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Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial treatment for COPD in primary care

Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial... www.nature.com/npjpcrm ARTICLE OPEN Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial treatment for COPD in primary care 1 2,3 1 Miriam Barrecheguren , Mónica Monteagudo and Marc Miravitlles This epidemiological study aimed to describe and compare the characteristics and outcomes of COPD patients starting treatment with a long-acting anti-muscarinic (LAMA) or a combination of a long-acting beta-2 agonist (LABA)/LAMA in primary care in Catalonia (Spain) over a one-year period. Data were obtained from the Information System for the Development in Research in Primary Care (SIDIAP), a population database containing information of 5.8 million inhabitants (80% of the population of Catalonia). Patients initiating treatment with a LAMA or LABA/LAMA in 2015 were identified, and information about demographic and clinical characteristics was collected. Then, patients were matched 1:1 for age, sex, FEV1%, history of exacerbations, history of asthma and duration of treatment, and the outcomes between the two groups were compared. During 2015, 5729 individuals with COPD started treatment with a LAMA (69.8%) or LAMA/LABA (30.2%). There were no remarkable differences between groups except for a lower FEV1 and more previous hospital admissions in individuals on LABA/LAMA. The number of tests and referrals was low and decreased in both groups during follow-up. For the same severity status, the evolution was similar with a reduction in exacerbations in both groups. Treatment was changed during follow-up in up to 34.2% of patients in the LABA/LAMA and 26.3% in the LAMA group, but adherence was equally good for both. Our results suggest that initial therapy with LAMA in monotherapy may be adequate in a significant group of mild to moderate patients with COPD and a low risk of exacerbations managed in primary care. npj Primary Care Respiratory Medicine (2018) 28:36 ; doi:10.1038/s41533-018-0102-x INTRODUCTION the effectiveness of LABD and its combination with other agents in the usual clinical practice. The use of large population-based The aim of pharmacological treatment in chronic obstructive databases may help to increase the knowledge on real-life use of pulmonary disease (COPD) is to reduce symptoms, decrease the bronchodilator treatment in primary care. Therefore, the objective frequency and severity of exacerbations and improve exercise of this study was to describe the characteristics and outcomes of tolerance. Previous studies have demonstrated the efficacy of COPD patients starting inhaled treatment with a LAMA or a long-acting bronchodilators (LABD) in improving lung function, combination of LABA/LAMA in primary care in Catalonia (Spain) respiratory symptoms, exacerbations, exercise capacity and quality 2 1,3,4 over a 1 year period. of life and constitute the cornerstone of COPD treatment. Among LABD, long-acting anti-muscarinic agents (LAMA) have shown greater efficacy in the prevention of exacerbations 5,6 compared to long-acting β2-agonists (LABA), and therefore, RESULTS guidelines recommend the use of LAMA over LABA as the initial During 2015, we identified 5729 individuals with a codified 1,3,4 treatment in COPD. diagnosis of COPD who started treatment with either a LAMA In recent years, new treatments for COPD have been launched, (4001 or 69.8%) or LAMA/LABA (1728 or 30.2%). These patients most being LABD, inhaled corticosteroids (ICS) and combinations constituted the population of our study. Among the patients of the two, with the objective of improving patient outcomes in receiving a LAMA/LABA, 68.3% received the combination in the COPD. Recent studies have suggested that dual treatment with a same inhalation device. LAMA and a LABA results in greater bronchodilation and improved symptoms and health status compared to a LABD in mono- 7,8 Baseline characteristics therapy. However, most studies assessing the efficacy of double bronchodilation compared with monotherapy have included In total, 76.9% were men with a mean age of 66.3 (SD 11.1) years, moderate to severe patients with dyspnoea according to the with no differences between the LAMA or LAMA/LABA groups. 2,7,8 modified Medical Research Council (mMRC) ≥ 2 scale, exclud- The patients were diagnosed a mean of 3.3 (4.9) years before ing milder patients who may not present a significant improve- inclusion, with significant differences between groups [3.9 (5.3) ment with the addition of a second LABD. In addition, there is a years for the LABA/LAMA group vs. 3.1 (4.7) years for the LAMA lack of follow-up studies in real life in primary care investigating patients, p < 0.001]. The most frequent comorbidities were 1 2 Pneumology Department, Hospital Universitari Vall d´Hebron. Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; Primary Care University Research Institute Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain and Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain Correspondence: Marc Miravitlles (mmiravitlles@vhebron.net) Received: 14 March 2018 Revised: 24 August 2018 Accepted: 24 August 2018 Published in partnership with Primary Care Respiratory Society UK Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Table 1. Baseline characteristics of the patients studied Total N = 5729 Patients starting on LAMA N = 4001 Patients starting on LABA/LAMA N = p-value Sex (men) 4406 (76.9) 3043 (76.1) 1363 (78.9) 0.02 Age, years 66.25 (11.1) 66.42 (11.1) 65.84 (11.1) NS Years from diagnosis 3.33 (4.9) 3.08 (4.7) 3.91 (5.3) <0.001 BMI (Kg/m ) 29.14 (5.3) 29.04 (5.2) 29.36 (5.4) NS Smoking history (n,%) NS Never smoker 1115 (19.5) 792 (19.8) 323 (18.7) Active smoker 2232 (39) 1586 (39.6) 646 (37.4) Former smoker 2318 (40.5) 1588 (39.7) 730 (42.2) Unknown 64 (1.1) 35 (0.9) 29 (1.7) Phenotype (n,%) NS ACO 183 (3.2) 128 (3.2) 55 (3.2) Non exacerbator 1303 (22.7) 890 (22.2) 413 (23.9) Exacerbator 4243 (74.1) 2983 (74.6) 1260 (72.9) Comorbidities Asthma 262 (4.6) 184 (4.6) 78 (4.5) NS Bronchiectasis 233 (4.1) 180 (4.5) 53 (3.1) 0.01 OSA 331 (5.8) 232 (5.8) 99 (5.7) NS Ischaemic heart disease 808 (14.1) 570 (14.2) 238 (13.8) NS Heart failure 483 (8.4) 306 (7.6) 177 (10.2) 0.001 Atrial fibrilation 593 (10.4) 411 (10.3) 182 (10.5) NS Hypertension 3307 (57.7) 2303 (57.6) 1004 (58.1) NS Diabetes mellitus 1443 (25.2) 1002 (25) 441 (25.5) NS Dyslipidemia 2915 (50.9) 2069 (51.7) 846 (49) 0.05 Depression 1049 (18.3) 746 (18.6) 303 (17.5) NS Osteoporosis 396 (6.9) 290 (7.2) 106 (6.1) NS GERD 299 (5.2) 212 (5.3) 87 (5) NS Complementary tests Spirometries with FEV1 2271 (39.6) 1584 (39.6) 687 (39.8) NS FEV1 % 62.5 (18.9) 65.0 (18.6) 56.9 (18.5) <0.001 Severity N (%) (n = 2271) <0.001 Gold 1 354 (15.6) 296 (18.7) 58 (8.4) Gold 2 1415 (62.3) 1013 (64) 402 (58.5) Gold 3 424 (18.7) 236 (14.9) 188 (27.4) Gold 4 78 (3.4) 39 (2.5) 39 (5.7) Exacerbations during the previous 12 months, n (%) NS 0 exacerbations 2685 (46.9) 1871 (46.7) 814 (47.1) 1 exacerbations 1741 (30.4) 1240 (31.0) 501 (28.9) ≥2 exacerbations 1303 (22.7) 890 (22.2) 413 (23.9) Hospital admission during the previous 12 months, n (%) Total 449 (7.8) 294 (7.3) 155 (9) 0.03 Respiratory hospital admission 22 (0.4) 13 (0.3) 9 (0.5) NS Data are expressed as mean (SD) unless specified otherwise BMI body mass index, ACO asthma COPD overlap, OSA obstructive sleep apnoea, GERD gastrooesophageal reflux disease, FEV1 forced expiratory volume in 1 s, GOLD global initiative for obstructive chronic pulmonary disease hypertension (57.7%), diabetes mellitus (25.2%), dyslipidemia Longitudinal analysis: matching sub-cohort (50.9%) and depression (18.3%). For the longitudinal analysis we identified 1897 (33%) individuals Spirometry result with a FEV1 was available in only 40% of the who fulfilled the criteria for the diagnosis of COPD (Fig. 1). Finally, patients. Individuals treated with a combination of two bronch- of these, matching was possible for 524 patients from each odilators presented more severe disease, with a lower FEV1 % treatment group. (56.9% (18.5) vs. 65.0% (18.7), p < 0.001) and included a greater