Midregional Proatrial Natriuretic Peptide Predicts Survival in Exacerbations of COPD

CHEST

Original Research COPD

Midregional Proatrial Natriuretic Peptide Predicts Survival in Exacerbations of COPD Maurizio Bernasconi, MD; Michael Tamm, MD, FCCP; Roland Bingisser, MD, FCCP; David Miedinger, MD; Jörg Leuppi, MD; Beat Müller, MD; Mirjam Christ-Crain, MD; and Daiana Stolz, MD, MPH

Background: Recently, the use of systemic biomarkers to monitor and assess the clinical evolution of respiratory disease has gained interest. We investigated whether midregional proatrial natriuretic peptide (MR-proANP) predicts survival in patients with COPD when they are admitted to the hospital for exacerbation. Methods: One hundred sixty-seven patients (mean age 70 years old, 75 men) admitted to the hospital for exacerbation were followed up for 2 years. MR-proANP was measured on admission, after 14 days, and at 6 months. The predictive value of clinical, functional, and laboratory parameters on admission were assessed by Cox regression analyses. The time to death was analyzed by Kaplan-Meier survival curves. Results: MR-proANP level was significantly higher on admission for exacerbation, compared with recovery and stable state (P 5 .004 for the comparison among all time points). MR-proANP correlated with the Charlson condition and age-related score (P , .0001), left ventricular ejection fraction (P , .0001), C-reactive protein (P 5 .037), and FEV1% predicted (P 5 .004). MR-proANP levels were similar in patients requiring ICU treatment and in those treated in the medical ward (P 5 .086). Thirty-seven patients (22%) died within 2 years. MR-proANP levels were higher in nonsurvivors compared with survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001). Mortality was higher across MR-proANP quartiles (log rank P , .0001). Charlson condition and age-related score (P 5 .001), PaCO2 (P , .0001), and MR-proANP (P 5 .001) predicted mortality in the univariate Cox-regression model. Both MR-proANP and PaCO2 were independent predictors of mortality in the multivariate Cox regression model. Conclusions: MR-proANP at exacerbation is associated with 2-year long-term survival in patients with exacerbation of COPD. CHEST 2011; 140(1):91–99 Abbreviations: ANP 5 atrial natriuretic peptide; BNP 5 brain natriuretic peptide; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; MR-proANP 5 midregional proatrial natriuretic peptide

is currently the fourth-leading cause of COPD death worldwide and further increases in its prevalence and associated mortality are predicted for the coming decades.1-4 COPD is an increasing health economic problem, and exacerbations of COPD are the main cause of disease-related costs, morbidity, and

mortality.4,5 The primary cardiovascular complication of COPD is the development of pulmonary hypertension following structural changes in the pulmonary vasculature, which are known to occur because of persistent pulmonary vasoconstriction in response to chronic hypoxia.6

Manuscript received June 8, 2010; revision accepted October 27, 2010. Affiliations: From the Clinic for Pulmonary Medicine and Respiratory Cell Research (Drs Bernasconi, Tamm, Miedinger, and Stolz), the Division of Endocrinology, Diabetes and Clinical Nutrition (Dr Christ-Crain), the Department for Emergency Medicine (Dr Bingisser), and the Clinic for Internal Medicine (Dr Leuppi), University Hospital Basel, Basel; and the Clinic for Internal Medicine (Dr Müller), Hospital Aarau, Aarau, Switzerland. Funding/Support: Dr Stolz was supported by grants from the Swiss National Foundation [PP00P3_128412/1]. Dr Christ-Crain was supported by grants from the Swiss National Foundation

[PP00P3_123346]. Additional funding was granted by the Clinic of Pulmonary Medicine and Clinic of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, Switzerland. Correspondence to: Daiana Stolz, MD, MPH, Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben 4, Basel, CH-4031, Switzerland; e-mail: [email protected] © 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-1353

