed patients with COPD Mònica Monteagudo 1,2, Miriam Barrecheguren3, Iryna Solntseva1, Nafeesa Dhalwani4, Alison Booth4, Alexa Nuñez2,3, Dimitra Lambrelli4 and Marc Miravitlles 2,3 ✉ There is limited information about the initiation of triple therapy (TT) in patients with chronic obstructive pulmonary disease (COPD) in primary care. This was an observational, population-based study in patients identified from a primary care electronic medical records database in Catalonia from 2011 to 2015 aimed to identify the use of TT in patients with newly diagnosed COPD. A total of 69,668 newly diagnosed patients were identified of whom 11,524 (16.5%) initiated TT, of whom 8626 initiated TT at or immediately after COPD diagnosis. Among them, 72.3% were GOLD A/B, 14.6% were frequent exacerbators, and 7.1% had asthma–COPD overlap (ACO). Variables associated with TT initiation were: male sex, older age, previous exacerbations, ACO, a previous treatment regimen containing an inhaled corticosteroid, previous pneumonia, and history of lung cancer. A significant number of COPD patients in Primary Care initiated TT shortly after or even before an established COPD diagnosis. npj Primary Care Respiratory Medicine (2021)31:16 ; https://doi.org/10.1038/s41533-021-00227-x 1234567890():,; INTRODUCTION understand the reason for TT prescription in primary care, it is Treatments administered for patients with chronic obstructive important to analyze prescription patterns in large administrative pulmonary disease (COPD) in primary care do not always follow databases. The current study was conducted with the aim of national or international guidelines1–4. Patients with milder forms characterizing newly diagnosed patients with COPD initiating TT of the disease are frequently overtreated and, although less in primary care and investigating the factors associated with TT frequently, patients with more severe COPD may be under- prescription in these incident cases with COPD. treated1–4. In a majority of countries, the initial point of contact for patients with respiratory symptoms is through primary care where RESULTS targeted detection programs for the early diagnosis of COPD are supported5,6. Population of the study The availability of spirometry in primary care is key for early and A total of 69,668 newly diagnosed (incident) COPD patients were accurate diagnosis of COPD7, and initial treatment should be identified; of whom 11,524 (16.5%) initiated TT at some point implemented according to guidelines. The Global Strategy for during the study period. Among these patients, 2898 (25.2%) Obstructive Lung Disease (GOLD) recommends classifying patients initiated TT prior to COPD diagnosis, and 8626 (74.8%) at or after according to severity of symptoms and history of exacerbations COPD diagnosis (Fig. 1). into four categories. Initial treatment is based on one or two long- acting bronchodilators, or the combination of a long-acting beta-2 Clinical characteristics of patients initiating and not initiating agonist (LABA) and an inhaled corticosteroid (ICS) for more TT, and subgroups according to TT period of initiation symptomatic patients with frequent exacerbations8. When treat- The majority of incident patients with COPD were men (68.6%), ment with long-acting bronchodilators or with LABA/ICS is not with mean age of 68.3 years (standard deviation [SD]: 12.3 years). enough to control symptoms or prevent exacerbations, treatment Less than half (44.3%) had spirometry tests performed within may escalate to triple therapy (TT) with two bronchodilators (a 12 months before and 2 weeks after the index date, mean FEV1 (% LABA and a long-acting antimuscarinic agent [LAMA]) and ICS. predicted) was 65.3% (SD: 19.6%) and 47.6% had at least one Similarly, the Spanish guidelines also recommend TT as a step up exacerbation in the previous year (Table 1). from dual bronchodilation (LABA/LAMA) or from LABA/ICS, but not Incident patients with COPD who initiated TT more frequently as initial therapy9. had previous exacerbations (51.4 % versus 46.9%; χ2 test p < 0.001) Studies from different countries have demonstrated a frequent