As expected, there were no differences in the baseline number of patients classified as GOLD 3 and GOLD 4. Distribution characteristics between groups, although the time from diagnosis by phenotypes was similar between the two groups. Patients to treatment was longer in the combined group (3.7 (5.1) years vs. treated with double bronchodilation tended to have more 2.8 (4.3) years, p = 0.002) (Table 2). hospital admissions for all causes during the previous year but During the 12-month follow-up, only 22.7% of patients in the not for respiratory causes, although numbers were very small. The LAMA group underwent spirometry. The number of chest X-rays baseline characteristics of the cohort and by treatment group are and computerised tomography (CT) lung studies also significantly presented in Table 1. decreased in the LAMA group (Table 2). This group also showed a npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Fig. 1 Changes in the treatment pattern at 12 months of follow-up compared to baseline. Continous arrow: step-up or equivalent treatment; dashed arrow: step-down treatment. LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid significant reduction in the number of patients presenting an 15.3% (8.4% LAMA and 6.9% LABA), 4.8% changed to LABA/ICS exacerbation compared to the previous year (−13.9%, 95% CI: and 6.5% to no inhaled therapy (Table 4) (Fig. 1). −19.9;−7.9; p < 0.001) and in the mean number of exacerbations Changes in treatment differed according to severity. In the (−0.3, 95% CI: −0.4; −0.1; p < 0.001). The percentage of patients LAMA group less severe patients (GOLD 1 and 2) tended to consulting with a nurse or being referred to a specialist also continue on a LAMA (83.9% of GOLD 1 and 75.4% of GOLD 2). The significantly decreased in the LAMA group during the one-year most frequent change of treatment was escalation to LABA/LAMA follow-up. or discontinuation of all treatment. In the LABA/LAMA group, only Patients treated with a LABA/LAMA also showed a reduction in two thirds of GOLD 1 and 2 patients continued with the same the number of spirometries chest X-rays and CT scans performed treatment. Patients were frequently de-escalated to one LABD (Table 2). This group showed a reduction in the percentage of (23.7% of GOLD 1 and 26.1% of GOLD 2) or no maintenance patients presenting an exacerbation (−8.6%, 95% CI: −14.6; −2.6; therapy (Table 4). p < 0.001), and in the mean number of exacerbations (−0.2, 95% Up to 13.5% of GOLD 3 patients in the LAMA group were CI: −0.3; −0.1; p < 0.001). In addition, fewer patients consulted a escalated to LABA/LAMA, while GOLD 4 were more frequently nurse or were referred to a pulmonologist compared to the year escalated to triple therapy or were switched to LABA/ICS. In the before initiating treatment (−21.2%, 95% CI: −25.5; −16.8; p < LABA/LAMA group, GOLD 4 patients were switched to triple 0.001). therapy (5.9%) and more frequently to LABA/ICS (17.6%). On comparing the two groups, patients treated with a LAMA showed a greater reduction in the number of chest X-rays performed and the number of patients with any exacerbation DISCUSSION (percentage difference −5.3%, 95% CI: −9.2; −1.5; p < 0.001). The results of this study show that COPD patients starting Patients receiving LAMA were less frequently referred to the treatment with a LAMA or a LABA/LAMA in the primary care pulmonologist (mean difference 7.6%, 95% CI: 3.1; 12.2; p < 0.05). setting had no remarkable differences in clinical characteristics except in regard to disease severity; patients initially treated with the combination of bronchodilators had a lower FEV1 and a Changes in treatment and adherence during follow-up greater number of previous hospital admissions. The number of A total of 439 (83.8%) of the patients initially treated with a LAMA diagnostic tests and referrals was low in the two groups and continued receiving this treatment over the 1 year follow-up, decreased during the one-year follow up, especially in those although only 73.7% were treated with LAMA alone. The receiving a LAMA. After performing a matching analysis, we percentage of patients who continued with a LABA/LAMA observed that for the same severity status, the evolution was combination was 65.8% (Table 3). similar for individuals treated with a LAMA or LABA/LAMA. In up to We observed good adherence to treatment (proportion of days 34.2% of patients in the LABA/LAMA group and 26.3% in the covered [PDC] > 80%) in 71% of patients initiating with a LAMA LAMA group a change was made in treatment during follow-up, and 66.6% for LABA/LAMA. In the LABA/LAMA group, adherence but the adherence was equally good in both treatment schedules. was similar for patients treated with one or two devices (67.1 and During the year of the study, 5729 COPD individuals started 65.7%, respectively). Regarding changes in treatment, in the LAMA group, treatment treatment with either a LAMA or a LABA/LAMA. Among them, was escalated in 11.6% during the year of follow-up (7.4% to 1897 had confirmed COPD (coded for COPD plus airflow LABA/LAMA and 5.5% to triple therapy), 4.2% were switched to obstruction and smoking history). In Catalonia, a region with LABA/ICS and in 5.5% the treatment was de-escalated to no approximately 7.5 million inhabitants, a recent study also carried inhaled treatment. out using the SIDIAP (Information System for the Development of In the LABA/LAMA group, treatment was escalated to triple Research in Primary Care) database found that approximately therapy in 6.3%, being de-escalated to LABD in monotherapy in 7000 individuals were diagnosed with COPD every year between Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2018) 36 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK Table 2. 12-month follow up. Intra- and between groups differences based on initial treatment (LAMA vs. LAMA/LAMA) Patients starting on LAMA N = 524 Patients starting on LABA/LAMA N = 524 Baseline Follow-up Change % (follow-up- Baseline Follow-up Change % (follow-up- Differences between groups (change LAMA— baseline) (CI) baseline) (CI) change LABA/LAMA) (CI) Tests Spirometries with recorded FEV 524 (100) 119 (22.7) −77.3 (−80.9; −73.7)*** 524 (100) 132 (25.2) −74.8 (−78.5; −71.1)*** −2.5 (−7.6; 2.7) FEV % 58.6 (18.8) 60.8 (17.6) 2.1 (0.2; 6)* 58.4 (16.8) 58.6 (16.8) 0.2 (−0.8; 3.4) 1.9 (0.4; 3.9) 1, Severity N (%) Gold 1 56 (10.7) 17 (14.3) 42 (8) 8 (6.1) Gold 2 325 (62) 73 (61.3) 333 (63.5) 92 (69.7) Gold 3 118 (22.5) 26 (21.8) 132 (25.2) 30 (22.7) Gold 4 25 (4.8) 3 (2.5) 17 (3.2) 2 (1.5) Blood tests 379 (72.3) 359 (68.5) −3.8 (−9.3; 1.7) 382 (72.9) 371 (70.8) −2.1 (−7.5; 3.3) −1.7 (−3.8; 0.3) CXR 245 (46.8) 90 (17.2) −29.6 (−34.9; −24.2)*** 218 (41.6) 101 (19.3) −22.3 (−27.7; −16.9)*** −7.3 (−12.5; −2)** CT scan 45 (8.6) 27 (5.2) −3.4 (−6.5; −0.4)* 49 (9.4) 23 (4.4) −5(−8; −1.9)** 1.5 (−0.9; 4) Use of healthcare resources Patients with at least one exacerbation, n (%) 299 (57.1) 226 (43.1) −13.9 (−19.9; −7.9)*** 303 (57.8) 258 (49.2) −8.6 (−14.6; −2.6)** −5.3 (−9.2; −1.5)*** No. of exacerbations 1.1 (1.45) 0.85 (1.43) −0.3 (−0.4; −0.1)*** 1.23 (1.63) 1.04 (1.61) −0.2 (−0.3; −0.1)** −0.1 (−0.2; 0.1) Patients with at least one hospital admission, 30 (5.7) 38 (7.3) 1.5 (−1.5; 4.5) 38 (7.3) 45 (8.6) 1.3 (−1.9; 4.6) 0.2 (−1.2; 1.6) n (%) Hospital admissions 1.53 (0.86) 1.47 (1.01) −0.4 (−1.9; 1.1) 1.29 (0.65) 1.62 (1.32) 0.8 (−0.6; 2.1) −1.2 (−3.1; 0.8) Patients with at least one respiratory hospital 3 (0.6) 2 (0.4) −0.2 (−1; 0.6) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) −0.2 (−0.6; 0.2) admission, n (%) Respiratory hospital admissions 1.33 (0.58) 1 (0) – 00 –– Patients with at least one visit to GP, n (%) 519 (99) 520 (99.2) 0.2 (−0.9; 1.3) 520 (99.2) 522 (99.6) 0.4 (−0.5; 1.3) −0.2 (−0.8; 0.5) Visits to GP 8.2 (4.9) 8.2 (5.5) 0 (−0.5; 0.4) 8.6 (5.7) 9.1 (6.6) 0.5 (0; 1)* −0.5 (−1.2; 0.1) Patients with at least one nurse visit, n (%) 507 (96.8) 475 (90.6) −6.1 (−9; −3.2)*** 500 (95.4) 480 (91.6) −3.8 (−6.8; −0.8)* −2.3 (−4.9; 0.3) Nurse visits 6.8 (9.8) 7.5 (10.8) 0.5 (−0.1; 1) 6.7 (6.8) 7.01 (8.4) 0.2 (−0.5; 0.9) 0.3 (−0.6; 1.2) Patients with at least one visit to 1 (0.2) 0 −0.2 (−0.6; 0.2) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) −0.2 (−0.6; 0.2) pulmonologist, n (%) Visits to pulmonologist 0 0 – 00 –– Referrals to specialist 109 (20.8) 38 (7.3) −13.5 (−17.7; −9.4)*** 144 (27.5) 33 (6.3) −21.2 (−25.5; −16.8)*** 7.6 (3.1; 12.2)* Sick leave 27 (5.2) 16 (3.1) −2.1 (−4.5; 0.3) 32 (6.1) 19 (3.6) −2.5 (−5.1; 0.1) 0.4 (−1.4; 2.2) Respiratory sick leave 3 (0.6) 4 (0.8) 0.2 (−0.8; 1.2) 10 (1.9) 9 (1.7) −0.2 (−1.8; 1.4) 0.4 (−0.1; 0.9) Baseline data were collected during the 12 months prior to the first prescription of a LAMA or LABA/LAMA. Data are expressed as mean (SD) unless specified otherwise CI confidence interval, CXR chest x-ray, CT computerised tomography, GP general practitioner, FEV1 forced expiratory volume in 1 s, GOLD global initiative for obstructive chronic pulmonary disease *p < 0.05; **p < 0.01; ***p < 0.001 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. 