DÄ internationalArchive37/2018Medical Treatment of COPD

Original article

Medical Treatment of COPD

An analysis of guideline-adherent prescribing in a large national cohort (COSYCONET)

Dtsch Arztebl Int 2018; 115(37): 599-605; DOI: 10.3238/arztebl.2018.0599

Graf, J; Jörres, R A; Lucke, T; Nowak, D; Vogelmeier, C F; Ficker, J H

Background: Chronic obstructive pulmonary disease (COPD) is common around the world and carries a high morbidity and mortality. Symptom- and risk-oriented drug treatment is recommended, both in Germany and in other countries. It is not yet known to what extent the treatment that is actually delivered in Germany corresponds to the current recommendations in the guidelines.

Methods: As recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2017, 2281 patients of the national COPD cohort COSYCONET (COPD and Systemic Consequences–Comorbidities Network) were classified into Gold classes A—D on the basis of disease-specific manifestations and the frequency of exacerbations. Moreover, the regular use of medications was documented and categorized according to active substance groups. For all groups, the documented treatment that was actually given was compared to the recommended treatment.

Results: 67.6% of the patients received a combination of a long-acting anticholinergic drug (LAMA) and a long-acting beta-mimetic drug (LABA), while 65.8% received inhaled corticosteroids (ICS), 11.7% theophylline, and 12.6% oral corticosteroids (OCS). Despite recommendations to the contrary, 66% of the patients in Groups A and B (low exacerbation rates) were treated with ICS; some of these patients carried an additional diagnosis of bronchial asthma. There was evidence of undertreatment mainly in groups C and D (high exacerbation rate), because many of the patients in these groups were not treated with LAMA or LAMA/LABA as recommended.

Conclusion: The observed deviations from the recommended treatment, some of which were substantial, might lead to suboptimal treatment outcomes as well as to avoidable side effects of medication.

LNSLNS

Chronic obstructive pulmonary disease (COPD) is a globally widespread disease with high morbidity and mortality, affecting approximately 13% of the adult population in Germany (1). Besides pulmonary rehabilitation and avoidance of relevant noxious substances, effective medical treatments are available to improve symptoms and prevent exacerbations. Currently, the treatment recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) consortium (2) issued in 2017 represent the accepted international standard on which national guidelines are based.

In the past, the treatment-relevant classification of COPD was primarily or partially based on the spirometric severity of airway obstruction; by contrast, the latest GOLD recommendations (2) are grounded exclusively in the evaluation of patient symptoms and exacerbation rates. From this, four groups—A, B, C, and D—are derived by combining low (A, C) versus high (B, D) severity of symptoms and low (A, B) versus high (C, D) exacerbation risk. Each group is linked to a recommended pharmacotherapy and, if available, alternative treatment options (Figure 1).

Treatment recommendations of the GOLD consortium
Treatment recommendations of the GOLD consortium
Figure 1
Treatment recommendations of the GOLD consortium

For Germany, data on the pharmacotherapy of COPD are available from disease management programs (3), but prospective data are lacking (eMethods). For their analysis, large cohorts established for scientific purposes and not linked to intervention studies, such as the German COPD cohort COSYCONET (“COPD and Systemic Consequences–Comorbidities Network“), are best suited. This BMBF-sponsored long-term study under the umbrella of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL) recruited 2741 patients and, besides extensive examinations and testing, collected data on medication (4).

The primary aim of this sub-study of COSYCONET is to describe the long-term COPD medications; the secondary aim is to compare this treatment with the GOLD 2017 treatment recommendations, focusing on the aspect of over- and under-medication.

Methods

Patients

From September 2010 (pilot phase) to December 2013, altogether 2741 patients were recruited (visit V1) at 31 study sites; in 2014 and 2015, the data of the follow-up visits V2 and V3 were collected (4). The grades of severity GOLD 1–4 were assigned based on the spirometric forced expiratory volume in 1 second (FEV1) in % of the predicted value (5). Only patients with FEV1/forced vital capacity (FVC) ratio of <70% (2) were included in our analysis (n = 2291).