and had more previous visits to primary care (9.8 [SD: 7.4] versus use of TT in patients considered at low risk (patients with GOLD A 8.1 [SD: 6.3]; T-test p < 0.001); but less frequently had available or B disease). A recent study in the United Kingdom showed that spirometry records (34.5% versus 46.3%; χ2 test p < 0.001) than 13.7% of GOLD A and 26.2% of GOLD B received TT2; similarly, patients who did not initiate TT. These differences were also data from Switzerland observed a use of TT in 13.8% of GOLD A observed between patients who initiated TT before diagnosis, and 28.2% of GOLD B patients1. It is important to understand with more exacerbations (57.2% versus 49.4%; χ2 test p < 0.001) whether this represents overtreatment of COPD or whether some and patients with spirometry tests (32.1% versus 35.3%; χ2 test p < of these patients could have been GOLD D patients that improved 0.001) compared to patients who initiated TT at or after COPD in the GOLD classification because of the efficacy of TT. In order to diagnosis. Generally, patients who initiated TT prior to diagnosis 1 Primary Care University Research Institute Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain. 2Medicine Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 3 Pneumology Department, Hospital Universitari Vall d´Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain. 4Evidera, London, UK. ✉email: marcm@separ.es Published in partnership with Primary Care Respiratory Society UK M Monteagudo et al. 2 N N N N 1234567890():,; N N N Fig. 1 Flowchart of the study. COPD: chronic obstructive pulmonary disease; TT: triple therapy. also appeared to have a higher prevalence of comorbidities accounting for all patients who initiated TT at some point during (particularly respiratory related) than patients who initiated TT at the study period, before or after COPD diagnosis. Restricting the or after COPD diagnosis. No significant differences were observed sample to patients who initiated TT at or after COPD diagnosis, in blood eosinophil concentration (BEC) between groups (Table 1). median time from COPD diagnosis to TT initiation was 196 days (IQR: 15; 620 days). The median time to TT was shorter for GOLD C/ Characteristics of patients who initiated TT at or after COPD D patients (151 days; IQR: 11; 535 days) compared to GOLD A/B diagnosis and according to severity of disease (217 days; IQR: 18; 644 days) (Fig. 2). Regarding phenotypes, time Among the 8626 patients who initiated TT at or after COPD to TT initiation was shorter in frequent exacerbators (123 days; diagnosis, 6237 (72.3%) were GOLD A/B and 1260 (14.6%) were IQR: 13; 462 days) compared to infrequent (160 days; IQR: 10; frequent exacerbators. A total of 615 (7.1%) were classified as 560 days) and non-exacerbators (254 days; IQR: 122; 686 days) asthma–COPD overlap (ACO) (Table 2). ACO patients had a lower (Table 3 and Fig. 3). proportion of males (53.2%), were slightly younger 65.7 years (SD: 11.9 years), and had a higher BEC (275 cells/ml; SD: 185) than Factors independently associated with time to TT initiation patients who did not have ACO. Patients with prior treatment including an ICS showed a higher Regarding spirometry, it was more frequently performed in likelihood to initiate TT earlier than patients with no prior ICS GOLD C/D patients with up to 61.1% compared to 25.5% of treatment (Table 4). Similarly, more severe GOLD stage (C/D) (HR = GOLD A/B, and these patients also had the lowest FEV1 (%) values 2.36, 95% CI: 2.21–2.53; logistic regression analysis p < 0.001), (40.7%, SD: 18.5) compared to GOLD A/B (66.7%, SD: 11.7). followed by ACO (HR = 1.89, 95% CI: 1.74–2.06; p < 0.001), and Distribution of comorbidities was similar between subgroups exacerbators (HR = 1.56, 95% CI: 1.52–1.61; p < 0.001) were (Table 2). associated with earlier initiation of TT. Older age, male sex, and Patients with ACO were the group most frequently treated with pneumonia and lung cancer were also significantly associated with a regimen including an ICS before initiating TT (54.8%) compared higher probability of early TT initiation (Table 4). with