2007 and 2012, but only 11.3 and 3.7% were initially treated with a LAMA or a LABA/LAMA combination in 2012, respectively, suggesting that the use of LABD has increased in recent years. Interestingly, almost two thirds of the patients started with a LAMA and only one third with a LABA/LAMA combination, which is consistent with data from the UK where the most frequent initial treatment for COPD in primary care is a LAMA. In our study, only 40% of the patients had undergone spirometry with an available FEV1 measurement, which is consistent with previous data from primary care in our coun- 9,11,12 13–15 try and in other European countries. Moreover, along the 12 months after the initiation of the therapy, a follow-up spirometry was performed in only one quarter of the patients in each group. We found that patients with a codified diagnosis of COPD treated with the combination of bronchodilators had a lower FEV1 and more previous hospital admissions for all causes. However, we found no differences in other relevant clinical characteristics, such as phenotype or the number of previous out-patient exacerba- tions. Furthermore, previous hospital admissions for respiratory causes were similar, and very low, in both groups. We observed the same results when we analyzed only patients with confirmed COPD (data not shown). To avoid biases due to different degree of severity, we performed a matching analysis to compare the evolution of COPD patients by group therapy. Firstly, in order to exclude asthma or other respiratory diseases possibly miscodified as COPD as far as possible, we selected only patients who had a history of smoking and a FEV1/FVC < 0.7. Secondly, we matched individuals from both treatment groups by age, sex, FEV1, previous history of exacerbations, history of asthma and duration of treatment during the first 12 months of follow-up. After matching, we found that the evolution of patients treated with a LAMA or a LABA/LAMA did not significantly differ. The assessments performed during follow- up were similar for both groups with a low number of tests performed, visits to the nurse and referrals, although chest X-rays and referrals to the chest physician were even less frequent in the LAMA group. Patients in both groups presented a significant reduction in the number of exacerbations after the initiation of treatment, 8,16 consistent with previous clinical trials. Interestingly, in the LAMA group there was a greater reduction in the number of patients presenting an exacerbation, compared to patients initially receiving two bronchodilators. In contrast with these results, previous randomised control trials have shown that a LABA/LAMA combination can improve exacerbation outcomes in comparison to monotherapy. The Spark study, which was designed to evaluate the effect of dual bronchodilator treatment on exacer- bations, reported a reduced annual rate of moderate or severe exacerbations with indacaterol/glycopyrronium compared to glycopyrronium alone. These differences in outcomes are probably due to the population studied. Spark included severe COPD individuals with a FEV1 < 50% and at least one exacerbation in the previous year, while our study population included less severe patients with a majority of GOLD 2 and 45% of patients without any exacerbation in the previous year. Changes in treatment were more frequent in the LABA/LAMA group. The most frequent change was de-escalation to a LABA or a LAMA (15.3%) followed by no treatment. This was more common in milder patients, while GOLD 4 patients tended to continue with the combination of bronchodilators. In comparison, changes in treatment were slightly less frequent in the LAMA group, with the most frequent change being escalation to a LABA/LAMA combination or triple therapy (12.9%), while 6.8% switched to a LABA or LABA/ICS. An analysis of the Pharmo database in the Netherlands found more frequent changes in treatment in patients on LAMAs, with persistence rates at 1, 2, and 3 years of only 25%, 14% and 8% respectively. In contrast with our data, Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2018) 36 Table 3. Pharmacological treatment at the first prescription of a LAMA or a LABA/LAMA and after a 12-month follow-up Patients starting on LAMA Patients starting on LABA/LAMA N = 524 N = 524 Beginning End (12 month) Change % Beginning End (12 month) Change % Differences between groups (change LAMA—change LABA/LAMA) (CI) (End-beginning)(CI) (End-beginning) (CI) Treatment by drug SABA 92 (17.6) 68 (13) −4.6 (−8.9; −0.2)* 98 (18.7) 77 (14.7) −4(−8.5; 0.5) −0.6 (−3; 1.9) SAMA 47 (9) 34 (6.5) −2.5 (−5.7; 0.7) 54 (10.3) 38 (7.3) −3.1 (−6.5; 0.4) 0.6 (−1.4; 2.6) LABA 0 27 (5.2) 5.2 (3.3; 7)*** 196 (37.4) 117 (22.3) −15.1 (−20.5; −9.6)*** 20.2 (16.6; 23.8)*** LAMA 524 (100) 439 (83.8) −16.2 (−19.4; −13.1)*** 184 (35.1) 140 (26.7) −8.4 (−14; −2.8)** −7.8 (−11.8; −3.9)*** SABA + SAMA 0 0 0 (0; 0) 0 1 (0.2) 0.2 (−0.2; 0.6) −0.2 (−0.6; 0.2) LABA + LAMA 0 22 (4.2) 4.2 (2.5; 5.9)*** 343 (65.5) 282 (53.8) −11.6 (−17.5; −5.7)*** 15.8 (12.6; 19.1)*** LABA + ICS 0 49 (9.4) 9.4 (6.9; 11.8)*** 0 41 (7.8) 7.8 (5.5; 10.1)*** 1.5 (−1.9; 4.9) ICS 0 14 (2.7) 2.7 (1.3; 4.1)*** 0 25 (4.8) 4.8 (2.9; 6.6)*** −2.1 (−4.4; 0.2) Methylxanthines 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) 2 (0.4) 1 (0.2) −0.2 (−0.8; 0.5) 0.2 (−0.2; 0.6) IPDE4 0 0 0 (0; 0) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) 0 (0; 0) SABA short-acting beta-2 agonist, SAMA short-acting anti-muscarinic, LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid, PDE4 phosphodiesterase 4 inhibitor *p < 0.05; **p < 0.01; ***p < 0.001 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Table 4. Changes in treatment pattern according to severity (GOLD stages) during the 12-month follow-up in patients in both groups matched for age, sex, FEV1%, previous history of exacerbations, history of asthma and duration of treatment Patients starting on LAMA N = 524 Patients starting on LABA/LAMA N = 524 Total Gold 1 Gold 2 Gold 3 Gold 4 Total Gold 1 Gold 2 Gold 3 Gold 4 N = 56 N = 325 N = 118 N = 25 N = 42 N = 333 N = 132 N = 17 LAMA 386 (73.7) 47 (83.9) 245 (75.4) 78 (66.1) 16 (64) 44 (8.4) 6 (14.3) 31 (9.3) 7 (5.3) 0 LABA 7 (1.3) 0 5 (1.5) 2 (1.7) 0 36 (6.9) 1 (2.4) 30 (9) 5 (3.8) 0 ICS 5 (1) 1 (1.8) 2 (0.6) 1 (0.8) 1 (4) 7 (1.3) 1 (2.4) 4 (1.2) 2 (1.5) 0 LABA/LAMA 39 (7.4) 3 (5.4) 20 (6.2) 16 (13.6) 0 345 (65.8) 28 (66.7) 209 (62.8) 95 (72) 13 (76.5) LABA/ICS 22 (4.2) 1 (1.8) 12 (3.7) 5 (4.2) 4 (16) 25 (4.8) 1 (2.4) 13 (3.9) 8 (6.1) 3 (17.6) LAMA/ICS 7 (1.3) 0 4 (1.2) 3 (2.5) 0 0 0 0 0 0 LAMA/LABA/ICS 29 (5.5) 1 (1.8) 17 (5.2) 8 (6.8) 3 (12) 33 (6.3) 2 (4.8) 20 (6) 10 (7.6) 1 (5.9) No treatment 29 (5.5) 3 (5.4) 20 (6.2) 5 (4.2) 1 (4) 34 (6.5) 3 (7.1) 26 (7.8) 5 (3.8) 0 Data are expressed as n (%) LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid most patients were changed to ICS/LABA. Wurst et al. also therapy with LAMA in monotherapy may be adequate for a observed a lower persistence to newly initiated LAMA, with 10% of significant group of mild to moderate patients with COPD and a patients receiving the addition of other therapies or 9% being low risk of exacerbations managed in primary care. switched from LAMA mainly to LABA/ICS and with many patients discontinuing therapy. Another study that described the changes to triple therapy