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Original Research: COPD |

Comorbidities and Short-term Prognosis in Patients Hospitalized for Acute Exacerbation of COPDComorbidity and Prognosis in COPD Hospitalized Patients: The EPOC en Servicios de Medicina Interna (ESMI) Study FREE TO VIEW

Pedro Almagro, MD; Francisco Javier Cabrera, MD; Jesus Diez, MD; Ramon Boixeda, MD; M. Belen Alonso Ortiz, MD; Cristina Murio, MD; Joan B. Soriano, MD; for the Working Group on, COPD, Spanish Society of Internal Medicine*
Author and Funding Information

From the Internal Medicine Service (Dr Almagro), Hospital Universitario Mutua De Terrassa, Barcelona; Internal Medicine Service (Dr Cabrera), Hospital General Universitario Gregorio Marañón, Madrid; Internal Medicine Service (Dr Diez), Hospital Royo Villanova, Zaragoza; Internal Medicine Service (Dr Boixeda), Hospital de Mataró, Barcelona; Internal Medicine Service (Dr Alonso Ortiz), Hospital Juan Negrín, Gran Canaria; Medical Departament (Dr Murio), Laboratorios Chiesi, Barcelona; and Programa de Epidemiología e Investigación Clínica (Dr Soriano), Fundación Caubet-Centro Internacional de Medicina Respiratoria Avanzada (CIMERA), Baleares, Spain.

Correspondence to: Pedro Almagro, MD, Hospital Mutua de Terrassa, Barcelona University, Plaza Dr Robert No. 5, 08221 Terrassa, Barcelona, Spain; e-mail: 19908pam@comb.cat

*

A complete list of study investigators is provided in e-Appendix 1.


Funding/Support: This work was supported by Chiesi España.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(5):1126-1133. doi:10.1378/chest.11-2413
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Background:  Comorbidities are frequent in patients hospitalized for COPD exacerbation, but little is known about their relation with short-term mortality and hospital readmissions. Our hypothesis is that the frequency and type of comorbidities impair the prognosis within 12 weeks after discharge.

Methods:  A longitudinal, observational, multicenter study of patients hospitalized for a COPD exacerbation with spirometric confirmation was performed. Comorbidity information was collected using the Charlson index and a questionnaire that included other common conditions not included in this index. Dyspnea, functional status, and previous hospitalization for COPD or other reasons among other variables were investigated. Information on mortality and readmissions for COPD or other causes was collected up to 3 months after discharge.

Results:  We studied 606 patients, 594 men (89.9%), with a mean (SD) age of 72.6 (9.9) years and a postbronchodilator FEV1 of 43.2% (21.2). The mean Charlson index score was 3.1 (2.0). On admission, 63.4% of patients had arterial hypertension, 35.8% diabetes mellitus, 32.8% chronic heart failure, 20.8% ischemic heart disease, 19.3% anemia, and 34% dyslipemia. Twenty-seven patients (4.5%) died within 3 months. The Charlson index was an independent predictor of mortality (P < .003; OR,1.23; 95% CI, 1.07-1.40), even after adjustment for age, FEV1, and functional status measured with the Katz index. Comorbidity was also related with the need for hospitalization from the ED, length of stay, and hospital readmissions for COPD or other causes.

Conclusions:  Comorbidities are common in patients hospitalized for a COPD exacerbation, and they are related to short-term prognosis.

Figures in this Article

According to the definition by GOLD (Global Initiative for Obstructive Lung Disease), COPD is an inflammatory disease, characterized by extrapulmonary manifestations in many patients.1 Among these systemic manifestations are the presence of associated diseases, namely comorbidities that have a significant influence on health-related quality of life, use of resources, and prognosis. It is well known that patients with COPD have an increased prevalence of cardiovascular disease, cancer, and depression, in comparison with the general population, even after adjustment for other risk factors such as smoking or dyslipidemia.2 These comorbidities are related to the systemic inflammation that characterizes the disease.3 In fact, cardiovascular disease and cancer are frequent causes of death in COPD, particularly in patients with moderate and mild severity COPD.4

Although comorbidities may be present from the moment of the initial diagnosis,5,6 their frequency increases with COPD progression, and they are particularly common in patients with more advanced disease, such as those hospitalized for a COPD exacerbation.7 In these patients, comorbidity is related with a poor survival rate in subsequent years.8

The main purpose of our study was to explore comorbidities associated with COPD in patients hospitalized for exacerbation and to examine their effect on short-term mortality and hospital readmissions up to 3 months after discharge.