the 41.2% for all the groups. About a quarter of patients had no previous treatment the year before initiating TT (Table 2). DISCUSSION Time between COPD diagnosis and initiation of triple therapy The results of the current study have shown that 16.5% of patients Over the study period, median time between diagnosis and TT with a new diagnosis of COPD in primary care initiated TT during initiation was 49 days (interquartile range [IQR]: −1; 439 days) the 5-year study period. Interestingly one quarter of patients npj Primary Care Respiratory Medicine (2021) 16 Published in partnership with Primary Care Respiratory Society UK M Monteagudo et al. 3 Table 1. Clinical characteristics of incident COPD patients and subgroups according to TT initiation and period of initiation. Incident COPD Incident COPD Incident COPD p TT initiation at or TT initiation p patients N = patients who do not patients who after COPD before COPD 69,668 initiate TT N = initiated TT N = diagnosis N = 8626 diagnosis N = 58,144 (83.5%) 11,524 (16.5%) (74.8%) 2898 (25.2%) Age, mean (SD) 68.3 (12.3) 68.1 (12.5) 69.3 (11.3) <0.001 68.8 (11.1) 70.8 (11.6) <0.001 Sex, men 68.6 67.9 72.6 <0.001 73.6 69.4 <0.001 Duration of follow-up in 27.1 (16.6) 26.3 (16.5) 30.8 (16.1) <0.001 33.8 (15.6) 21.6 (14.1) <0.001 months, mean (SD) Body mass index, mean (SD) 28.7 (5.3) 28.6 (5.2) 29.3 (5.5) <0.001 29.3 (5.5) 29.5 (5.6) NS Respiratory comorbidities Upper respiratory infection 24.9 25.8 20.4 <0.001 19.3 23.9 <0.001 Asthma 6.9 5.9 11.9 <0.001 9.7 18.5 <0.001 Pneumonia 6.6 6.2 9 <0.001 7.6 13.1 <0.001 Bronchiectasis 3.5 3.2 5.1 <0.001 4.3 7.7 <0.001 Other comorbidities Hypertension 53.2 52.8 55.1 <0.001 54.5 56.8 0.03 Cancer 12.5 12.3 13.6 <0.001 13 15.4 0.001 Diabetes mellitus 21.8 21.6 23.4 <0.001 22.4 26.3 <0.001 Hypercholesterolemia 44.7 45.3 42 <0.001 41.4 43.8 0.02 Anxiety 15.9 16.2 14.4 <0.001 13.9 15.8 0.01 Depression 16.1 16.2 15.4 0.05 14.7 17.6 <0.001 Osteoarthritis 22.3 22.6 20.7 <0.001 24 19.6 <0.001 Spirometry 44.3 46.3 34.5 <0.001 35.3 32.1 0.002 FEV1 (%); mean (SD) 65.3 (19.6) 67.1 (18.9) 55.1 (19.5) <0.001 54.6 (19.4) 56.4 (19.6) 0.02 Patients with exacerbations 47.6 46.9 51.4 <0.001 49.4 57.2 <0.001 Number of exacerbations, 0.6 (0.8) 0.6 (0.82) 0.7 (0.92) <0.001 0.7 (0.8) 0.9 (1,05) <0.001 mean (SD) Visits to primary care, mean 8.4 (6.6) 8.1 (6.3) 9.8 (7.4) <0.001 9.7 (7.3) 10.3 (7.7) <0.001 (SD) Blood eosinophil, mean (SD) 249 (156) 248 (167) 252 (180) NS 253 (178) 248 (188) NS The data are %, unless otherwise indicated. P values obtained by χ or T-Student tests. 2 SD standard deviation, FEV1 forced expired volume in 1 s, LAMA long-acting anticholinergic agent, LABA long-acting beta-2 agonist, ICS inhaled corticosteroid. initiated TT even before the diagnosis of COPD was recorded in +32,000 patients with COPD in primary care were treated with TT the electronic medical records. Patients who were frequent during the first year after diagnosis15. It is important to contrast exacerbators or had ACO were more likely to initiate TT earlier, these figures with the current GOLD recommendations that do which is in accordance with COPD treatment recommendations8,9. not include TT as initial therapy in any of the GOLD groups, but However, it appears that BEC did not influence the decision to only as step up when initial therapy is not effective in controlling initiate TT in this study. symptoms or preventing exacerbations8,16,17. In order to analyze the characteristics of patients initiating TT After excluding patients who initiated TT before COPD and time to TT initiation we focused on the patients who initiated diagnosis, the remaining incident patients with COPD initiated TT at or after diagnosis of COPD. The rationale of this was to avoid TT a median of 196 days after diagnosis, with a shorter period any bias that may be introduced by analyzing characteristics of observed in frequent exacerbators and GOLD C/D patients, which patients who, at the time of prescribing, might have been is in line with treatment recommendations8. It is of note that diagnosed with other diseases, such as asthma, or not diagnosed