found that starting with a LAMA was one of the least frequent schedules and represented only 9.5% among all the METHODS patients finally receiving triple therapy. This was an epidemiological study with retrospective analysis of long- In our population, adherence was good and did not significantly itudinal follow-up data that aimed to compare the characteistics of the differ between the LAMA (71%) and LABA/LAMA groups (66.6%). COPD patients initiating treatment with a LAMA or a combination of Other studies analysing the persistence of treatment with LAMAs LAMA/LABA in primary care in 2015 and their clinical evolution over a 12- month follow-up period. in Spain have described similar results. One study only included The data for this study was obtained from the SIDIAP database, a individuals treated with aclidinium or tiotropium and observed an computerised database containing anonymized patient records for the 5.8 initially high persistence with LAMA that progressively decreased 20 21 million people registered in one of the 279 primary care centres of the to 50% after 1 year of follow-up. Izquierdo et al. conducted Catalan Health Institute (approximately 80% of the population of another population-based study in Castile-La Mancha (Spain) and Catalonia). All the general practitioners in the Catalan Public Health observed a high rate of compliance (from 80 to 120%) in patients Service use the same eCAP software to record the clinical information of treated with LAMAs. their patients. Health professionals gather this information using ICD-10 The main limitation of the present study is the lack of data on codes and structured forms designed for the collection of variables such as dyspnoea (mMRC) or the COPD assessment test, which may be smoking history or body mass index or test results such as spirometries. implicated in therapeutic decision making. However, an observa- SIDIAP combines information from the electronic medical records with tional study aimed at identifying predictors of physician treatment data from other databases and registers including the Pharmacy Register choice in primary care in the UK observed that the mMRC score (medication dispensed in pharmacies) and the National Death registry. The was a weak predictor of therapeutic choice, and had no impact study was approved by the Research and Ethics Committee of the IDIAP on the treatment modifications to triple therapy. Other Jordi Gol Institute of Research In Primary Care (Barcelona, Spain). limitations inherent to database studies are diagnostic and miscoding biases. To minimise these biases we only included Study population individuals with confirmed COPD (codified diagnosis plus smoking history and FEV1/FVC < 0.7) in the longitudinal matched analysis. For the first objective of the comparison of characteristics of COPD patients In contrast, the main strength of our study is the large coverage of initiating treatment with a LAMA or LAMA/LABA, we selected all individuals older than 40 years who started treatment with either a LAMA or a the database, including more than 80% of the population of combination of a LAMA and a LABA (separately or in one device) during Catalonia (Spain), thereby ensuring the representativeness of our 2015 and were diagnosed with COPD at or before the date of the first data. prescription of maintenance therapy. Patients were required to have at In conclusion, our study suggests that Primary Care physicians least 2 years of continuous data (1 year before and 1 year after the first in Catalonia more frequently prescribe a LABA/LAMA combination prescription of maintenance therapy). instead of a LAMA for the most severe COPD patients, consistent For the second objective, comparison of the clinical evolution and 1,3,4,23 with guideline recommendations. Most patients initiating changes in treatment over a 12-month follow-up period in patients initially treatment with a LAMA remain stable during follow-up and treated with a LAMA or a LABA/LAMA, only patients with a confirmed frequently continue on the same treatment over time. In contrast, diagnosis of COPD defined as a history of smoking and spirometry with 9,21 patients initially treated with a LABA/LAMA combination are more FEV1/FVC < 0.7 were included, as in previous studies. In addition, likely to be switched to other treatment schedules, particularly de- patients were matched 1:1 for age, sex, FEV1%, previous history of escalation to a single LABD. This was more frequently observed in exacerbations, history of asthma and duration of treatment in order to GOLD 1 and 2 patients, which suggests unnecessary over- account for the possible differences in clinical characteristics and the treatment in milder stages of the disease. Adherence to treatment severity of patients initiating treatment with a LAMA in monotherapy or was high in both treatment groups. Our results suggest that initial with two bronchodilators (Fig. 2). npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. DATA AVAILABILITY The data that support the findings of this study are available from IDIAP Jordi Gol but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IDIAP Jordi Gol. ACKNOWLEDGEMENTS The study was supported by an unrestricted grant from Gebro Pharma. Miriam Barrecheguren is the recipient of a Rio Hortega contract in the 2017 Strategic Action Health Call from the Instituto de Salud Carlos III for the years 2018–2019. AUTHOR CONTRIBUTIONS M.M., M. Monteagudo and M.B. designed the study. M. Monteagudo prepared the database and performed the analyses. All the authors were involved in the study methodology and interpretation of results. M.B. wrote the first draft. All the authors commented on the manuscript and contributed to the final version. ADDITIONAL INFORMATION Fig. 2 Flowchart of the patients included in the study. SIDIAP information system for research in primary care, COPD chronic Competing interests: M.B. has received speaker fees from Grifols, Menarini, GSK and obstructive pulmonary disease, LABA long-acting beta-2 agonist, consulting fees from Novartis and Gebro Pharma. M.M. has received speaker fees LAMA long-acting anti-muscarinic, Hx history, FEV1 forced expira- from Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Grifols and Novartis, and tory volume in 1 s, FVC forced vital capacity consulting fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Gebro Pharma, CSL Behring, Novartis and Grifols. The other author declares no competing interests. Measurements Severity was assessed based on GOLD stages in the patients for whom a Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims FEV1 value was available (stage 1 mild, FEV ≥ 80% predicted, stage 2 in published maps and institutional affiliations. moderate 50% ≤ FEV1 < 80% predicted; stage 3 severe, 30% ≤ FEV1 < 50% predicted; stage 4 very severe FEV < 30% predicted). Exacerbations were identified by diagnostic codes and by treatment (patients receiving REFERENCES antibiotics and/or oral corticosteroids in the absence of another codified 1. Vogelmeier, C. F. et al. Global Strategy for the Diagnosis, Management, and infectious event such as tonsillitis or urine infection). Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Patients with two or more exacerbations during the year before Summary. Arch. Bronconeumol. 53, 128–149 (2017). initiation of therapy were classified as having a frequent exacerbator 2. 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Characteristics of patients with COPD newly prescribed a long-acting bronchodilator: a retrospective cohort Open Access This article is licensed under a Creative Commons study. Int J. Chron. Obst. Pulm. Dis. 9, 1021–1031 (2014). Attribution 4.0 International License, which permits use, sharing, 19. Brusselle, G. et al. The inevitable drift to triple therapy in COPD: an analysis of adaptation, distribution and reproduction in any medium or format, as long as you give prescribing pathways in the UK. Int J. Chron. Obst. Pulm. Dis. 10, 2207–2217 (2015). appropriate credit to the original author(s) and the source, provide a link to the Creative 20. Monteagudo, M. et al. Characteristics of COPD patients initiating treatment with Commons license, and indicate if changes were made. The images or other third party aclidinium or tiotropium in primary care in Catalonia: a population-based study. material in this article are included in the article’s Creative Commons license, unless Int J. Chron. Obst. Pulm. Dis. 12, 1145–1152 (2017). indicated otherwise in a credit line to the material. If material is not included in the 21. Izquierdo, J. L., Paredero, J. M. & Piedra, R. Relevance of dosage in adherence to article’s Creative Commons license and your intended use is not permitted by statutory treatment with long-acting anticholinergics in patients with COPD. Int J. Chron. regulation or exceeds the permitted use, you will need to obtain permission directly Obst. Pulm. Dis. 11, 289–293 (2016). from the copyright holder. To view a copy of this license, visit http://creativecommons. 