Abstract
Background: The impact of hospital emergency care and inward admission for acute exacerbations of COPD on inhaled maintenance treatment is not well known. Objective: Therefore, we evaluated the impact of short-stay emergency hospital care and inward admission for acute exacerbation of COPD (eCOPD) on inhaled maintenance treatment prescribed at discharge. Design: Prospective observational cohort study of patients presenting with eCOPD at emergency departments in 16 hospitals of the Spanish healthcare system. The ethics committee at each hospital approved the study and patients provided an informed consent before inclusion. We classified the patients according to the severity of COPD: mild/moderate (FEV1 ≥ 50% predicted) or severe/very severe (FEV1 < 50% predicted) and need of inward hospitalisation. We analysed changes to maintenance treatment on discharge according to GOLD strategy. Results: 1559 patients, 65% required hospitalisation. The most common maintenance treatment was inhaled corticoids (ICS) (80.9%) followed by long-acting beta-agonists (LABA) (75.4%). The most common combination was triple therapy (LABA+ LAMA+ICS) (56.2%) followed by LABA+ICS dual therapy (18.2%) regardless of the severity of COPD. In more than 60% of patients treatment was not changed at discharge. The most common change in treatment was a reduction when discharge was from emergency care and an increase after hospitalisation (-21.6% and +19.5% in severe/very severe COPD, respectively). Conclusions: Emergency hospital care for eCOPD does not usually induce changes in inhaled maintenance treatment for COPD regardless of the duration of the hospital stay.
Introduction
Chronic obstructive pulmonary disease (COPD) is a progressive disease that affects near 10% of the population aged 40 to 80 years in Spain (Citation1). Associated with high morbidity and mortality, COPD results in high costs related to both loss of health-related quality of life and use of healthcare resources. The costs are the highest for patients with more severe COPD and for patients with acute exacerbations of COPD (eCOPD) (Citation2). Repeated admission to hospital for severe eCOPD is also associated with increased mortality (Citation3). Adherence to inhaled maintenance treatment for COPD in line with the recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) is associated with improved symptom control, lower risk of exacerbations, and lower healthcare costs (Citation4,Citation5).
GOLD strategy (Citation4) recommended, at the time of the study, short-acting beta agonists (SABA) for mild COPD with intermittent symptoms, adding one or more long-acting bronchodilators in moderate or severe COPD with persistent symptoms, and inhaled corticosteroids (ICS) in patients with severe COPD and repeated eCOPD. Data about adherence to these recommendations is limited and varies in function of the population studied and healthcare context (Citation6). Likewise, we do not know to what extent being treated for an eCOPD, independently of clinical management of eCOPD, leads to a change in maintenance treatment. This study evaluated the impact of the type of hospital care for eCOPD (short-stay emergency care or inward admission) on changes to maintenance treatment.
Methods
This was a prospective observational cohort study with the participation of 16 public hospitals from different regions in Spain; which were described in detail in a previous publication (Citation7). The ethics committee at each hospital approved the study and patients provided an informed consent before inclusion.
From June 2008 through September 2010, we included all patients diagnosed with COPD who presented with eCOPD at the emergency department of a participating hospital. The clinical diagnosis of COPD was confirmed by the existence of prior spirometry showing a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) less than 70% (FEV1/FVC < 70%). An eCOPD was defined as a worsening of dyspnea, cough, and/or expectoration that required a change in the patient's baseline treatment (Citation4). We excluded all patients with complicated COPD, defined as those other acute processes that might manifest as an eCOPD (pneumonia, pneumothorax, pulmonary thromboembolism, heart failure) (Figure ). Both maintenance therapy as the treatment of exacerbation were established according to the criteria of the physicians responsible in each case.
Figure 1. Flow chart of eCOPD and patients with COPD in the study.
During the study, duly trained research staff recorded the following variables from a standardised questionnaire: age, sex, Charlson Comorbidity Index (Citation8), number of hospital admissions for eCOPD in the preceding year, grade of dyspnea before the episode (according to the mMRC scale)(9), spirometry parameters before the episode (FEV1%, FEV1/FVC), treatment with long-term oxygen therapy, prior treatment with oral theophylline, and inhaled drug therapy in the stable stage prior to the exacerbation. We classified this last variable into the following mutually exclusive therapeutic strategies: no treatment, treatment only with short acting beta agonists (SABA), monotherapy with long-acting beta-agonists (LABA), long-acting muscarinic antagonists (LAMA) or inhaled glucocorticoids (ICS), dual therapy (LABA + LAMA or LABA + ICS or LAMA + ICS), or triple therapy (LABA + LAMA + ICS).