around one quarter of newly diagnosed COPD patients did not at all. Moreover, the group of patients initiating TT at or after have any inhaled treatment before TT. Among the remaining diagnosis of COPD constituted three quarters of the whole patients, the most frequent treatment received before TT was population. LABA/ICS followed by LABA/LAMA. These results are different from The observed 16.5% of incident patients with COPD initiating TT represents an increase from the 12% observed in a previous study those observed in a previous study by Monteagudo et al.18 in over in Spain conducted between 2007 and 201210 and is higher than 34,000 prevalent COPD cases with TT from the same database, in the 7.5% of patients initiating TT after COPD diagnosis observed in whom the most frequent previous treatment was LAMA (22.5%) a large database study in the United States11. However, it is lower followed by LABA/ICS (15.2%). Mapel et al.19 in the United States than the percentages observed in other European cohorts: also found that the most frequent treatment before TT was LAMA Vetrano et al.12 found that 21% of patients with COPD had TT (15.4%) followed by LABA/ICS (7.7%). It might be that incident as their first inhaled prescription. In the United Kingdom, Wurst COPD cases initiating TT may be more symptomatic and, et al.13 observed that 23% of patients with incident COPD initiated therefore, they are more frequently started already on LABA/ICS TT, and another recent study described an increase in the use of (and early stepped up to TT) instead of starting on monotherapies. TT as initial therapy from <1% in 2002 to 28% in 2014, with a small It is of note that only 34.5% of patients who initiated TT had reduction to 22% in 201614. In Italy, a 6.3% from a population of spirometry recorded in their clinical records. The underuse of Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2021) 16 M Monteagudo et al. 4 Table 2. Characteristics of incident TT patients who initiated treatment at or after COPD diagnosis and according to severity of disease and clinical phenotypes (n = 8626). Incident GOLD A/B GOLD C/D ACO Frequent Infrequent Non- COPD-TT N = 6237 N = 2389 N = 615 exacerbators exacerbators exacerbators patients (72.3%) (27.7%) (7.13%) N = 1260 (14.6%) N = 3002 (34.8%) N = 4364 (50.6%) N = 8626 Age, mean (SD) 68.8 (11.1) 68.9 (11.1) 68.3 (11.3) 65.7 (11.9) 69.3 (12.2) 68.4 (11.4) 68.9 (10.6) Sex, men 73.6 74.1 72.3 53.2 64 71.3 78 Body mass index, mean (SD) 29.3 (5.5) 29.4 (5.4) 29.02 (5.7) 29.5 (5.3) 29.8 (5.8) 29.2 (5.4) 29.1 (5.5) Respiratory comorbidities Upper respiratory 19.3 16.7 26 20.3 36 20.4 13.7 infection Asthma 9.7 8.5 12.9 100 16.4 9.7 7.8 Pneumonia 7.6 6 11.9 7.2 18.3 10.7 2.4 Bronchiectasis 4.3 3.4 6.5 4.4 8.9 5.4 2.1 Other comorbidities Hypertension 54.5 54.3 54.8 51.9 58.1 52.2 55 Cancer 13 12.7 13.8 9.4 15.2 12.4 12.8 Diabetes mellitus 22.4 22.3 22.7 19.3 24.3 21.4 22.5 Hypercholesterolemia 41.4 40.7 43.1 38.2 46.7 39.9 40.9 Anxiety 13.9 13.5 15.2 17.7 19.2 14.1 12.3 Depression 14.7 14.5 15.3 19.8 18 15 13.6 Osteoarthritis 24 19.1 21 22.1 26.7 18.7 18.2 Spirometry 35.3 25.5 61.1 42.6 34.6 34.1 38.4 FEV1 (%), mean (SD) 54.6 (19.4) 66.7 (11.7) 40.7 (18.5) 59.1 (19.9) 56.1 (20.2) 54.7 (19.1) 53.8 (19.6) Patients with exacerbations 49.4 41.9 69.1 59.5 100 100 0 Number of exacerbations, 0.7 (0.8) 0.42 (0.49) 1.37 (1.19) 0.88 (0.9) 2.4 (0.7) 1(0) 0 mean (SD) Visits to primary care, mean 9.7 (7.3) 9.3 (7.1) 10.6 (7.7) 9.7 (7.1) 12.7 (8.5) 9.7 (7.5) 8.8 (6.5) (SD) Blood eosinophil, mean (SD) 253 (178) 254 (182) 252 (167) 275 (185) 253 (178) 254 (182) 253 (175) Treatment (12-month prior) LAMA monotherapy 3.4 3.2 3.8 2.9) 4.1 3.5 3.1 Combinations therapy LABA + ICS 35.3 34.7 36.7 50.1 39.1 35.5 34.1 LAMA + ICS 5.7 5.5 6.2 4.7 7.3 5.9 5.4 LABA + LAMA 11.5 11.3 11.9 9.2 10.7 10.9 12.1 None previous treatment 2511 (29.1) 1864 (29.8) 647 (27.1) 162 (26.3) 343 (27.2) 875 (29.1) 1293 (29.6) The data are %, unless otherwise indicated SD standard deviation, FEV1 forced expired volume in 1 s, LAMA long-acting anticholinergic agent, LABA long-acting beta-2 agonist, ICS inhaled