Data collection

All patients were asked to bring along all medications they had been taking (4). COPD-associated symptoms were assessed using the COPD Assessment Test (CAT) and the modified MRC score (mMRC) (2). Exacerbations were graded according to GOLD criteria. Based on these data, patients were allocated to the groups A–D. Since group allocation based on CAT scores can differ from that based on mMRC scores, both instruments were used for data collection. Given the descriptive nature of this study, comparative statistics were not applied.

Medication evaluation

Respiratory medications were grouped into classes of active substances using ATC codes (6) and compared with the therapy recommended by the GOLD guidelines (Figure 1). Over-treatment was defined as a regimen comprising at least one active substance not included in the recommendations for the respective group. Under-treatment was defined as a regimen lacking at least one substance group recommended as an indispensable component. Theophylline as long-term therapy is no longer included in the GOLD recommendations, but is still used in Germany. Therefore, we referred to the German National Disease Management Guideline (NVL, Nationale Versorgungsleitlinie) as a supplementary resource (7) which states that theophylline can be added to treatment with long-acting bronchodilators in patient group D (frequent exacerbations and inadequately controlled symptoms). For roflumilast, a selective phosphodiesterase 4 (PDE4) inhibitor, we based our evaluation, in accordance with the GOLD guidelines, on its approval criteria—especially the limitation to FEV1<50% predicted and the bronchitic phenotype in COPD patients with frequent exacerbations (8). According to the GOLD recommendations, long-term use of oral glucocorticoids (OCS) should best be avoided and should only be considered (besides during acute exacerbations) as a last resort after all other treatment options have been exhausted.

Results

Of the 2291 patients with FEV1/VC<70% (Tiffeneau-index), 2281 patients could be assigned to the groups GOLD A–D. The corresponding distribution of drug classes is shown in Figure 2.

Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).
Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).
Figure 2
Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).

Table 1 shows the frequencies of the drug classes in the groups A–D based on CAT and eTable 1 based on mMRC. Combinations, representing a recommended treatment or an over-treatment, are highlighted in color. In the same way, sub-treatments are highlighted in Table 2 and eTable 2. Although CAT and mMRC results differed with regard to group sizes, generally the pharmacologic treatments were similar. In the following, their summarized frequencies are shown as ranges.

Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on over-treatment
Table 1
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on under-treatment
Table 2
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on over-treatment
eTable 1
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on under-treatment
eTable 2
Results for various drug classes with focus on under-treatment

Treatment with LABA, LAMA and/or ICS

In the groups A–C, 36.1 to 40.6% of patients received a long-acting beta2-agonist (LABA) as a single agent, while 63.3 to 79.5% received a long-acting muscarinic antagonist (LAMA) as a single agent; this is in line with the guideline recommendations. At the same time, 50.5 to 51.8% of patients in group A received LABA plus LAMA—an over-treatment according to GOLD. Furthermore, in the groups A and B 46.2 to 68.1% of patients received an inhaled corticosteroid (ICS), in 32.0 to 50.0% of cases as a LABA + ICS combination treatment and in 32.4 to 56.6% of cases as a triple therapy (LABA/LAMA/ICS). According to GOLD, ICS is considered an over-treatment in the groups A and B. In the groups C and D, both LAMA and LABA or ICS can be indicated; thus, no over-treatment was identified here. In the groups C and D, 72.3 to 80.2% of patients received both LABA and LAMA and 57.4 to 71.4% received a triple therapy (combination of LABA, LAMA, ICS [single-agent or combination treatments]).

GOLD recommends a long-acting bronchodilator (LAMA, LABA) for group B. In group B, 5.2 to 10.2% of patients received neither LABA nor LAMA—indicative of under-treatment (Table 2). Even in the groups C and D, 2.4 to 3.0% of patients were not treated with a long-acting bronchodilator. For the groups C and D, the GOLD recommendations specify an initial therapy with a LAMA which can be escalated to LAMA/LABA or LAMA/LABA/ICS, if required. In group C, 18.9 to 21.9% of patients received a LABA without a LAMA and thus were undertreated; this percentage was 9.2–12.2% in group D. In the groups C and D, 3.6 to 6.8% of the patients received a LABA monotherapy, even though this treatment strategy was not in line with the recommendations.