The EPOC en Servicios de Medicina Interna (ESMI) study (ie, COPD in Internal Medicine Services study) is a longitudinal, observational, multicenter study, conducted in 70 ED and internal medicine services in Spain, that included the first 10 consecutive patients seen for a COPD exacerbation during a 1-year period (October 2009-October 2010). Exacerbation was defined as a change in the symptoms of patients, beyond daily variations and requiring a change in regular medication.9 Inclusion criteria were as follows: (1) age above 40 years, (2) admission for COPD exacerbation, and (3) forced spirometry with a postbronchodilator FEV1 < 80% predicted and an FEV1/FVC < 0.70. Exclusion criteria were as follows: (1) a previous diagnosis of asthma or bronchiectasis as predominant disease, or other explainable cause of obstructive airflow limitation, (2) acute pulmonary edema or pneumonia upon admission, (3) inability to perform spirometry or noncompliance with spirometric criteria, and (4) admission for reasons other than an exacerbation of COPD.

During admission, all patients were evaluated with a standardized questionnaire. Data collected included time from the first medical diagnosis of COPD, hospitalizations for COPD or other pathologies in the previous year, and home status (family, alone, nursing home). Functional status at baseline was assessed with the Katz index.10 Comorbidity was documented using the previously validated Charlson index, a standard scale with 15 chronic diseases graded for severity of disease.11 For comparative analysis, a point was subtracted from the total score on the Charlson index, as all patients had COPD, which adds a point in this index. Additionally, comorbidity data were collected using a specific questionnaire which included pathologies that were considered relevant, whether included or not in the Charlson index. To calculate the total of comorbidities, one point was added for each one of the following pathologies: ischemic heart disease, heart failure, peripheral vascular disease, cerebrovascular disease, dementia, connective tissue disease, liver disease, kidney failure, diabetes mellitus, AIDS, hypertension, osteoporosis, sleep apnea syndrome, dyslipidemia, presence of psychologic disorders (anxiety or depression), active malignancy (including leukemia and lymphoma), arrhythmia, anemia, and venous thromboembolic disease. Data on medical treatment previous to hospitalization, during hospitalization and upon discharge were also collected. Dyspnea was measured using the modified Medical Research Council (mMRC) scale, and length of stay was recorded. Patients were followed up to 3 months after discharge, and a spirometric test was performed if it had not been done previously. At this time, survival, cause of death, and time between hospital discharge and mortality were collected, and hospital readmissions for COPD or other causes were recorded.

Statistical Analysis

Qualitative variables were expressed as absolute frequencies and percentages, while quantitative variables were summarized as mean and SD in the case of normally distributed or median otherwise. Comparison among means was made with the Student t test for independent samples. The Mann-Whitney U test was used for variables not normally distributed. The χ2 test or the Fisher exact test was used for the comparison of proportions. For time-dependent variables we used the Cox logistic regression and Kaplan-Meier statistics. Multivariate statistics were performed using a multiple logistic regression analysis or Cox, whenever indicated. The analysis was performed with SPSS 15.0 (IBM Software), and all analyses were based on the bilateral hypothesis with statistical significance below 0.05.

The study was approved by the Clinical Investigation Ethics Committee of the Hospital Mútua de Terrassa (EO/0922_0709). All patients participated voluntarily and signed written informed consent forms.

Overall, 679 patients were screened, and 606 were included. Fifteen patients were excluded for having an incomplete minimum data set, and another 58 cases were unable to perform spirometry or did not fulfill spirometric criteria for COPD. In 48 cases, spirometry was not available within the 6-month period before admission and could not be performed between discharge and follow-up visit, but a prior diagnosis of COPD with spirometric confirmation was available. These patients were included in the study of comorbidity, although spirometric data were considered as “missing” in the current analysis (Fig 1). No differences existed between included and excluded patients in terms of age, sex, smoking history, or dyspnea measured by the mMRC (data not shown).