22. Gruffydd-Jones, K. et al. Changes in initial COPD treatment choice over time and org/licenses/by/4.0/. factors influencing prescribing decisions in UK primary care: a real-world study. NPJ Prim. Care Respir. Med. 26, 16002 (2016). © The Author(s) 2018 23. Thomas, M., Halpin, D. & Miravitlles, M. When is dual bronchodilation indicated in COPD? Int J. Chron. Obst. Pulm. 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Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial treatment for COPD in primary care

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Springer Journals
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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Medicine/Public Health, general; Primary Care Medicine; Internal Medicine; Pneumology/Respiratory System; Thoracic Surgery
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10.1038/s41533-018-0102-x
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www.nature.com/npjpcrm ARTICLE OPEN Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial treatment for COPD in primary care 1 2,3 1 Miriam Barrecheguren , Mónica Monteagudo and Marc Miravitlles This epidemiological study aimed to describe and compare the characteristics and outcomes of COPD patients starting treatment with a long-acting anti-muscarinic (LAMA) or a combination of a long-acting beta-2 agonist (LABA)/LAMA in primary care in Catalonia (Spain) over a one-year period. Data were obtained from the Information System for the Development in Research in Primary Care (SIDIAP), a population database containing information of 5.8 million inhabitants (80% of the population of Catalonia). Patients initiating treatment with a LAMA or LABA/LAMA in 2015 were identified, and information about demographic and clinical characteristics was collected. Then, patients were matched 1:1 for age, sex, FEV1%, history of exacerbations, history of asthma and duration of treatment, and the outcomes between the two groups were compared. During 2015, 5729 individuals with COPD started treatment with a LAMA (69.8%) or LAMA/LABA (30.2%). There were no remarkable differences between groups except for a lower FEV1 and more previous hospital admissions in individuals on LABA/LAMA. The number of tests and referrals was low and decreased in both groups during follow-up. For the same severity status, the evolution was similar with a reduction in exacerbations in both groups. Treatment was changed during follow-up in up to 34.2% of patients in the LABA/LAMA and 26.3% in the LAMA group, but adherence was equally good for both. Our results suggest that initial therapy with LAMA in monotherapy may be adequate in a significant group of mild to moderate patients with COPD and a low risk of exacerbations managed in primary care. npj Primary Care Respiratory Medicine (2018) 28:36 ; doi:10.1038/s41533-018-0102-x INTRODUCTION the effectiveness of LABD and its combination with other agents in the usual clinical practice. The use of large population-based The aim of pharmacological treatment in chronic obstructive databases may help to increase the knowledge on real-life use of pulmonary disease (COPD) is to reduce symptoms, decrease the bronchodilator treatment in primary care. Therefore, the objective frequency and severity of exacerbations and improve exercise of this study was to describe the characteristics and outcomes of tolerance. Previous studies have demonstrated the efficacy of COPD patients starting inhaled treatment with a LAMA or a long-acting bronchodilators (LABD) in improving lung function, combination of LABA/LAMA in primary care in Catalonia (Spain) respiratory symptoms, exacerbations, exercise capacity and quality 2 1,3,4 over a 1 year period. of life and constitute the cornerstone of COPD treatment. Among LABD, long-acting anti-muscarinic agents (LAMA) have shown greater efficacy in the prevention of exacerbations 5,6 compared to long-acting β2-agonists (LABA), and therefore, RESULTS guidelines recommend the use of LAMA over LABA as the initial During 2015, we identified 5729 individuals with a codified 1,3,4 treatment in COPD. diagnosis of COPD who started treatment with either a LAMA In recent years, new treatments for COPD have been launched, (4001 or 69.8%) or LAMA/LABA (1728 or 30.2%). These patients most being LABD, inhaled corticosteroids (ICS) and combinations constituted the population of our study. Among the patients of the two, with the objective of improving patient outcomes in receiving a LAMA/LABA, 68.3% received the combination in the COPD. Recent studies have suggested that dual treatment with a same inhalation device. LAMA and a LABA results in greater bronchodilation and improved symptoms and health status compared to a LABD in mono- 7,8 Baseline characteristics therapy. However, most studies assessing the efficacy of double bronchodilation compared with monotherapy have included In total, 76.9% were men with a mean age of 66.3 (SD 11.1) years, moderate to severe patients with dyspnoea according to the with no differences between the LAMA or LAMA/LABA groups. 2,7,8 modified Medical Research Council (mMRC) ≥ 2 scale, exclud- The patients were diagnosed a mean of 3.3 (4.9) years before ing milder patients who may not present a significant improve- inclusion, with significant differences between groups [3.9 (5.3) ment with the addition of a second LABD. In addition, there is a years for the LABA/LAMA group vs. 3.1 (4.7) years for the LAMA lack of follow-up studies in real life in primary care investigating patients, p < 0.001]. The most frequent comorbidities were 1 2 Pneumology Department, Hospital Universitari Vall d´Hebron. Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; Primary Care University Research Institute Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain and Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain Correspondence: Marc Miravitlles (mmiravitlles@vhebron.net) Received: 14 March 2018 Revised: 24 August 2018 Accepted: 24 August 2018 Published in partnership with Primary Care Respiratory Society UK Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Table 1. Baseline characteristics of the patients studied Total N = 5729 Patients starting on LAMA N = 4001 Patients starting on LABA/LAMA N = p-value Sex (men) 4406 (76.9) 3043 (76.1) 1363 (78.9) 0.02 Age, years 66.25 (11.1) 66.42 (11.1) 65.84 (11.1) NS Years from diagnosis 3.33 (4.9) 3.08 (4.7) 3.91 (5.3) <0.001 BMI (Kg/m ) 29.14 (5.3) 29.04 (5.2) 29.36 (5.4) NS Smoking history (n,%) NS Never smoker 1115 (19.5) 792 (19.8) 323 (18.7) Active smoker 2232 (39) 1586 (39.6) 646 (37.4) Former smoker 2318 (40.5) 1588 (39.7) 730 (42.2) Unknown 64 (1.1) 35 (0.9) 29 (1.7) Phenotype (n,%) NS ACO 183 (3.2) 128 (3.2) 55 (3.2) Non exacerbator 1303 (22.7) 890 (22.2) 413 (23.9) Exacerbator 4243 (74.1) 2983 (74.6) 1260 (72.9) Comorbidities Asthma 262 (4.6) 184 (4.6) 78 (4.5) NS Bronchiectasis 233 (4.1) 180 (4.5) 53 (3.1) 0.01 OSA 331 (5.8) 232 (5.8) 99 (5.7) NS Ischaemic heart disease 808 (14.1) 570 (14.2) 238 (13.8) NS Heart failure 483 (8.4) 306 (7.6) 177 (10.2) 0.001 Atrial fibrilation 593 (10.4) 411 (10.3) 182 (10.5) NS Hypertension 3307 (57.7) 2303 (57.6) 1004 (58.1) NS Diabetes mellitus 1443 (25.2) 1002 (25) 441 (25.5) NS Dyslipidemia 2915 (50.9) 2069 (51.7) 846 (49) 0.05 Depression 1049 (18.3) 746 (18.6) 303 (17.5) NS Osteoporosis 396 (6.9) 290 (7.2) 106 (6.1) NS GERD 299 (5.2) 212 (5.3) 87 (5) NS