corticosteroid. with the initiation of TT in newly diagnosed patients with COPD. This expected finding included characteristics such as increasing age, more severe GOLD stage, and more frequent exacerbations. Another characteristic significantly associated with TT initiation was the ACO phenotype, which is also in alignment with current recommendations, that recommend the use of ICS in combination with long-acting bronchodilators to prevent exacerbations, in M particular in patients with eosinophilic profile or a previous diagnosis of asthma8,9. Fig. 2 Median time from COPD diagnosis to TT according to GOLD However, other identified factors associated with the initiation subgroups for patients who initiate triple therapy at or after diagnosis of COPD. COPD: chronic obstructive pulmonary disease; of TT were unexpected. Male sex was significantly associated with TT: triple therapy; GOLD: global strategy for obstructive lung disease. TT initiation in patients with incident COPD. This gender bias is difficult to explain and is not linked to the well-described spirometry is still a pending issue in primary care that may affect diagnostic bias20, since all patients had a diagnosis of COPD. This diagnostic accuracy. finding should be analyzed in other studies that investigate In multivariate analysis, we observed that some variables that whether it is due to a trend toward overprescription in men, or, define the severity of the disease were significantly associated alternatively an underprescription in women. npj Primary Care Respiratory Medicine (2021) 16 Published in partnership with Primary Care Respiratory Society UK M Monteagudo et al. 5 −327 (−611; −108) Non-exacerbators Non-exacerbators Non-exacerbators 254 (122; 686) 91 (0; 539) (N = 5603) (N = 4364) (N = 1239) M −221 (−561; −69) Fig. 3 Median time from COPD diagnosis to TT according to 160 (10; 560) Exacerbators Exacerbators Exacerbators phenotypes for patients who initiate triple therapy at or after 59 (0; 417) Frequent Exacerbators Infrequent Frequent Exacerbators Infrequent Frequent Exacerbators Infrequent (N = 3759) (N = 3002) diagnosis of COPD. COPD: chronic obstructive pulmonary disease; (N = 757) TT: triple therapy; ACO: asthma-COPD overlap. Table 4. Predictive value of the different characteristics of patients −206 (−466; −71) −303 (−674.5; −125.5) −216 (−514; −71) newly diagnosed with COPD for time to initiation of TT. 0 (−133.2; 196.7) 123 (13; 462) Hazard ratio 95% p value (N = 2162) (N = 1260) confidence (N = 902) interval Lower Upper Age (for every year) 1.006 1.004 1.008 <0.001 Male 1.38 1.32 1.45 <0.001 44 (−35.7; 429.5) ACOS (N = 233) Underweight <18.5 (vs normal 1.40 1.11 1.78 0.004 IQR interquartile range, TT triple therapy, ACO asthma–COPD overlap, GOLD Global initiative for Obstructive Lung Disease. ACO (N = 848) ACO (N = 615) 235 (21; 637) 18.5–25) Overweight >25–30 (vs normal 1.02 0.95 1.10 0.51 18.5–25) Time passed between COPD diagnosis and triple therapy treatment according to subgroups. Obese >30 (vs normal 18.5–25) 1.27 1.18 1.37 <0.001 Missing (vs normal 18.5–25) 1.50 1.41 1.61 <0.001 26.5 (−27; 349.7) GOLD C/D (vs A/B) 2.36 2.21 2.53 <0.001 151 (11; 535) Infrequent exacerbator (vs non- 1.05 1.00 1.10 0.03 GOLD A/B (N = 8224) GOLD C/D GOLD A/B (N = 6237) GOLD C/D GOLD A/B (N = 1987) GOLD C/D (N = 3300) (N = 2389) exacerbator) (N = 911) Exacerbatora (vs non- 1.56 1.52 1.61 <0.001 exacerbator) Asthma–COPD overlap 1.89 1.74 2.06 <0.001 LAMA/ICS 2.81 2.45 3.23 <0.001 −292 (−610; −94) LABA/ICS 1.90 1.82 2.00 <0.001 217 (18; 644.5) 60.5 (0; 472.7) LABA/LAMA 1.69 1.53 1.86 <0.001 Pneumonia 1.33 1.23 1.43 <0.001 Lung cancer 1.81 1.57 2.07 <0.001 All hazard ratios are adjusted for each variable presented in the table. LAMA long-acting anticholinergic agent, LABA long-acting beta-2 agonist, −256 (−567.2; −82.7) ICS inhaled corticosteroid. a Patients who initiate TT at or after diagnosis of COPD Exacerbator refers to patients with at least one exacerbation the Patients who initiate TT before the diagnosis of COPD previous year. All (N = 11524) All (N = 8626) All (N = 2898) 196 (15; 620) 49 (−1; 439) Another