Mean age of the studied population patients was 72.6 years (SD, 9.9; range, 41-94); 594 (89.9%) were men, and mean postbronchodilator FEV1 was 43% (21.2). A total of 94.2% patients were former smokers or ex-smokers with a mean average of 55.5 (28) packs/year. Regarding previous hospitalization, 71% of patients had required at least one admission for COPD exacerbation during the previous year, with a mean of 2.2 (1.5) and with a hospital duration of 19.4 (16.5) days, while 65.3% had been hospitalized for other reasons during the same period, with a mean of 2.51 (1.73). In 127 cases (21%), the current hospitalization was the first admission for COPD exacerbation, whereas in the remaining cases the first admission occurred a mean of 6.1 years earlier. No prior diagnosis of COPD was made in 7.6% of patients, while the mean time from the first diagnosis for the rest of the participants was 8.5 (6.4) years.

Regarding ambulatory control, 39% were followed mainly by their family doctor, while the rest were also controlled by pulmonologists (46%), internists (27%), or other specialists (8%); 4.6% did not undergo ambulatory controls until the current admission. Only 11% were included in a program of ambulatory pulmonary rehabilitation. The main demographic, clinical, and respiratory characteristics of the total population are shown in Table 1.

Table Graphic Jump Location
Table 1 —Demographic and Clinical Characteristics of Participants With COPD (N = 606)

Summary variables are presented as mean ± SD for quantitative variables, and count (%) for discrete variables. GOLD = Global Initiative for Chronic Obstructive Lung Disease; mMRC = modified Medical Research Council.

The average score on the Charlson index was 3.1 (2). The most commonly observed comorbidities in this index were heart failure (32.8%), diabetes without complications (28.4%), and ischemic heart disease (20.8%). Regarding comorbidities not included in the Charlson index, the most frequent were arterial hypertension (63.4%), osteoporosis (16%), abdominal obesity (> 102 cm in men and > 88 cm in women) (29%), dyslipidemia (34%), anemia (19.3%, of which 9% were considered iron deficiency), and psychologic disorders: depression (15%) or anxiety (18.3%). Table 2 shows the main comorbidities grouped according to whether they are included in the Charlson index. Men had a higher score on the Charlson index, 3.1 ± 2 vs 2.5 ± 2, but not when assessing the scale of total comorbidities. On the one hand, men with COPD also more frequently had previous ischemic heart disease (P < .001), myocardial infarction (P < .001), chronic renal failure (P = .02), and hypertension (P = .02); on the other hand, women had more osteoporosis (P < .001), anxiety (P < .001), and depression (P < .001). Regarding ambulatory treatment prior to current admission, 89.4% of the patients received long-acting β agonists (LABAs), 87.6% inhaled corticosteroids, and 79.4% long-acting antimuscarinics. Other treatments were diuretics (54.5%), statins (40.3%), angiotensin-converting enzyme inhibitors (30.4%), angiotensin II receptor antagonists (26.4%), β-blockers (11.1%), antiplatelet drugs (36.6%), and warfarin or other anticoagulation drugs (18%).

Table Graphic Jump Location
Table 2 —Frequencies of Comorbidities by Charlson Index Data and Global Questionnaire

DM = diabetes mellitus.

A total of 69 patients (11.1%) were discharged from the ED without requiring conventional hospitalization. Patients who required conventional hospitalization, compared with those discharged home from ED, were older (73.2 years vs 67.7 years, P < .001), with lower FEV1 (42% vs 52%, P < .001), a greater number of associated comorbidities (3.7 vs 2.6, P < .001), higher scores on the Charlson index (3.1 vs 2.5, P < .01), more dyspnea measured with the mMRC scale (2.4 vs 2.0, P < .001), more admissions for COPD in the previous year (1.7 vs 1.5, P < .001), lower Po2 at the time of the visit to the ED (60 mm Hg vs 66 mm Hg, P = .03), and higher functional dependency measured by the Katz index (5.2 vs 5.7, P = .005). After adjusting all significant variables in a logistic regression analysis, the number of global comorbidities expressed numerically or the Charlson index, postbronchodilator FEV1, and the number of hospitalizations for COPD in the previous year maintained independent statistical significance.

The length of the stay in hospitalized patients was 9.3 (7.6) days. This was also related to comorbidity measured with Charlson index or the total number of comorbidities (P < .001), independent of FEV1, age, and sex.