Theophylline and roflumilast

In group D, 16.5–18.8% of patients received theophylline (Table 1); however, 5.7–13.5% of group A–C patients were also treated with theophylline and thus overtreated. In the groups A–C, however, theophylline was almost always (92.9 to 100%) administered in combination with a LABA and/or a LAMA.

According to the GOLD recommendations, the use of the PDE4 inhibitor roflumilast may be considered in group D patients experiencing frequent exacerbations despite LAMA/LABA/ICS treatment. Under these conditions, roflumilast is approved for patients with bronchitic phenotype. It was administered to 16.5–19.4% of patients in group D, but also to 2.0–9.8% of patients in the groups A–C (Table 1). In the groups A–D (CAT), 22% of the roflumilast patients had FEV1 values ≥ 50% predicted; the means were 55, 43, 53, and 40% predicted, respectively. In 3.2% of group D patients (high exacerbation risk), the low FEV1 required for the use of roflumilast was not given.

Inhaled and oral corticosteroids

To further explore the signs of over-treatment with ICS in the groups A and B (Table 1), it was investigated whether these could be explained by asthma as a comorbidity. According to their medical histories, 17.6% of the 2281 patients had been diagnosed with bronchial asthma. In the groups A and B with ICS treatment this percentage rose to 20.2%, in the groups C and D with ICS treatment to 25.2%.

In group D, OCS were used in 21.5–25.4% of patients. Even though these percentages declined in the groups C–A, they were 4.5–5.7% even in group A (Table 1). These observations gave rise to the question whether other potential indications for OCS were present in these patients, such as rheumatoid arthritis and atopic dermatitis. Altogether, 8.2% of patients in the groups A–D had rheumatoid arthritis and 12.7% had arthritis or dermatitis. In the groups A and B with OCS, 8.0–22.2% of the patients had at least one of the two additional diagnoses, while in the groups C and D the percentage of 10.3–17.0% was in the range of the overall cohort. Another possible explanation for the use of OCS in patients of the lower exacerbation categories (A/B) is that these patients had experienced an episode of exacerbation which had been treated with OCS, and the short-term OCS treatment was mistakenly reported by the patient as a long-term therapy. However, 70.0–90.9% of OCS patients in group A and 49.2–54.9% in group B reported no episode of exacerbation during the last 12 months.

Discussion

The aim of this analysis was to obtain reliable data on the pharmacotherapy of COPD in Germany and to compare these with the current recommendations. It was found that patients with COPD were treated intensely with the available medications, but signs of over-treatment were detected under some conditions.

As a benchmark for adequate treatment, we chose the recommendations of the GOLD consortium in its current version (2017) (2) which solely rely on a classification based on symptoms and exacerbations. As these recommendations use clear, well-defined criteria (Figure 1), they enabled a comparison of the actual and recommended pharmacological treatments. Even though recruitment for this cohort was already completed by the end of 2013, the follow-up visits (until 2015) showed a high degree of consistency in medications; consequently, it is likely that these observations are still valid for the current pharmacologic therapy of COPD in Germany. Moreover, earlier recommendations (9) were not fundamentally different from those given in 2017 (2); the changes were mostly related to theophylline and ICS. At the same time, the new “ABCD” grouping which is exclusively based on symptoms and exacerbations is better suited for application in everyday clinical practice than the earlier version.

Since the current version of the GOLD recommendations does no longer contain positive criteria for oral theophylline treatment, but theophylline is still used in the long-term therapy of COPD in Germany, we based our evaluation of the indication for theophylline on the German National Disease Management Guideline (Nationale Versorgungsleitlinie, NVL); otherwise, any administration of theophylline would have had to be classified as over-treatment. For the evaluation of the use of roflumilast it appeared to be adequate to include the criteria of its approval (especially FEV1<50% predicted and frequent exacerbations under LAMA/LABA therapy) in the assessment.