Complementary tests Spirometries with FEV1 2271 (39.6) 1584 (39.6) 687 (39.8) NS FEV1 % 62.5 (18.9) 65.0 (18.6) 56.9 (18.5) <0.001 Severity N (%) (n = 2271) <0.001 Gold 1 354 (15.6) 296 (18.7) 58 (8.4) Gold 2 1415 (62.3) 1013 (64) 402 (58.5) Gold 3 424 (18.7) 236 (14.9) 188 (27.4) Gold 4 78 (3.4) 39 (2.5) 39 (5.7) Exacerbations during the previous 12 months, n (%) NS 0 exacerbations 2685 (46.9) 1871 (46.7) 814 (47.1) 1 exacerbations 1741 (30.4) 1240 (31.0) 501 (28.9) ≥2 exacerbations 1303 (22.7) 890 (22.2) 413 (23.9) Hospital admission during the previous 12 months, n (%) Total 449 (7.8) 294 (7.3) 155 (9) 0.03 Respiratory hospital admission 22 (0.4) 13 (0.3) 9 (0.5) NS Data are expressed as mean (SD) unless specified otherwise BMI body mass index, ACO asthma COPD overlap, OSA obstructive sleep apnoea, GERD gastrooesophageal reflux disease, FEV1 forced expiratory volume in 1 s, GOLD global initiative for obstructive chronic pulmonary disease hypertension (57.7%), diabetes mellitus (25.2%), dyslipidemia Longitudinal analysis: matching sub-cohort (50.9%) and depression (18.3%). For the longitudinal analysis we identified 1897 (33%) individuals Spirometry result with a FEV1 was available in only 40% of the who fulfilled the criteria for the diagnosis of COPD (Fig. 1). Finally, patients. Individuals treated with a combination of two bronch- of these, matching was possible for 524 patients from each odilators presented more severe disease, with a lower FEV1 % treatment group. (56.9% (18.5) vs. 65.0% (18.7), p < 0.001) and included a greater As expected, there were no differences in the baseline number of patients classified as GOLD 3 and GOLD 4. Distribution characteristics between groups, although the time from diagnosis by phenotypes was similar between the two groups. Patients to treatment was longer in the combined group (3.7 (5.1) years vs. treated with double bronchodilation tended to have more 2.8 (4.3) years, p = 0.002) (Table 2). hospital admissions for all causes during the previous year but During the 12-month follow-up, only 22.7% of patients in the not for respiratory causes, although numbers were very small. The LAMA group underwent spirometry. The number of chest X-rays baseline characteristics of the cohort and by treatment group are and computerised tomography (CT) lung studies also significantly presented in Table 1. decreased in the LAMA group (Table 2). This group also showed a npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Fig. 1 Changes in the treatment pattern at 12 months of follow-up compared to baseline. Continous arrow: step-up or equivalent treatment; dashed arrow: step-down treatment. LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid significant reduction in the number of patients presenting an 15.3% (8.4% LAMA and 6.9% LABA), 4.8% changed to LABA/ICS exacerbation compared to the previous year (−13.9%, 95% CI: and 6.5% to no inhaled therapy (Table 4) (Fig. 1). −19.9;−7.9; p < 0.001) and in the mean number of exacerbations Changes in treatment differed according to severity. In the (−0.3, 95% CI: −0.4; −0.1; p < 0.001). The percentage of patients LAMA group less severe patients (GOLD 1 and 2) tended to consulting with a nurse or being referred to a specialist also continue on a LAMA (83.9% of GOLD 1 and 75.4% of GOLD 2). The significantly decreased in the LAMA group during the one-year most frequent change of treatment was escalation to LABA/LAMA follow-up. or discontinuation of all treatment. In the LABA/LAMA group, only Patients treated with a LABA/LAMA also showed a reduction in two thirds of GOLD 1 and 2 patients continued with the same the number of spirometries chest X-rays and CT scans performed treatment. Patients were frequently de-escalated to one LABD (Table 2). This group showed a reduction in the percentage of (23.7% of GOLD 1 and 26.1% of GOLD 2) or no maintenance patients presenting an exacerbation (−8.6%, 95% CI: −14.6; −2.6; therapy (Table 4). p < 0.001), and in the mean number of exacerbations (−0.2, 95% Up to 13.5% of GOLD 3 patients in the LAMA group were CI: −0.3; −0.1; p < 0.001). In addition, fewer patients consulted a escalated to LABA/LAMA, while GOLD 4 were more frequently nurse or were referred to a pulmonologist compared to the year escalated to triple therapy or were switched to LABA/ICS. In the before initiating treatment (−21.2%, 95% CI: −25.5; −16.8; p < LABA/LAMA group, GOLD 4 patients were switched to triple 0.001). therapy (5.9%) and more frequently to LABA/ICS (17.6%). On comparing the two groups, patients treated with a LAMA showed a greater reduction in the number of chest X-rays performed and the number of patients with any exacerbation DISCUSSION (percentage difference −5.3%, 95% CI: −9.2; −1.5; p < 0.001). The results of this study show that COPD patients starting Patients receiving LAMA were less frequently referred to the treatment with a LAMA or a LABA/LAMA in the primary care pulmonologist (mean difference 7.6%, 95% CI: 3.1; 12.2; p < 0.05). setting had no remarkable differences in clinical characteristics except in regard to disease severity; patients initially treated with the combination of bronchodilators had a lower FEV1 and a Changes in treatment and adherence during follow-up greater number of previous hospital admissions. The number of A total of 439 (83.8%) of the patients initially treated with a LAMA diagnostic tests and referrals was low in the two groups and continued receiving this treatment over the 1 year follow-up, decreased during the one-year follow up, especially in those although only 73.7% were treated with LAMA alone. The receiving a LAMA. After performing a matching analysis, we percentage of patients who continued with a LABA/LAMA observed that for the same severity status, the evolution was combination was 65.8% (Table 3). similar for individuals treated with a LAMA or LABA/LAMA. In up to We observed good adherence to treatment (proportion of days 34.2% of patients in the LABA/LAMA group and 26.3% in the covered [PDC] > 80%) in 71% of patients initiating with a LAMA LAMA group a change was made in treatment during follow-up, and 66.6% for LABA/LAMA. In the LABA/LAMA group, adherence but the adherence was equally good in both treatment schedules. was similar for patients treated with one or two devices (67.1 and During the year of the study, 5729 COPD individuals started 65.7%, respectively). Regarding changes in treatment, in the LAMA group, treatment treatment with either a LAMA or a LABA/LAMA. Among them, was escalated in 11.6% during the year of follow-up (7.4% to 1897 had confirmed COPD (coded for COPD plus airflow LABA/LAMA and 5.5% to triple therapy), 4.2% were switched to obstruction and smoking history). In Catalonia, a region with LABA/ICS and in 5.5% the treatment was de-escalated to no approximately 7.5 million inhabitants, a recent study also carried inhaled treatment. out using the SIDIAP (Information System for the Development of In the LABA/LAMA group, treatment was escalated to triple Research in Primary Care) database found that approximately therapy in 6.3%, being de-escalated to LABD in monotherapy in 7000 individuals were diagnosed with COPD every year between Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2018) 36 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK Table 2. 