Of the 606 included patients, 470 (78%) completed follow-up and outpatient visit at 3 months. Patients who could not attend the outpatient control had required more frequent hospital admission in the previous year (P < .001), needed chronic home oxygen therapy more frequently (P < .04), and more often suffered dementia (P < .04), hemiplegia (P < .03), or cardiac arrhythmia (P < .001). However, there were no differences regarding age, functional status (Katz index), sex, Charlson index, or the total number of comorbidities. The reasons for failure of follow-up control were death in 27 cases (20%), multiple hospital readmissions in 14 (10.3%), other reasons in 38 cases (28%), and missing in the rest (41.7%).

All-cause mortality at 3 months was, therefore, 4.5% (27 of 606). The causes of death were respiratory failure in 17 cases, stroke in three, cardiovascular in two, cancer in two, and other causes in three. Mean follow-up for deceased patients was 40 days (28) (interquartile range, 25%-75%: 13-64 days). Mortality at 3 months was associated with age, number of hospital admissions for COPD or other causes in the previous year, greater dyspnea (mMRC), chronic home oxygen therapy, more functional dependence (Katz index), and comorbidities both measured with the Charlson index and total of comorbidities. Several conditions analyzed separately were also associated with increased mortality (Table 3), namely ischemic heart disease and chronic heart failure (Figs 2, 3). The severity of COPD as measured by the postbronchodilator FEV1, stratified according to the GOLD classification, was also associated with decreased survival (Fig 4).

Table Graphic Jump Location
Table 3 —Crude Mortality Predictors at 3 mo

HR = hazard ratio. See Table 1 legend for expansion of other abbreviation.

Figure Jump LinkFigure 2. Mortality and ischemic heart disease.Grahic Jump Location
Figure Jump LinkFigure 4. Mortality and FEV1 (GOLD). GOLD = Global Initiative for Chronic Obstructive Lung Disease.Grahic Jump Location

In a multivariate analysis (Table 4), it can be seen that increasing age (but with borderline non-significance), reduced FEV1 stratified according to GOLD guidelines, higher functional dependence measured with the Katz index, and increasing comorbidity measured with the Charlson index were independently associated with total mortality.

Table Graphic Jump Location
Table 4 —Mortality: Multivariate Analysis (Cox Regression)

See Table 1 and 3 legends for expansion of abbreviations.

a 

FEV1 stratified according GOLD guidelines.

Data on readmissions are available for 484 surviving patients. Of these, 98 (20.2%) were readmitted for COPD within a 3-month period after discharge, with a mean frequency of 1.26 readmissions, while 68 (14%) were hospitalized for other reasons. Overall, 28% of patients had required at least one new hospitalization.

Readmissions for a new exacerbation of COPD were related with the number of hospitalizations for COPD during the previous year (P < .0001), dyspnea (P < .004), FEV1 stratified according to the GOLD guidelines (P < .001), chronic home oxygen use (P < .004), presence of cor pulmonale (< .002), functional dependence measured by the Katz index (P < .0001), and Charlson index stratified into two or more points (corresponding to two mild or one severe disease other than COPD) (P = .02).

Readmissions for other diseases were attributable in 15 cases (22%) to heart failure, 12 to infections (18%), seven to ischemic heart disease (10%), six to bone fractures (9%), six to stroke, and the rest to miscellaneous causes. Predictors of readmission for any cause were the Katz index (P < .003), and hospitalization during the previous year for both COPD and another cause (both P < .001). The baseline Charlson index stratified into two or more points was significantly higher in patients who required rehospitalization (P < .05), independent of age, sex, and FEV1.

Our study confirms the high prevalence of comorbidity in patients hospitalized for exacerbation of COPD and its importance in relation to short-term prognosis in this population, namely to the need for a readmission or mortality within 3 months after hospital discharge. Although previous studies have shown the relationship between comorbidity and posthospital mortality, these studies have usually been based on long-term follow-up.7,12,13 Other significant predictors of mortality such as age, FEV1, dyspnea, or functional dependence measured by the Katz index were also associated with mortality after a COPD hospitalization.8

The most common comorbidities observed in our study were ischemic heart disease affecting 20.8% of patients, of whom 11.6% had a previous myocardial infarction, 32.8% had heart failure, 35.8% had diabetes mellitus, 63.4% had arterial hypertension, and 33.8% had dyslipidemia. This prevalence is slightly higher than what was observed in previous studies conducted with a similar methodology,14 but definitively greater than that reported in retrospective studies based on hospital databases.12

In our study, comorbidity measured by the Charlson index or with an extended comorbidity questionnaire was confirmed as an independent predictor of mortality at 3 months after discharge, and was additionally related to an increased need for hospitalization after consultation for acute exacerbation in the ED, increased length stay in conventional hospitalization, and subsequent readmissions for COPD or other diseases.