The therapy with inhaled medications in the groups A to D differed in part significantly from the GOLD recommendations. The same applied to theophylline and roflumilast. Overall, the results of our analysis indicated a trend towards over- rather than under-treatment. Over-treatment with ICS was primarily found in the groups A and B, i.e. among patients with low exacerbation rates. Under-treatment was most prevalent in group C, i.e. among patients with relatively low symptom severity, but increased exacerbation rates, many of whom did not receive a baseline therapy with a LAMA

Surprisingly, a high proportion of patients with long-term OCS therapy was identified. This could only to some extent be explained by comorbidities. It is conceivable that in individual cases the long-term medication may not have been recorded correctly (erroneous reporting of acute therapy as long-term therapy), contributing to an overestimation of the percentage of patients with long-term OCS therapy. However, similar percentages were also found during the follow-up visits, and there was hardly any association with past exacerbations. The use of OCS was only explained by comorbidities in some patients. Consequently, it must be assumed that in Germany a substantial proportion of patients with COPD receives inadequate long-term therapy with OCS—given the significant adverse effects of OCS, this is a highly relevant finding.

In an actual individual case, physicians often find it difficult to choose the best pharmacological treatment regimen, as the guidelines can only provide general guidance. On the level of the individual patient, factors such as drug intolerance, interactions or treatment-limiting comorbidities, but also patient preferences or individual treatment experiences have to be taken into account. It is likely that such factors which are difficult to document in a standardized form during a large study have played a role in some patients. Against this background, the terms “over-treatment” and “under-treatment” used here should not be misinterpreted as indicating a false medical decision, but should only be understood as a descriptive term to indicate a deviation from the current recommendations which may be well justified by special circumstances of individual patients. Nevertheless, the question remains whether the observed considerable deviations from current recommendations can be explained by individual factors alone and in which patient groups the differences between the reality of patient care and the formal recommendations are particularly striking. Finding a reliable answer to this answer requires data of high standardized quality, which is the case with COSYCONET (4, 6, 1013), even when taking into account that participants in a long-term study may receive a higher level of medical care compared to the average level for German COPD patients (14).

This review found that the pharmacotherapy received by a large proportion of COPD patients in Germany differs from what one would normally expect. Here, a key finding is the observation that two thirds of German COPD patients received an ICS which, however, was not indicated in about half of these cases according to the latest international treatment recommendations. This deviation is relevant not only because of the costs of ICS, but also because of the significant potential side effects associated with inhaled corticosteroids (2). ICS may have been prescribed to treat comorbid asthma; the percentage of ICS use in patients with asthma as an additional diagnosis was indeed slightly higher, but this cannot explain the majority of inadequate therapies. It is more likely that general uncertainties with regard to the differentiation between COPD and asthma were the driving force, leading to a frequent use of ICS with COPD to prevent under-treatment of potential asthma, even if this had not been diagnosed explicitly. Thus, in everyday clinical practice it seems to be imperative to clearly distinguish between COPD and asthma—this includes that asthma may be diagnosed as a comorbidity in COPD. To what extent easy-to-obtain parameters, such as eosinophilia in the peripheral blood, can be useful here is subject to ongoing research.

Another important factor leading to over-treatment with ICS could be that earlier recommendations regarded ICS as significantly more important compared to how its role is viewed today. Data on the specialty of the treating physicians were not available to us. Earlier studies indicate that the majority of pulmonologists followed the GOLD recommendations, while non-pulmonologists rather relied on national guidelines (15, 16). With the latter being usually based on past GOLD recommendations, significant changes in the GOLD recommendations are implemented into national clinical guidelines with delay. This also may have contributed to the observed over-treatment with ICS—compared to the current GOLD recommendations.