12-month follow up. Intra- and between groups differences based on initial treatment (LAMA vs. LAMA/LAMA) Patients starting on LAMA N = 524 Patients starting on LABA/LAMA N = 524 Baseline Follow-up Change % (follow-up- Baseline Follow-up Change % (follow-up- Differences between groups (change LAMA— baseline) (CI) baseline) (CI) change LABA/LAMA) (CI) Tests Spirometries with recorded FEV 524 (100) 119 (22.7) −77.3 (−80.9; −73.7)*** 524 (100) 132 (25.2) −74.8 (−78.5; −71.1)*** −2.5 (−7.6; 2.7) FEV % 58.6 (18.8) 60.8 (17.6) 2.1 (0.2; 6)* 58.4 (16.8) 58.6 (16.8) 0.2 (−0.8; 3.4) 1.9 (0.4; 3.9) 1, Severity N (%) Gold 1 56 (10.7) 17 (14.3) 42 (8) 8 (6.1) Gold 2 325 (62) 73 (61.3) 333 (63.5) 92 (69.7) Gold 3 118 (22.5) 26 (21.8) 132 (25.2) 30 (22.7) Gold 4 25 (4.8) 3 (2.5) 17 (3.2) 2 (1.5) Blood tests 379 (72.3) 359 (68.5) −3.8 (−9.3; 1.7) 382 (72.9) 371 (70.8) −2.1 (−7.5; 3.3) −1.7 (−3.8; 0.3) CXR 245 (46.8) 90 (17.2) −29.6 (−34.9; −24.2)*** 218 (41.6) 101 (19.3) −22.3 (−27.7; −16.9)*** −7.3 (−12.5; −2)** CT scan 45 (8.6) 27 (5.2) −3.4 (−6.5; −0.4)* 49 (9.4) 23 (4.4) −5(−8; −1.9)** 1.5 (−0.9; 4) Use of healthcare resources Patients with at least one exacerbation, n (%) 299 (57.1) 226 (43.1) −13.9 (−19.9; −7.9)*** 303 (57.8) 258 (49.2) −8.6 (−14.6; −2.6)** −5.3 (−9.2; −1.5)*** No. of exacerbations 1.1 (1.45) 0.85 (1.43) −0.3 (−0.4; −0.1)*** 1.23 (1.63) 1.04 (1.61) −0.2 (−0.3; −0.1)** −0.1 (−0.2; 0.1) Patients with at least one hospital admission, 30 (5.7) 38 (7.3) 1.5 (−1.5; 4.5) 38 (7.3) 45 (8.6) 1.3 (−1.9; 4.6) 0.2 (−1.2; 1.6) n (%) Hospital admissions 1.53 (0.86) 1.47 (1.01) −0.4 (−1.9; 1.1) 1.29 (0.65) 1.62 (1.32) 0.8 (−0.6; 2.1) −1.2 (−3.1; 0.8) Patients with at least one respiratory hospital 3 (0.6) 2 (0.4) −0.2 (−1; 0.6) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) −0.2 (−0.6; 0.2) admission, n (%) Respiratory hospital admissions 1.33 (0.58) 1 (0) – 00 –– Patients with at least one visit to GP, n (%) 519 (99) 520 (99.2) 0.2 (−0.9; 1.3) 520 (99.2) 522 (99.6) 0.4 (−0.5; 1.3) −0.2 (−0.8; 0.5) Visits to GP 8.2 (4.9) 8.2 (5.5) 0 (−0.5; 0.4) 8.6 (5.7) 9.1 (6.6) 0.5 (0; 1)* −0.5 (−1.2; 0.1) Patients with at least one nurse visit, n (%) 507 (96.8) 475 (90.6) −6.1 (−9; −3.2)*** 500 (95.4) 480 (91.6) −3.8 (−6.8; −0.8)* −2.3 (−4.9; 0.3) Nurse visits 6.8 (9.8) 7.5 (10.8) 0.5 (−0.1; 1) 6.7 (6.8) 7.01 (8.4) 0.2 (−0.5; 0.9) 0.3 (−0.6; 1.2) Patients with at least one visit to 1 (0.2) 0 −0.2 (−0.6; 0.2) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) −0.2 (−0.6; 0.2) pulmonologist, n (%) Visits to pulmonologist 0 0 – 00 –– Referrals to specialist 109 (20.8) 38 (7.3) −13.5 (−17.7; −9.4)*** 144 (27.5) 33 (6.3) −21.2 (−25.5; −16.8)*** 7.6 (3.1; 12.2)* Sick leave 27 (5.2) 16 (3.1) −2.1 (−4.5; 0.3) 32 (6.1) 19 (3.6) −2.5 (−5.1; 0.1) 0.4 (−1.4; 2.2) Respiratory sick leave 3 (0.6) 4 (0.8) 0.2 (−0.8; 1.2) 10 (1.9) 9 (1.7) −0.2 (−1.8; 1.4) 0.4 (−0.1; 0.9) Baseline data were collected during the 12 months prior to the first prescription of a LAMA or LABA/LAMA. Data are expressed as mean (SD) unless specified otherwise CI confidence interval, CXR chest x-ray, CT computerised tomography, GP general practitioner, FEV1 forced expiratory volume in 1 s, GOLD global initiative for obstructive chronic pulmonary disease *p < 0.05; **p < 0.01; ***p < 0.001 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. 2007 and 2012, but only 11.3 and 3.7% were initially treated with a LAMA or a LABA/LAMA combination in 2012, respectively, suggesting that the use of LABD has increased in recent years. Interestingly, almost two thirds of the patients started with a LAMA and only one third with a LABA/LAMA combination, which is consistent with data from the UK where the most frequent initial treatment for COPD in primary care is a LAMA. In our study, only 40% of the patients had undergone spirometry with an available FEV1 measurement, which is consistent with previous data from primary care in our coun- 9,11,12 13–15 try and in other European countries. Moreover, along the 12 months after the initiation of the therapy, a follow-up spirometry was performed in only one quarter of the patients in each group. We found that patients with a codified diagnosis of COPD treated with the combination of bronchodilators had a lower FEV1 and more previous hospital admissions for all causes. However, we found no differences in other relevant clinical characteristics, such as phenotype or the number of previous out-patient exacerba- tions. Furthermore, previous hospital admissions for respiratory causes were similar, and very low, in both groups. We observed the same results when we analyzed only patients with confirmed COPD (data not shown). To avoid biases due to different degree of severity, we performed a matching analysis to compare the evolution of COPD patients by group therapy. Firstly, in order to exclude asthma or other respiratory diseases possibly miscodified as COPD as far as possible, we selected only patients who had a history of smoking and a FEV1/FVC < 0.7. Secondly, we matched individuals from both treatment groups by age, sex, FEV1, previous history of exacerbations, history of asthma and duration of treatment during the first 12 months of follow-up. After matching, we found that the evolution of patients treated with a LAMA or a LABA/LAMA did not significantly differ. The assessments performed during follow- up were similar for both groups with a low number of tests performed, visits to the nurse and referrals, although chest X-rays and referrals to the chest physician were even less frequent in the LAMA group. Patients in both groups presented a significant reduction in the number of exacerbations after the initiation of treatment, 8,16 consistent with previous clinical trials. Interestingly, in the LAMA group there was a greater reduction in the number of patients presenting an exacerbation, compared to patients initially receiving two bronchodilators. In contrast with these results, previous randomised control trials have shown that a LABA/LAMA combination can improve exacerbation outcomes in comparison to monotherapy. The Spark study, which was designed to evaluate the effect of dual bronchodilator treatment on exacer- bations, reported a reduced annual rate of moderate or severe exacerbations with indacaterol/glycopyrronium compared to glycopyrronium alone. These differences in outcomes are probably due to the population studied. Spark included severe COPD individuals with a FEV1 < 50% and at least one exacerbation in the previous year, while our study population included less severe patients with a majority of GOLD 2 and 45% of patients without any exacerbation in the previous year. Changes in treatment were more frequent in the LABA/LAMA group. The most frequent change was de-escalation to a LABA or a LAMA (15.3%) followed by no treatment. This was more common in milder patients, while GOLD 4 patients tended to continue with the combination of bronchodilators. In comparison, changes in treatment were slightly less frequent in the LAMA group, with the most frequent change being escalation to a LABA/LAMA combination or triple therapy (12.9%), while 6.8% switched to a LABA or LABA/ICS. An analysis of the Pharmo database in the Netherlands found more frequent changes in treatment in patients on LAMAs, with persistence rates at 1, 2, and 3 years of only 25%, 14% and 8% respectively. In contrast with our data, Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2018) 36 Table 3. Pharmacological treatment at the first prescription of a LAMA or a LABA/LAMA and after a 12-month follow-up Patients starting on LAMA Patients starting on LABA/LAMA N = 524 N = 524 Beginning End (12 month) Change % Beginning End (12 month) Change % Differences between groups (change LAMA—change LABA/LAMA) (CI) (End-beginning)(CI) (End-beginning) (CI) Treatment by drug SABA 92 (17.6) 68 (13) −4.6 (−8.9; −0.2)* 98 (18.7) 77 (14.7) −4(−8.5; 0.5) −0.6 (−3; 1.9) SAMA 47 (9) 34 (6.5) −2.5 (−5.7; 0.7) 54 (10.3) 38 (7.3) −3.1 (−6.5; 0.4) 0.6 (−1.4; 2.6) LABA 0 27 (5.2) 5.2 (3.3; 7)*** 196 (37.4) 117 (22.3) −15.1 (−20.5; −9.6)*** 20.2 (16.6; 23.8)*** LAMA 524 (100) 439 (83.8) −16.2 (−19.4; −13.1)*** 184 (35.1) 140 (26.7) −8.4 (−14; −2.8)** −7.8 (−11.8; −3.9)*** SABA + SAMA 0 0 0 (0; 0) 0 1 (0.2) 0.2 (−0.2; 0.6) −0.2 (−0.6; 0.2) LABA + LAMA 0 22 (4.2) 4.2 (2.5; 5.9)*** 343 (65.5) 282 (53.8) −11.6 (−17.5; −5.7)*** 15.8 (12.6; 19.1)*** LABA + ICS 0 49 (9.4) 9.4 (6.9; 11.8)*** 0 41 (7.8) 7.8 (5.5; 10.1)*** 1.5 (−1.9; 4.9) ICS 0 14 (2.7) 2.7 (1.3; 4.1)*** 0 25 (4.8) 4.8 (2.9; 6.6)*** −2.1 (−4.4; 0.2) Methylxanthines 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) 2 (0.4) 1 (0.2) −0.2 (−0.8; 0.5) 0.2 (−0.2; 0.6) IPDE4 0 0 0 (0; 0) 1 (0.2) 1 (0.2) 0 (−0.5; 0.5) 0 (0; 0) SABA short-acting beta-2 agonist, SAMA short-acting anti-muscarinic, LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid, PDE4 phosphodiesterase 4 inhibitor *p < 0.05; **p < 0.01; ***p < 0.001 Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. Table 4. Changes in treatment pattern according to severity (GOLD stages) during the 12-month follow-up in patients in both groups matched