Mortality was also higher in patients with cardiovascular disease, such as ischemic heart disease, heart failure, stroke, and peripheral vascular disease. The relationship between COPD and cardiovascular disease is well documented in the literature and in fact is a common cause of mortality in these patients.4,15 Cohort studies show that patients with COPD are twice as likely to have ischemic heart disease and four times as likely to suffer heart failure as age- and sex-matched control subjects even after adjusting for various confounders.16 Moreover, the risk of a cardiovascular event, particularly myocardial infarction, increases after an episode of COPD exacerbation.17 Our patients have a very high prevalence of classic cardiovascular risk factors such as smoking exposure, hypertension, diabetes mellitus, dyslipidemia, or abdominal obesity, among others. Therefore, optimizing the treatment of comorbidity and cardiovascular risk factors should be a priority in the care of patients with COPD.18 Of utmost priority, apart from optimizing any COPD treatment, is detecting and treating associated diseases, including cardiovascular risk factors. Treatment of osteoporosis, depression, and others should also be a priority in the care of patients with COPD. Several retrospective studies have shown an association with reduced mortality with the use of statins, angiotensin-converting enzyme inhibitors, or β-blockers, all of which also tend to be underutilized in patients with COPD and ischemic heart disease.1921 The presence of depressive symptoms has also been associated with increased mortality in patients hospitalized for COPD, although again in longer-term studies.7,22

Previous studies on comorbidity and its relationship with the risk of hospitalization and readmission in COPD have shown conflicting results. For example, regarding the need for hospitalization in patients visiting the ED for acute exacerbation, two studies conducted in Canada found no relationship between the presence of associated diseases and the need for hospitalization.23,24 However, in both studies only limited numbers of comorbidities were considered, and one of them even excluded patients with concomitant heart failure, a condition that occurs in 30% of patients hospitalized for COPD.25 In contrast, studies performed using validated tools to evaluate comorbidity such as the Charlson index have shown that the presence of comorbidity and greater functional dependency are both predictors of hospitalization in both COPD and heart failure,26 results which are similar to those observed in the present study. Similarly, in our study, the length of hospital stay was significantly higher in patients with more comorbidities, confirming data from previous studies.27,28

Finally, comorbidity was also associated with more readmissions, either for COPD or other causes, in the 3 months after discharge. To our knowledge, no previous studies have demonstrated a relation between Charlson index and hospital readmissions,2931 except a retrospective study based on an electronic hospital database. Unfortunately, that study did not detail the observed comorbidities.32

Our study has several limitations, the first being the small number of women included, similar to other studies performed in Spain. This is related to the secular trends of smoking in Spain, with most women exposed to active smoking only after the 1950s. A number of comorbidities in our study, such as osteoporosis and psychologic disorders, are more common in women, while ischemic heart disease predominates in men, confirming the results of previous studies.25 Second, most of the patients included in our study had been hospitalized in internal medicine departments, and probably were more likely to present a greater number of comorbidities than those hospitalized in respiratory services. In Spain, between 40% and 50% of exacerbations of COPD are treated in internal medicine services, which generally often see older patients with more comorbidities.33 However, the observed mortality and readmissions at 3 months are similar to those reported in a study conducted in Spain with over 1,200 patients hospitalized in different units and hospitals.34 Third, regrettably, we have no full, protocolized mortality data of 55 patients who were lost to follow-up (accounting for 9% of the total sample tested). However, these patients are comparable to the rest, so we have no evidence to suspect that mortality outcomes are different. As an additional limitation, cardiac biomarkers (eg, troponin or brain natriuretic peptide), which have recently been highlighted as very important in predicting prognosis,35 were not measured in all participants. Finally, our study design did not take into account seasonality or type of acute exacerbations of COPD.36,37 As per methods, each investigator included the first 10 consecutive patients seen for a COPD exacerbation during a 1-year period (October 2009-October 2010). More than one-half of patients were included in February, March, and April (data not shown).