surprising finding is the significant association of TT initiation and the diagnosis of pneumonia. It is well recognized that the use of ICS is a risk factor for pneumonia in patients with Time between COPD diagnosis Time since COPD diagnosis to COPD21 and, therefore, the opposite association would be Time since TT to diagnosis expected. A hint to explain this paradox can be found in the Total incident TT cohort next characteristic associated with initiation of TT, which is the diagnosis of lung cancer. The possible explanation could be that both patients with episodes of pneumonia and lung cancer and TT (in days) Median, (IQR) may visit the primary care physician more frequently with more Median (IQR) Median (IQR) TT (in days) respiratory complaints, therefore, stepping up treatment to (in days) Table 3. include ICS may be more likely. However, the association between the initiation of TT and pneumonia suggests that PCP may not be aware of the risk of pneumonia associated with the use of ICS, in Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2021) 16 M Monteagudo et al. 6 particular in patients with more severe disease, underweight, and misclassification and over-estimation of exacerbations, consecutive epi- with low BEC22,23. sodes with less than 21 days between prescriptions and physician visits Finally, we did not find an association between TT initiation and were considered as a single event. BEC. Whilst it must be considered that the relevance of the use of The study was approved by the Research and Ethics Committee of the IDIAP Jordi Gol Institute of Research in Primary Care (Barcelona, Spain). BEC to guide ICS treatment in COPD has only appeared in recent Since anonymized data were collected retrospectively, no informed years, the 2012 edition of the Spanish Guideline on treatment of consent was considered necessary. COPD already mentioned the use of BEC to classify patients as ACO and personalize the prescription of ICS predominantly to patients with this phenotype24. Our data and other large database Statistical analysis studies18,25 show that BEC are available for the great majority of Description of variables was performed with absolute frequencies and patients with COPD in primary care and therefore can be a useful corresponding percentages. Continuous variables were described using the mean and SD, while time from diagnosis to TT initiation in days was biomarker for the appropriate use of ICS in COPD26. described using the median and IQR. In conclusion, we have observed that around 15% of newly Categorical variables were compared using the χ2 or Fisher exact test diagnosed patients with COPD initiate TT. Among them, one where applicable. Quantitative variables were compared using the T-test or quarter had no previous inhaled therapy. Although these findings Mann–Whitney U test. may not be consistent with current COPD guidelines, the The variables significantly and independently associated with time to observation that patients with ACO and frequent exacerbations initiation of TT in newly diagnosed patients were identified by means of a were more likely to start TT and started TT earlier is in alignment logistic regression analysis. The results were described using hazard ratios with treatment recommendations. with a 95% confidence interval and p values. All statistical analyses were performed using the statistical software package Statistical Package for Social Science (SPSS) version 20.0 (IBM, Chicago, IL, USA). A p value <0.05 was considered significant. METHODS Study design This was a retrospective study with longitudinal follow-up. Data analyzed Reporting summary were obtained from the Information System for the Development of Further information on research design is available in the Nature Research Research in Primary Care (SIDIAP) database; this database includes Reporting Summary linked to this article. anonymized electronic medical records from 270 primary care centers with a reference population of 5.8 million people in Catalonia (Spain), which represents more than 80% of the total population27. This database DATA AVAILABILITY has been