For daily clinical practice the results of this analysis suggest that in some COPD patients the indication for treatment with ICS should be critically reviewed. In this context, large studies showed that even in patients with advanced COPD, high-dose ICS treatment can be discontinued without triggering exacerbations, provided that a strict LAMA/LABA regimen is adhered to (17). By contrast, other studies (18, 19) continued to further evaluate the efficacy of ICS treatment in COPD, especially as a component of triple therapy which was observed in many of the patients analyzed here. Furthermore, the oral long-term therapy with theophylline, which still enjoys widespread use in Germany despite the fact that the current GOLD recommendations see no positive indication for it any longer, should be critically reviewed in each individual patient in the light of the associated cardiac side effects and the current evidence from published studies (20). Consistent implementation of the 2017 GOLD recommendations (2) and the corresponding German guideline (21) is desirable in any case.

In summary, this analysis indicates that many German patients with COPD are over-treated or, to a lesser extent, under-treated compared to current guideline recommendations. Future non-interventional studies—among others, the continuation of the COSYCONET cohort—should thoroughly analyze the clinical characteristics of these patients, the pharmacotherapy they actually receive, and, if possible, the medication compliance to identify further areas where patient care—but possibly also the recommendations—can be improved.

Funding

COSYCONET is supported by the German Federal Ministry of Education and Research (BMBF; funding code 01 GI 0881) as part of the Competence Network Asthma and COPD (ASCONET) under the umbrella of the German Center for Lung Research (DZL). Additional funding for COSYCONET is provided by unrestricted grants of AstraZeneca GmbH, Bayer Schering Pharma AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Chiesi GmbH, GlaxoSmithKline, Grifols Deutschland GmbH, MSD Sharp & Dohme GmbH, Mundipharma GmbH, Novartis Deutschland GmbH, Pfizer Pharma GmbH, and Takeda Pharma Vertrieb GmbH & Co. KG. These monies are used to fund investigations and laboratory testing at the study sites.

Conflict of interest
Prof. Nowak owns shares in mixed funds, which contain, among others, stocks of pharmaceutical companies. He is a member of the Advisory Boards of Pfizer with regard to smoking cessation. He received reimbursement of meeting participation fees for congresses as well as accommodation expenses from Mundipharma and Boehringer Ingelheim. He received fees for preparing continuing medical education events from Med Update.

Prof. Ficker owns shares in equity funds which contain, among others, stocks of pharmaceutical companies. He received consulting fees and lecture fees from Astra-Zeneca, Berlin Chemie, Boehringer Ingelheim, CSL-Behring, GlaxoSmithKline, Grifols, KW Medpoint, Med Update, Novartis, Takeda, and TEVA. Funding for the conduct of clinical studies was provided to his department by Novartis and CSL-Behring.

Prof. Vogelmeier received consulting fees and lecture fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, and Berlin Chemie. He received funding for a research project initiated by him from Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, and Takeda.

PD Jörres received fees for continuing medical education events on pulmonary function, which are not related to medications, from GSK.

Jana. Graf and Dr. Lucke declare that they have no conflict of interest.

Manuscript received on 19 January 2018, revised version accepted on 3 May 2018

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Joachim H. Ficker
Ärztlicher Leiter der Medizinischen Klinik mit Schwerpunkt Pneumologie, Allergologie, Schlafmedizin am Klinikum Nürnberg
Universitätsklinik der Paracelsus Medizinischen Privatuniversität
Prof.-Ernst-Nathan-Str. 1
90419 Nürnberg, Germany
ficker@klinikum-nuernberg.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref3718