We recorded patients’ destination after discharge from emergency care as either short-stay emergency care (< 48 h stay) or hospital inward admission (> 48 h stay). At the time of discharge to home from emergency care or from the ward in hospitalized patients, we recorded the prescribed inhaled treatment, so we could compare it with the treatment prescribed before the eCOPD. For this reason, we excluded patients who died during hospitalisation from the analyses (Figure ).
Statistical analysis
For the analyses, we took into account only the first episode of eCOPD for each patient, regardless of the number of episodes in the same patient during the recruitment period; thus, the unit of analysis was the patient.
We created the variable “change in treatment” to analyse modifications to treatment at discharge from the emergency area or from the hospital ward. We considered these treatments to fall on a therapeutic scale (SABA / MONOTHERAPIES / DUAL THERAPY / TRIPLE THERAPY); thus, we considered that treatment increased with each step up on the scale, decreased with each step down on the scale, and remained unchanged when kept on the same step of the scale.
We did a descriptive analysis of the quantitative and qualitative variables and a bivariate analysis of the independent variables after the dicotomization of FEV1. To compare quantitative variables, we used the nonparametric Mann–Whitney U; to compare qualitative variables, we used the Chi-square test.
To compare the treatment prior to the eCOPD with the treatment prescribed at discharge (paired ordinal variables), we used the marginal homogeneity test and Kendall's nonparametric τb. The marginal homogeneity test is an extension of the McNemar test that considers the multinomial response and stems from the null hypothesis in which the marginal frequencies of the rows and columns are similar. Kendall's nonparametric τb is a nonparametric measure of correlation in which the sign of the coefficient indicates the direction of the relationship and the absolute value of the coefficient indicates its strength; with possible values ranging from -1 to 1. Significance was set at 5% for all tests. SPSS Statistics 20 (IBM software) was used for all analyses.
Results
Figure is a flowchart showing how patients were included or excluded. A total of 1559 patients were included; 1013 (65%) were hospitalised for more than 48 h and 546 (35%) were discharged to home from emergency care within 48 h. Patients with severe/very severe COPD (FEV1 < 50% predicted) required hospitalisation more often than those with mild/moderate COPD (FEV1 ≥ 50% predicted): 68% versus 58% (p < 0.001). Table reports the baseline characteristics of the study population.
Table 1. Baseline characteristics of the study population
Table reports the maintenance treatment for COPD prior to the eCOPD. Overall, the most common inhaled therapy was ICS (80.9%), followed by LABA (75.4%), which was the most common type of bronchodilator. Approximately 10% of all patients received oral theophylline in addition to inhaled therapy. Although very few patients (≤ 0.5%) were not receiving any treatment before eCOPD, 6.6% were receiving only SABA. Monotherapy with long-acting bronchodilators was uncommon, reaching a maximum of 7.2% for LAMA in patients with mild/moderate COPD, and followed by single treatment with ICS in 5.6% of the patients. Dual therapy with two bronchodilators (LABA + LAMA) or with LAMA + ICS was also uncommon (< 5%), being the most common dual therapy LABA + ICS (18.2%), both in patients with mild/moderate COPD and in those with severe/very severe COPD. The most common therapeutic regimen in both severity groups was inhaled triple therapy (LABA + LAMA + ICS) (56.2%).
Table 2. Maintenance treatment according to pharmacological groups and therapeutic strategy used
When we evaluated the changes in maintenance therapy for COPD after eCOPD, we found that in most cases (60.9%–73.3%), treatment remained on the same therapeutic step in both patients with mild/moderate COPD and in those with severe/very severe COPD (Figure ). Interestingly, in patients discharged home directly after emergency treatment, the most common change consisted of reducing the intensity of maintenance treatment; this was true for both patients with mild/moderate COPD (14.4%) and those with severe/very severe COPD (21.6%). By contrast, in patients who were admitted to hospital after emergency care, the most common change consisted of intensifying maintenance treatment; true for both patients with mild/moderate COPD (25.2%) and for those with severe/very severe COPD (19.5%). The differences between the changes to maintenance treatment prescribed from the emergency departments and those prescribed after hospitalisation are statistically significant, both in patients with mild/moderate COPD (p = 0.002) and in those with severe/very severe COPD (p < 0.001).
Figure 2. Treatment modification according to FEV1 and discharge.