In summary, we confirm the presence of comorbidity in patients hospitalized for COPD is high and related to the later need for hospitalization, length of stay and hospital readmissions. Moreover, comorbidity is also related to survival, and some severe comorbidities, mainly cardiovascular, chronic kidney disease, depression, and dementia, are by themselves associated with increased mortality as early as 3 months after discharge. Accurate evaluation and treatment of these associated diseases may improve the prognosis of these patients.18

Author contributions: Dr Almagro had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Almagro: contributed to study design, analysis and interpretation of the data, and writing of the manuscript

Dr Cabrera: contributed to data collection and review of the manuscript.

Dr Diez: contributed to data collection and review of the manuscript.

Dr Boixeda: contributed to data collection and review of the manuscript.

Dr Alonso Ortiz: contributed to data collection and review of the manuscript.

Dr Murio: contributed to study design and writing of the manuscript.

Dr Soriano: contributed to study design, analysis and interpretation of the data, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Additional information: The e-Appendix 1 can be found in the “Supplemental Materials” area of the online article.

GOLD

Global Initiative for Chronic Obstructive Lung Disease

mMRC

modified Medical Research Council

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San Román Terán C, Guijarro Merino R, Gómez Huelgas R, Montero Ribas L. Epidemiología hospitalaria de la EPOC en España. Rev Clin Esp. 2007;207(s):suppl 1):3-7.
 
Pozo-Rodríguez F, Alvarez CJ, Castro-Acosta A, et al; por el Grupo AUDIPOC España por el Grupo AUDIPOC España. Clinical audit of patients admitted to hospital in Spain due to exacerbation of COPD (AUDIPOC study): method and organisation [in Spanish]. Arch Bronconeumol. 2010;46(7):349-357. [CrossRef] [PubMed]
 
Chang CL, Robinson SC, Mills GD, et al Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764-768. [CrossRef] [PubMed]
 
Aaron SD, Donaldson GC, Whitmore GA, Hurst JR, Ramsay T, Wedzicha JA Time course and pattern of COPD exacerbation onset. Thorax. 2012;67(3):238-243. [CrossRef] [PubMed]
 
Donaldson GC, Goldring JJ, Wedzicha JA Influence of season on exacerbation characteristics in patients with COPD. Chest. 2012;141(1):94-100. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 2. Mortality and ischemic heart disease.Grahic Jump Location
Figure Jump LinkFigure 4. Mortality and FEV1 (GOLD). GOLD = Global Initiative for Chronic Obstructive Lung Disease.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographic and Clinical Characteristics of Participants With COPD (N = 606)

Summary variables are presented as mean ± SD for quantitative variables, and count (%) for discrete variables. GOLD = Global Initiative for Chronic Obstructive Lung Disease; mMRC = modified Medical Research Council.

Table Graphic Jump Location
Table 2 —Frequencies of Comorbidities by Charlson Index Data and Global Questionnaire

DM = diabetes mellitus.

Table Graphic Jump Location
Table 3 —Crude Mortality Predictors at 3 mo

HR = hazard ratio. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
Table 4 —Mortality: Multivariate Analysis (Cox Regression)

See Table 1 and 3 legends for expansion of abbreviations.

a 

FEV1 stratified according GOLD guidelines.

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San Román Terán C, Guijarro Merino R, Gómez Huelgas R, Montero Ribas L. Epidemiología hospitalaria de la EPOC en España. Rev Clin Esp. 2007;207(s):suppl 1):3-7.
 
Pozo-Rodríguez F, Alvarez CJ, Castro-Acosta A, et al; por el Grupo AUDIPOC España por el Grupo AUDIPOC España. Clinical audit of patients admitted to hospital in Spain due to exacerbation of COPD (AUDIPOC study): method and organisation [in Spanish]. Arch Bronconeumol. 2010;46(7):349-357. [CrossRef] [PubMed]
 
Chang CL, Robinson SC, Mills GD, et al Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764-768. [CrossRef] [PubMed]
 
Aaron SD, Donaldson GC, Whitmore GA, Hurst JR, Ramsay T, Wedzicha JA Time course and pattern of COPD exacerbation onset. Thorax. 2012;67(3):238-243. [CrossRef] [PubMed]
 
Donaldson GC, Goldring JJ, Wedzicha JA Influence of season on exacerbation characteristics in patients with COPD. Chest. 2012;141(1):94-100. [CrossRef] [PubMed]
 
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