used and validated for epidemiological research in respiratory The data that support the findings of this study belong to the Catalan Healthcare diseases25,28. System and are not publicly available. They were used under license for the current study. Data are, however, available from the corresponding authors upon reasonable Patient selection request and with permission of Information System for the Development of Research in Primary Care (SIDIAP). Included patients were those over 40 years of age with a first diagnosis of COPD (International Classification of Disease—10th Edition) between January 1, 2011 and December 31, 2015. Patients were required to have Received: 2 October 2020; Accepted: 3 February 2021; at least 12 months of available medical record data prior to diagnosis of COPD. Among incident patients with COPD, those who initiated TT were defined as having prescriptions for LAMA, LABA, and ICS with an overlap of 30 days or more. 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Pharmacological treatment of stable phase. diagnosis were also collected. Arch. Bronconeumol. 53, 324–335 (2017). Exacerbation episodes were identified according to previously published 10. Barrecheguren, M. et al. Treatment patterns in COPD patients newly diagnosed in algorithms10,28. Briefly, we used a diagnostic code indicative of a primary care. A population-based study. Respir. Med. 11, 47–53 (2016). respiratory exacerbation, or receipt of corticosteroids and/or antibiotics 11. Simeone, J. C. et al. Initiation of triple therapy maintenance treatment among used for treating the episode. Exacerbations leading to hospitalizations or patients with COPD in the US. Int J. Chron. Obstruct Pulmon Dis. 12, 73–83 treated as part of inpatient care were not available in the data. To avoid (2017). npj Primary Care Respiratory Medicine (2021) 16 Published in partnership with Primary Care Respiratory Society UK M Monteagudo et al. 7 12. Vetrano, D. L. et al. Triple inhaled therapy in COPD patients: determinants of ACKNOWLEDGEMENTS prescription in primary care. Respir. Med. 154, 12–17 (2019). The current study has been funded by an unrestricted grant from AstraZeneca that 13. Wurst, K. E., Shukla, A., Muellerova, H. & Davis, K. J. Respiratory pharmacotherapy was also involved in study conception and protocol development. A.N. is the use in patients newly diagnosed with chronic obstructive pulmonary disease in a recipient of a Rio Hortega contract in the 2019 Strategic Action Health Call from the primary care setting in the UK: a retrospective cohort study. COPD 11, 521–530 Instituto de Salud Carlos III for the years 2020–2022. (2014). 14. Bloom, C. I., Elkin, S. L. & Quint, J. K. Changes in COPD inhaler prescriptions in the United Kingdom, 2000 to 2016. Int J. Chron. Obstruct Pulmon Dis. 14, 279–287 AUTHOR CONTRIBUTIONS (2019). D.L., N.D., and A.B. conceived and designed the study. M. Monteagudo and I.S. 15. Di Marco, F. et al. Characteristics of newly diagnosed COPD patients treated with coordinated statistical analyses. M. Miravitlles and M. Monteagudo wrote manuscript. triple inhaled therapy by general practitioners: a real world Italian study. NPJ Prim. All authors contributed to study design and analysis, drafting, reviewing, and critically Care Respir. Med. 27, 51 (2017). revising the paper, gave final approval of the version to be published, and agreed to 16. Calverley, P. M. A., Magnussen, H., Miravitlles, M. & Wedzicha, J. A. Triple therapy be accountable for all aspects of the work. in COPD: what we know and what we don’t. COPD 14, 648–662 (2017). 17. López-Campos, J. L. et al. The clinical implications of triple therapy in fixed-dose combination in COPD: from the trial to the patient. Arch. Bronconeumol. 56, 242–248 (2020). COMPETING INTERESTS 18. Monteagudo, M. et al. Treatment pathways before and after triple therapy in M. Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, COPD: a population-based study in Primary Care in Spain. Arch. Bronconeumol. Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols, and Novartis; 57, 205–213 (2020). consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, 19. Mapel, D. et al. A retrospective study to assess clinical characteristics and time to Bial, Gebro Pharma, Kamada, CSL Behring, Laboratorios Esteve, Ferrer, Mereo initiation of open-triple therapy among patients with chronic obstructive pul- Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis, Sanofi, and Grifols; and monary disease, newly established on long-acting mono or combination therapy. research grants from GlaxoSmithKline and Grifols. M.B. has received speaker fees Int J. Chron. Obstruct Pulmon Dis. 12, 1825–1836 (2017). from Grifols, Menarini, CSL Behring, and GSK and consulting fees from GSK and 20. Miravitlles, M. et al. Attitudes towards the diagnosis of chronic obstructive pul- Novartis. D.L., N.D., and A.B. are employees of Evidera. The authors confirm that there monary disease in Primary Care. Arch. Bronconeumol. 42, 3–8 (2006). are no other conflicts of interest to report. 21. Kew, K. M. & Seniukovich, A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Systematic Review. https://doi.org/ 10.1002/14651858.CD010115.pub2 (2014). ADDITIONAL INFORMATION 22. Crim, C. et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol Supplementary information The online version contains supplementary material compared with vilanterol alone in patients with COPD. Ann. Am. Thorac. Soc. 12, available at https://doi.org/10.1038/s41533-021-00227-x. 27–34 (2015). 23. Pavord, I. D., Lettis, S., Anzueto, A. & Barnes, N. Blood eosinophil count and Correspondence and requests for materials should be addressed to M.M. pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir. Med. 4, 731–741 (2016). Reprints and permission information is available at http://www.nature.com/ 24. Miravitlles, M. et al. Spanish COPD guidelines (GesEPOC). Pharmacological reprints treatment of stable COPD. Arch. Bronconeumol. 48, 247–257 (2012). 25. Miravitlles, M., Monteagudo, M., Solntseva, I. & Alcázar, B. Blood eosinophil counts Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims and their variability and risk of exacerbations in COPD: a population-based study. in published maps and institutional affiliations. Arch. Bronconeumol. 57, 13–20 (2021). 26. Kolsum, U., Southworth, T., Jackson, N. & Singh, D. Blood eosinophil counts in COPD patients compared to controls. Eur. Respir. J. 54, 1900633 (2019). 27. Bolíbar, B. et al. SIDIAP database: electronic clinical records in primary care as a source of information for epidemiologic research. Med Clin. 138, 617–621 Open Access This article is licensed under a Creative Commons (2012). Attribution 4.0 International License, which permits use, sharing, 28. Monteagudo, M., Roset, M., Rodríguez-Blanco, T., Muñoz, L. & Miravitlles, M. adaptation, distribution and reproduction in any medium or format, as long as you give Characteristics of COPD patients initiating treatment with aclidinium or tio- appropriate credit to the original author(s) and the source, provide a link to the Creative tropium in primary care in Catalonia: a population-based study. Int J. Chron. Commons license, and indicate if changes were made. The images or other third party Obstruct Pulmon Dis. 12, 1145–1152 (2017). material in this article are included in the article’s Creative Commons license, unless 29. Nuñez, A. et al. Practical guide to the identification and diagnosis of asthma- indicated otherwise in a credit line to the material. If material is not included in the COPD overlap (ACO). COPD 16, 1–7 (2019). article’s Creative Commons license and your intended use is not permitted by statutory 30. Soler-Cataluña, J. J. et al. Clinical characteristics and risk of exacerbations asso- regulation or exceeds the permitted use, you will need to obtain permission directly ciated with different diagnostic criteria of asthma-COPD overlap. Arch. Bronco- from the copyright holder. To view a copy of this license, visit http://creativecommons. neumol. 56, 282–290 (2020). org/licenses/by/4.0/. 31. Vestbo, J. et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 187, 347–365 (2013). © The Author(s) 2021 Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2021) 16