We also evaluated if the use of ICS (as dual or triple therapy) was related with hospital admissions during the previous year (Table ). We emphasize that the use of ICS as dual therapy in mild/moderate COPD was higher in those patients without previous hospital admissions: 39.8% versus 26.5% (p=0.011). Highlight also that 60% of the patients with mild/moderate COPD receiving triple therapy had not required admission to hospital in the year preceding the eCOPD.
Table 3. Use of inhaled corticosteroids-ICS (as dual or triple therapy) according to hospital admissions during the previous year
Table summarises the principal changes to maintenance treatment for COPD for both patients with mild/moderate COPD and those with severe/ very severe COPD. It is noteworthy that in 82/1559 (5.2%) of patients were prescribed only SABA at discharge after eCOPD from both emergency care and longer hospitalisation (previous inhaled treatment was even withdrawn in many cases). In 12/331 (3.6%) of the patients with severe/very severe COPD, maintenance treatment with long acting bronchodilators and/or ICS was reduced to only SABA on discharge from emergency care.
Table 4. Modification of inhaled maintenance therapy, according to severity of COPD and discharge: emergency versus hospitalization
Additionally, maintenance treatment remained unchanged after discharge in a high percentage of patients receiving only ICS before eCOPD, especially in those discharged to home from emergency care, although ICS was prescribed together with a long-acting bronchodilator in a smaller proportion of patients. Changes in maintenance treatment were prescribed mainly for patients requiring hospitalisation; being the most common changes from monotherapy with SABA or ICS to inhaled dual therapy with LABA + ICS or LAMA + ICS, and from either LAMA or LABA monotherapy or inhaled dual therapy (LABA + LAMA or LABA + ICS or LAMA + ICS) to inhaled triple therapy. Patients that were receiving triple therapy prior to eCOPD were normally prescribed the same treatment regimen after discharge from emergency care or from hospitalisation.
Discussion
To our knowledge, this is the first study to evaluate the impact of hospital emergency care for eCOPD on maintenance treatment for COPD in function of whether patients are discharged to home after a short-stay in emergency care or required inward admission.
When evaluating the appropriateness of treatment according to the GOLD strategy during the study period (Citation4), we observed that SABA, considered appropriate only for patients with intermittent symptoms, were the sole treatment prescribed for 6% of patients, regardless of the severity of COPD; a treatment regimen that may be considered as undertreatment for patients with severe/very severe COPD (GOLD III-IV).
Very few patients were receiving monotherapy with long-acting bronchodilators, the first therapeutic step and a pivotal treatment for COPD with persistent symptoms. In patients with mild or moderate COPD, monotherapy with LAMA was more common than monotherapy with LABA, but the proportion of patients thus treated was small (7% and 2%, respectively). During the study period, the only LAMA available was tiotropium, whereas two LABA drugs may be prescribed: salmeterol and formoterol. The clinical guidelines do not specify a first-choice long-acting bronchodilator. Although the difference in the use of the two classes of drugs was small, the greater use of tiotropium in monotherapy could be attributed to its administration in a single dose and its greater effectiveness in reducing the risk of exacerbations compared to salmeterol (Citation10–Citation13).
Evaluating the use of ICS in monotherapy, 5% of patients received this treatment, regardless of the severity of their COPD. Whereas ICS is the first-line treatment for asthma, ICS monotherapy is not recommended for COPD, where ICS should always be administered together with a long-acting bronchodilator when eCOPD persists, especially in patients with severe COPD (Citation14). Using ICS monotherapy can be the result of diagnostic problems in patients who have both COPD and asthma (up to 20%), a condition known as overlap syndrome (Citation15,Citation16). A significant proportion of ICS monotherapy in COPD has been also reported in other primary care studies; with figures up to 24% (Citation17).
In the second step of the therapeutic scale, we analysed three combinations of drugs administered in dual therapy: double bronchodilation (LABA + LAMA), indicated when adequate symptom control is not achieved with a single long-acting bronchodilator, and the combinations of a long-acting bronchodilator (LABA or LAMA) with ICS. Double bronchodilation was seldom used: only 3% of patients, regardless of their severity, received this treatment. Compared to LABA or LAMA monotherapy, double bronchodilation may result in significant improvements in lung function, the grade of dyspnea, and the need for SABA as rescue therapy. These improvements have also been reported compared to LABA + ICS (Citation18,Citation19), and double bronchodilation have also shown its usefulness in front of LAMA monotherapy for preventing eCOPD (Citation20).