eMethods, eTables:
www.aerzteblatt-international.de/18m0599

1.
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Karch A, Vogelmeier C, Welte T, et al.: The German COPD cohort COSYCONET: aims, methods and descriptive analysis of the study population at baseline. Respir Med 2016; 114: 27–37 CrossRef MEDLINE
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Houben-Wilke S, Jörres RA, Bals R, et al.: Peripheral artery disease and its clinical relevance in patients with chronic obstructive pulmonary disease in the COPD and Systemic Consequences–Comorbidities Network Study. Am J Respir Crit Care Med 2017; 195: 189–97 CrossRef MEDLINE
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Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich, German Center for Lung Research (DZL), Munich, Germany: Jana Graf, PD Dr. rer. nat. Rudolf A. Jörres, Dr. rer. biol. hum. Tanja Lucke, Prof. Dr. med. Dennis Nowak
Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, University Hospitals of Gießen and Marburg, Marburg site, German Center for Lung Research (DZL): Prof. Dr. med. Claus Vogelmeier
Department of Respiratory Medicine, Allergology and Sleep Medicine, General Hospital Nürnberg, Paracelsus Medical University, Nürnberg, Germany: Prof. Dr. med. Joachim
H. Ficker
Treatment recommendations of the GOLD consortium
Treatment recommendations of the GOLD consortium
Figure 1
Treatment recommendations of the GOLD consortium
Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).
Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).
Figure 2
Percentage distribution of the main drug classes for the GOLD groups A-D based on CAT (N = 2281).
Key messages
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on over-treatment
Table 1
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on under-treatment
Table 2
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on over-treatment
eTable 1
Results for various drug classes with focus on over-treatment
Results for various drug classes with focus on under-treatment
Results for various drug classes with focus on under-treatment
eTable 2
Results for various drug classes with focus on under-treatment
1. Geldmacher H, Biller H, Herbst A, et al.: Die Prävalenz der chronisch obstruktiven Lungenerkrankung (COPD) in Deutschland. Deutsch Med Wochenschr 2008; 133: 2609–14 CrossRef MEDLINE
2. Vogelmeier CF, Criner GJ, Martinez FJ, et al.: Global Strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report. Respirology 2017; 22: 575–601 CrossRef MEDLINE
3. Mehring M, Donnachie E, Fexer J, Hofmann F, Schneider A: Disease management programs for patients with COPD in Germany: a longitudinal evaluation of routinely collected patient records. Respir Care 2014; 59: 1123–32 CrossRef MEDLINE
4. Karch A, Vogelmeier C, Welte T, et al.: The German COPD cohort COSYCONET: aims, methods and descriptive analysis of the study population at baseline. Respir Med 2016; 114: 27–37 CrossRef MEDLINE
5. Quanjer PH, Stanojevic S, Cole TJ, et al.: Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40: 1324–43 CrossRef MEDLINE PubMed Central
6. Lucke T, Herrera R, Wacker M, et al.: Systematic analysis of self-reported comorbidities in large cohort studies – A novel stepwise approach by evaluation of medication. PLoS ONE 2016; 11: e0163408 CrossRef MEDLINE PubMed Central
7. Ollenschläger G, Kopp I, Lelgemann M: Die Nationale VersorgungsLeitlinie COPD. Med Klin 2007; 102: 50–5 CrossRef MEDLINE
8. Bone H, Bolognese M, Yuen C: Roflumilast (Daxas®). KVBW Verordnungsforum. 16: 39-45. https://repository.publisso.de/resource/frl:6402051/data.(last accessed on 27 June 2018).
9. Vestbo J, Hurd SS, Rodriguez-Roisin R: The 2011 revision of the global strategy for the diagnosis, management and prevention of COPD (GOLD)–why and what? Clin Respir J 2012; 6: 208–14 CrossRef MEDLINE
10. Houben-Wilke S, Jörres RA, Bals R, et al.: Peripheral artery disease and its clinical relevance in patients with chronic obstructive pulmonary disease in the COPD and Systemic Consequences–Comorbidities Network Study. Am J Respir Crit Care Med 2017; 195: 189–97 CrossRef MEDLINE
11.Fähndrich S, Biertz F, Karch A, et al.: Cardiovascular risk in patients with alpha-1-antitrypsin deficiency. Respir Res 2017; 18: 171 CrossRef MEDLINE PubMed Central
12. Kahnert K, Lucke T, Huber RM, et al.: Relationship of hyperlipidemia to comorbidities and lung function in COPD: results of the COSYCONET cohort. PLoS ONE 2017; 12: e0177501 CrossRef MEDLINE PubMed Central
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