for age, sex, FEV1%, previous history of exacerbations, history of asthma and duration of treatment Patients starting on LAMA N = 524 Patients starting on LABA/LAMA N = 524 Total Gold 1 Gold 2 Gold 3 Gold 4 Total Gold 1 Gold 2 Gold 3 Gold 4 N = 56 N = 325 N = 118 N = 25 N = 42 N = 333 N = 132 N = 17 LAMA 386 (73.7) 47 (83.9) 245 (75.4) 78 (66.1) 16 (64) 44 (8.4) 6 (14.3) 31 (9.3) 7 (5.3) 0 LABA 7 (1.3) 0 5 (1.5) 2 (1.7) 0 36 (6.9) 1 (2.4) 30 (9) 5 (3.8) 0 ICS 5 (1) 1 (1.8) 2 (0.6) 1 (0.8) 1 (4) 7 (1.3) 1 (2.4) 4 (1.2) 2 (1.5) 0 LABA/LAMA 39 (7.4) 3 (5.4) 20 (6.2) 16 (13.6) 0 345 (65.8) 28 (66.7) 209 (62.8) 95 (72) 13 (76.5) LABA/ICS 22 (4.2) 1 (1.8) 12 (3.7) 5 (4.2) 4 (16) 25 (4.8) 1 (2.4) 13 (3.9) 8 (6.1) 3 (17.6) LAMA/ICS 7 (1.3) 0 4 (1.2) 3 (2.5) 0 0 0 0 0 0 LAMA/LABA/ICS 29 (5.5) 1 (1.8) 17 (5.2) 8 (6.8) 3 (12) 33 (6.3) 2 (4.8) 20 (6) 10 (7.6) 1 (5.9) No treatment 29 (5.5) 3 (5.4) 20 (6.2) 5 (4.2) 1 (4) 34 (6.5) 3 (7.1) 26 (7.8) 5 (3.8) 0 Data are expressed as n (%) LABA long-acting beta-2 agonist, LAMA long-acting anti-muscarinic, ICS inhaled corticosteroid most patients were changed to ICS/LABA. Wurst et al. also therapy with LAMA in monotherapy may be adequate for a observed a lower persistence to newly initiated LAMA, with 10% of significant group of mild to moderate patients with COPD and a patients receiving the addition of other therapies or 9% being low risk of exacerbations managed in primary care. switched from LAMA mainly to LABA/ICS and with many patients discontinuing therapy. Another study that described the changes to triple therapy found that starting with a LAMA was one of the least frequent schedules and represented only 9.5% among all the METHODS patients finally receiving triple therapy. This was an epidemiological study with retrospective analysis of long- In our population, adherence was good and did not significantly itudinal follow-up data that aimed to compare the characteistics of the differ between the LAMA (71%) and LABA/LAMA groups (66.6%). COPD patients initiating treatment with a LAMA or a combination of Other studies analysing the persistence of treatment with LAMAs LAMA/LABA in primary care in 2015 and their clinical evolution over a 12- month follow-up period. in Spain have described similar results. One study only included The data for this study was obtained from the SIDIAP database, a individuals treated with aclidinium or tiotropium and observed an computerised database containing anonymized patient records for the 5.8 initially high persistence with LAMA that progressively decreased 20 21 million people registered in one of the 279 primary care centres of the to 50% after 1 year of follow-up. Izquierdo et al. conducted Catalan Health Institute (approximately 80% of the population of another population-based study in Castile-La Mancha (Spain) and Catalonia). All the general practitioners in the Catalan Public Health observed a high rate of compliance (from 80 to 120%) in patients Service use the same eCAP software to record the clinical information of treated with LAMAs. their patients. Health professionals gather this information using ICD-10 The main limitation of the present study is the lack of data on codes and structured forms designed for the collection of variables such as dyspnoea (mMRC) or the COPD assessment test, which may be smoking history or body mass index or test results such as spirometries. implicated in therapeutic decision making. However, an observa- SIDIAP combines information from the electronic medical records with tional study aimed at identifying predictors of physician treatment data from other databases and registers including the Pharmacy Register choice in primary care in the UK observed that the mMRC score (medication dispensed in pharmacies) and the National Death registry. The was a weak predictor of therapeutic choice, and had no impact study was approved by the Research and Ethics Committee of the IDIAP on the treatment modifications to triple therapy. Other Jordi Gol Institute of Research In Primary Care (Barcelona, Spain). limitations inherent to database studies are diagnostic and miscoding biases. To minimise these biases we only included Study population individuals with confirmed COPD (codified diagnosis plus smoking history and FEV1/FVC < 0.7) in the longitudinal matched analysis. For the first objective of the comparison of characteristics of COPD patients In contrast, the main strength of our study is the large coverage of initiating treatment with a LAMA or LAMA/LABA, we selected all individuals older than 40 years who started treatment with either a LAMA or a the database, including more than 80% of the population of combination of a LAMA and a LABA (separately or in one device) during Catalonia (Spain), thereby ensuring the representativeness of our 2015 and were diagnosed with COPD at or before the date of the first data. prescription of maintenance therapy. Patients were required to have at In conclusion, our study suggests that Primary Care physicians least 2 years of continuous data (1 year before and 1 year after the first in Catalonia more frequently prescribe a LABA/LAMA combination prescription of maintenance therapy). instead of a LAMA for the most severe COPD patients, consistent For the second objective, comparison of the clinical evolution and 1,3,4,23 with guideline recommendations. Most patients initiating changes in treatment over a 12-month follow-up period in patients initially treatment with a LAMA remain stable during follow-up and treated with a LAMA or a LABA/LAMA, only patients with a confirmed frequently continue on the same treatment over time. In contrast, diagnosis of COPD defined as a history of smoking and spirometry with 9,21 patients initially treated with a LABA/LAMA combination are more FEV1/FVC < 0.7 were included, as in previous studies. In addition, likely to be switched to other treatment schedules, particularly de- patients were matched 1:1 for age, sex, FEV1%, previous history of escalation to a single LABD. This was more frequently observed in exacerbations, history of asthma and duration of treatment in order to GOLD 1 and 2 patients, which suggests unnecessary over- account for the possible differences in clinical characteristics and the treatment in milder stages of the disease. Adherence to treatment severity of patients initiating treatment with a LAMA in monotherapy or was high in both treatment groups. Our results suggest that initial with two bronchodilators (Fig. 2). npj Primary Care Respiratory Medicine (2018) 36 Published in partnership with Primary Care Respiratory Society UK Effectiveness of LAMA compared to LAMA/LABAy M Barrecheguren et al. DATA AVAILABILITY The data that support the findings of this study are available from IDIAP Jordi Gol but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IDIAP Jordi Gol. ACKNOWLEDGEMENTS The study was supported by an unrestricted grant from Gebro Pharma. Miriam Barrecheguren is the recipient of a Rio Hortega contract in the 2017 Strategic Action Health Call from the Instituto de Salud Carlos III for the years 2018–2019. AUTHOR CONTRIBUTIONS M.M., M. Monteagudo and M.B. designed the study. M. Monteagudo prepared the database and performed the analyses. All the authors were involved in the study methodology and interpretation of results. M.B. wrote the first draft. All the authors commented on the manuscript and contributed to the final version. ADDITIONAL INFORMATION Fig. 2 Flowchart of the patients included in the study. SIDIAP information system for research in primary care, COPD chronic Competing interests: M.B. has received speaker fees from Grifols, Menarini, GSK and obstructive pulmonary disease, LABA long-acting beta-2 agonist, consulting fees from Novartis and Gebro Pharma. M.M. has received speaker fees LAMA long-acting anti-muscarinic, Hx history, FEV1 forced expira- from Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Grifols and Novartis, and tory volume in 1 s, FVC forced vital capacity consulting fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Gebro Pharma, CSL Behring, Novartis and Grifols. The other author declares no competing interests. 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