Although the evidence supporting LAMA + ICS dual therapy is considered insufficient to recommend it the GOLD strategy (Citation21), this combination was somewhat more common than double bronchodilation in our study. One possible explanation for this therapeutic approach is that LAMA + ICS can be an alternative treatment in patients with poor tolerance to LABAs (Citation22). The combination LABA + ICS was the most common regardless of patients'severity and previous admissions to hospital, being the second most common therapeutic combination after triple therapy.
Triple therapy (LABA + LAMA + ICS), the last step on the therapeutic scale, was the most common treatment strategy regardless of the severity of COPD, being used in 56% of all patients. It is noteworthy that 60% of the patients with mild/moderate COPD receiving triple therapy had not required admission to hospital in the year preceding the eCOPD, which probably corresponds to overtreatment. A recent study of 561 patients admitted to hospital for eCOPD in Canada reported that 56% were receiving triple therapy at the time of admission and 69% were prescribed triple therapy at discharge; percentages of monotherapy and double bronchodilation in that study were low (Citation23). When evaluating the appropriateness of maintenance treatment for COPD and especially the use of ICS, it is important to bear in mind that we know the number of severe eCOPD in the preceding year (those that required admission to hospital) but not the number of mild or moderate eCOPD.
One of the most important findings of our study is that in most cases emergency care for eCOPD did not result in a change in the maintenance treatment for COPD. One possible reason for not changing the maintenance treatment for COPD is that some professionals focus exclusively on treating the eCOPD without considering whether the maintenance treatment was appropriate, leaving decisions about this matter to the patient's regular physician. In patients with eCOPD requiring admission to hospital, it is more likely that if the maintenance treatment for COPD is changed it will be increased. By contrast, in patients discharged to home from emergency care, the most common modification was a reduction in treatment, which occurred even in 21% of patients with severe/very severe COPD. Among the factors that could be related to this greater reduction in maintenance treatment, we should consider greater variability in the specialisation of physicians on emergency care teams, less time available for studying emergency patients, less familiarity with clinical guidelines for COPD, and greater familiarity with the use of SABA in the urgent management of eCOPD than with long-acting bronchodilators (Citation24).
Our analysis of the changes to maintenance treatment shows that the scaled treatment scheme recommended in GOLD strategy for COPD is generally not applied. Treatment changes very rarely included the steps of monotherapy with a long-acting bronchodilator or dual bronchodilation; instead, most modifications involved a change to dual therapy with ICS (LABA + ICS) or triple therapy, especially after hospitalisation. In COPD, overtreatment with ICS is common (Citation25,Citation26) and conflicting results have been published about whether the additional costs of triple therapy compared to dual bronchodilation are associated with less consumption of healthcare resources in COPD (Citation27,Citation28) or with better disease control.
The frequent use of triple therapy can be related with inappropriate treatment prior to admission, which would call for greater intensification of maintenance treatment on discharge, skipping the steps on the therapeutic scale proposed by the GOLD strategy prior to triple therapy. Another factor favoring the frequent use of triple therapy is the availability of combination LABA + ICS inhalers along the study period as the only dual therapy administered in a single device, which also helps to explain overtreatment with ICS (Citation25). New combination inhalers with fixed doses of LABA + LAMA have been recently added to the treatment arsenal for COPD, and in the next few years it would be possible to determine their impact on current practice that may induce a reduction in the overall use of ICS.
Finally, it is important to point out that the most recent update of the GOLD strategy in 2011 represents an important modification of the classification and treatment schemes used beforehand, emphasizing the importance of multidimensional assessment of COPD based on the presence of symptoms, the severity of the obstruction of airflow, and the presence of exacerbations. Given the scant adherence to the therapeutic steps proposed in the GOLD strategy, it is difficult to know to what extent this latest update will be implemented in different healthcare contexts.
In conclusion, patients attended for eCOPD at hospitals were treated mainly with inhaled triple therapy or with LABA + ICS dual therapy; very few patients were treated with long-acting bronchodilators in monotherapy or with dual bronchodilation, and ICS stands out as the most commonly prescribed drug class. In most cases, hospital care for eCOPD does not result in changes to maintenance treatment, regardless of whether patients require inward admission or are treated solely as a short-stay in the emergency department. Reductions in maintenance treatment were significantly more common in patients discharged to home from emergency care, which should be avoided in clinical practice.
Declaration of Interest Statement
The authors report no conflicts of interest in this study. The authors alone are responsible for the content and writing of the paper. XP, CM, and MB designed the study, participated in the acquisition of data, interpreted the results, drafted the manuscript, and approved its final version. JG interpreted the results and reviewed the manuscript for intellectual content. JMQ conceived and coordinated the main study CE, SV and AS, participated in the acquisition of data. MP supported the statistical analysis. All authors critically reviewed the manuscript. All of them read and approved the final manuscript.
Competing Interests
Members of the IRYSS-COPD Group
The IRYSS-COPD group included the following co-investigators: Dr. Jesús Martínez-Tapias (Dirección Económica, Área Gestión Sanitaria Sur Granada); Alba Ruiz (Hospital de Motril, Granada); Dr. Eduardo Briones (Epidemiology Unit, Primary Care, Sevilla); Dr. Emilio Perea-Milla, Francisco Rivas and Dr. Silvia Vidal (Servicio de Epidemiología, Hospital Costa del Sol, Málaga – REDISSEC); Dr. Maximino Redondo (Servicio de Laboratorio, Hospital Costa del Sol, Málaga- REDISSEC); Javier Rodríguez Ruiz (Responsable de Enfermería del Área de Urgencias, Hospital Costa del Sol, Málaga); Dr. Marisa Baré, Núria Torà (Clinical Epidemiology, Parc Taulí Sabadell-UAB and REDISSEC), Dr. Gemma Navarro (Epidemiology, Parc Taulí); Dr. Concepción Montón (Pneumology Service, Parc Tauli and REDISSEC); Dr. Manel Lujan, Dr. Amalia Moreno, Dr. Josune Ormaza, Dr. Xavier Pomares (Pulmonology Service, Parc Taulí); Dr. Juli Font (Medicine and Emergency Department; Parc Taulí), Dr. Cristina Estirado, Dr. Joaquim Gea (Pulmonology Department, Hospital del Mar. CEX, UPF. CIBERES. Barcelona); Dr. Juan Antonio Blasco, Dr. Nerea Fernández de Larrea (Unidad de Evaluación de Tecnologías Sanitarias, Agencia Laín Entralgo, Madrid); Dr. Ana Santiago, Dr. Ana Martínez-Virto (Pulmonology and Emergency Department, Hospital La Paz, Madrid); Dr. Esther Pulido (Servicio de Urgencias, Hospital Galdakao-Usansolo, Bizkaia); Dr. Jose Luis Lobo (Servicio de Neumología, Hospital Txagorritxu, Araba); Dr. Mikel Sánchez (Servicio de Urgencias, Hospital Galdakao-Usansolo, Bizkaia); Dr. Luis Alberto Ruiz (Servicio de Respiratorio, Hospital Cruces, Bizkaia); Dr. Ane Miren Gastaminza (Hospital San Eloy, Bizkaia); Dr. Ramon Agüero (Servicio de Neumología, Hospital Marqués de Valdecilla, Santander); Dr. Gabriel Gutiérrez (Servicio de Urgencias, Hospital Cruces, Bizkaia); Dr. Belén Elizalde (Dirección Territorial de Gipuzkoa); Dr. Felipe Aizpuru (Unidad de Investigación, Hospital Txagorritxu, Álava/REDISSEC); Dr. Inmaculada Arostegui (Departamento de Matemática Aplicada, Estadística e Investigación Operativa, UPV- REDISSEC); Amaia Bilbao (Hospital de Basurto-REDISSEC); Dr. Eva Tabernero and Carmen M. Haro (Hospital de Santa Marina); Dr. Cristóbal Esteban (Servicio de Neumología, Hospital Galdakao-Usansolo-REDISSEC, Bizkaia); Dr. Nerea González, Susana García, Iratxe Lafuente, Urko Aguirre, Irantzu Barrio; Miren Orive, Edurne Arteta, Dr. Jose M. Quintana (Unidad de Investigación, Hospital Galdakao-Usansolo, Bizkaia / REDISSEC).
Acknowledgments
We are grateful for the support of the 16 participating hospitals, as well as the members of the various services, research, quality units, and medical records sections of these hospitals. We also gratefully acknowledge the patients who participated in the study.
The authors also acknowledge the detailed review of the manuscript by Dr. Eduard Monsó and the editorial assistance provided by John Giba.
Funding
This work was supported in part by grants from the Fondo de Investigación Sanitaria (PI06\1010, PI06\1017, PI06\714, PI06\0326, PI06\0664); and the thematic networks- Red IRYSS (Investigación en Resultados y Servicios Sanitarios (G03\220) and REDISSEC (Health Services Research on Chronic Diseases Network; RD12/0001/0007) – of the Instituto de Salud Carlos III.
References
- Miravitlles M, Soriano JB, García-Río F, et al.Prevalence of COPD in Spain: Impact of undiagnosed COPD on quality of life and daily life activities. Thorax 2009; 64(10):863–868.
- Miravitlles M, Murio C, Guerrero T, Gisbert R. Costs of chronic bronchitis and COPD: a 1-year follow-up study. Chest 2003; 123(3):784–791.
- Soler-Cataluna JJ, Martínez MA, Román P, et al.Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60(11):925–931.
- Global Initiative for Chronic Obstructive Lung Disease. Global strategy fort he diagnosis, management, and prevention of COPD. 2007. Available from: http://www.goldcopd.com (accessed).
- Asche C, Leader S, Plauschinat C, et al.Adherence to current guidelines for chronic obstructive pulmonary disease (COPD) among patients treated with combination of long-acting bronchodilators or inhaled corticosteroids. Int J Chron Obstruct Pulmon Dis 2012; 7:201–209.
- Mularski RA, Asch SM, Shrank WH, et al.The quality of obstructive lung disease care for adults in the United States as measured by adherence to recommended processes. Chest 2006; 130(6):1844–1850.
- Quintana JM, Esteban C., Barrio I, et al.The IRYSS-COPD appropriateness study: objectives, methodology, and description of the prospective cohort. BMC Health Serv Res 2011; 11:322.
- Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987; 40(5):373–383.
- Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54:581–586.
- Tashkin DP, Celli B, Senn S, et al.A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359(15):1543–1554.
- Troosters T, Celli B, Lystig T, et al.Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir J 2010; 36(1):65–73.
- Vogelmeier C, Hederer B, Glaab T, et al.Tiotropium vs salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364(12):1093–1103.
- Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 9:CD009157.
- Calverley PM, Anderson JA, Celli B, et al.Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356(8):775–789.
- Soriano JB, Davis KJ, Coleman B, et al.The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 2003; 124(2):474–481.
- Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 2009; 64(8):728–735.
- Miravitlles M, Andreu I, Romero Y, et al.Difficulties in differential diagnosis of COPD and asthma in primary care. Br J Gen Pract 2012; 62(595):e68–75.
- Van Noord J, Aumann J, Janssens E, et al.Combining tiotropium and salmeterol in COPD: Effects on air flow obstruction and symptoms. Respir Med 2010; 104(7):995–1004.
- Mezzi K, Pallante J, Alagappan V, et al.Once-Daily QVA149 Demonstrates superior outcomes in COPD patients previously treated with fixed-dose long-acting β2-agonist/inhaled corticosteroid (LABA/ICS): The ILLUMINATE Study. Chest 2014; 145:424A.
- Wedzicha J, Ficker J, Niewohner D, et al.Dual bronchodilation with once-daily QVA149 reduces exacerbations, improves lung function and health status versus glycopyrronium and tiotropium in severe-to-very severe COPD patients: the SPARK Study. Chest 2014; 145:406A.
- Vestbo J, Hurd SS, Agusti AG, et al.Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD Executive Summary. Am J Respir Crit Care Med 2013; 187(4):347–365.
- Decramer M, Hanania N, Lötvall J, Yawn B. The safety of long-acting ß2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013; 8:53–64.
- Dault R, Dubé A, Blais L, et al.Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care center for exacerbation of their disease. Can J Hosp Pharm 2012; 65(5):373–379.
- Roche N, Lepage T, Bourcereau J, Terrioux P. Guidelines versus clinical practice in the treatment of chronic obstructive pulmonary disease. Eur Respir J 2001; 18(6):903–908.
- De Miguel J, Izquierdo JL, Rodríguez JM, et al.Drug treatment of Chronic Obstructive Pulmonary Disease on two levels of patient care: degree of compliance with recommended protocols. Arch Bronconeumol 2003; 39(5):195–202.
- White P, Thornton H, Pinnock H, et al.Overtreatment of COPD with inhaled corticosteroids – Implications for safety and costs: Cross-sectional observational study. Plos One 2013; 8(10):e75221.
- Asche C, Leader S, Plauschinat C, et al.Adherence to current guidelines for chronic obstructive pulmonary disease (COPD) among patients treated with combination of long-acting bronchodilators or inhaled corticosteroids. Int J Chron Obstruct Pulmon Dis 2012; 7:201–209.
- Kozma C, Paris A, Plauschinat C, et al.Comparison of resource use by COPD patients on inhaled therapies with long-acting bronchodilators: a database study. BMC Pulmon Med 2011; 11:61.