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Age, comorbidities, FEV1, loss of fat-free mass, long-term use of oral corticosteroids, respiratory failure, and recurrent need of hospitalization for exacerbation have been identified as risk factors associated with higher mortality in COPD.7-10 Recently, interest has been expressed about the use of systemic biomarkers of inflammatory response and cardiac stress in the risk stratification of patients with exacerbation of COPD. Interest has also been expressed in their role in monitoring and assessing the clinical evolution of the disease.11-14 Atrial natriuretic peptide (ANP) is a peripheral and pulmonary artery vasodilator, a natriuretic and diuretic hormone, which is released from myocardial cells in the atria, and in some cases in the ventricles, in response to volume expansion and increased cardiac wall stress.15-19 ANP circulates primarily as a 28-amino-acid polypeptide, consisting of amino acids 99 to 126 from the C-terminal end of its prohormone, pro-ANP. ANP blocks the pulmonary vasopressor response to acute hypoxia via stimulation of cyclic guanosine monophosphate accumulation in the pulmonary vasculature in rats,20 reduces pulmonary vascular resistance, and attenuates hypoxia-induced pulmonary hypertension.21 Severe acute hypoxia induced by hypoxic exercise leads to increased ANP levels in healthy subjects.22 In a mouse model, ANP was shown to play an important antifibrogenic role in the pulmonary vascular adaptation to chronic hypoxia.21 The high concentration of ANP in the right atrium led to considering its effect on pulmonary circulation and its role in COPD.11 ANP is expected to correlate with atrial pressure challenges in exacerbation and might, therefore, be a superior prognostic biomarker to brain natriuretic peptide (BNP) in the COPD population.23 The midregional proatrial natriuretic peptide (MR-proANP) has a much longer half-life than mature ANP and has, therefore, been suggested as a more reliable analyte for measurement. In this study, we aimed to assess whether circulating serum levels of MR-proANP predict mortality independent of comorbidities in a well-characterized cohort of patients with COPD admitted to the hospital for exacerbation. The primary end point of this study was all-cause mortality during the 2-year follow-up. Secondary end points were the need for intensive care during the initial hospitalization and the recurrence of exacerbation of COPD requiring hospitalization within 2 years. Materials and Methods Setting and Study Population This prospective cohort study assessed short- and long-term mortality in patients with exacerbations of COPD recruited in the Procalcitonin Guidance of Antibiotic Therapy in Chronic

Obstructive Lung Disease (ProCOLD) study.24 Data were analyzed from 167 patients admitted to the ED of the University Hospital Basel, Switzerland, for exacerbation of COPD from November 2003 to March 2005. A complete description has been reported elsewhere.24 In brief, the primary end point of this study was to evaluate the prescription and duration of antibiotic use in patients randomly assigned procalcitonin as compared with usual care. The analysis of prognostic predictors in the study population was a predefined secondary end point of the protocol. To be eligible for the study, admitted patients must have received a diagnosis of COPD exacerbation on the basis of clinical history, physical examination, and chest radiograph and had to meet the postbronchodilator spirometric criteria for COPD according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines within 48 h after inclusion.4 Spirometry was performed by trained lung function technicians according to American Thoracic Society guidelines within 48 h of inclusion. Immunocompromised patients and those with cystic fibrosis, active pulmonary TB, or infiltrates on chest radiographs on presentation were excluded from the evaluation. Spontaneously expectorated sputum samples were obtained and examined using standard techniques.14 Anthonisen criteria and exacerbation type were recorded for all the included patients.25 After full recovery, all patients were reevaluated during outpatient visits 14 to 18 days (recovery) and 6 months (stable state) after initial hospital admission. The follow-up assessment included medical history, physical examination, blood tests, and chest radiograph. In addition to the described evaluation, the study cohort included in the present analyses was followed up for another 18 months (ie, for a total of 2 years). Historical echocardiography results obtained during the 6 months prior to hospital admission were acquired from hospital medical records. Relevant pulmonary arterial hypertension was defined as an estimated systolic pulmonary arterial pressure above 35 mm Hg as measured by echocardiography.26 The study was carried out according to the principles of the Declaration of Helsinki and was approved by our local ethics committee (Ethics Commission Beider Basel 232/03). Written informed consent was obtained from all participating patients. Outcome The recovery phase was defined as the time point following exacerbation (14-18 days), in which patients were evaluated based on clinical, laboratory, and lung functional criteria. Stable state was defined as the time point of a follow-up visit without any reported worsening of the patient’s condition beyond normal day-to-day variations and with no need for change in regular medication in the preceding 4 weeks, which comprised a clinical, laboratory, and lung function assessment. Exacerbation of COPD was defined as “a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.”27 All patients were followed up for a mean (⫾ SD) duration of 28.4 ⫾ 5.0 months. Exacerbation recurrence was defined as a new exacerbation occurring after full recovery (14-18 days) from the initial exacerbation and presenting within 2 years of inclusion in the study. Patients who survived until follow-up were categorized as survivors, whereas patients who died within the follow-up period were categorized as nonsurvivors. The cause of death was adjudicated based on the review of medical records (University Hospital Basel, neighborhood institutions, nursing homes, daycare centers, emergency medical services, and family physicians) and on personal interviews with attending physicians and/or family physicians. Medical record review was performed by two independent, board-certified pulmonary specialists. Vital status was additionally confirmed by family physicians and/or health insurance companies.

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Measurement of MR-proANP Using a sandwich immunoassay, MR-proANP (epitopes covering amino acids 53-90 of the prohormone N-terminal portion of proANP) was detected in EDTA plasma from all patients on the day of admission to the hospital (exacerbation), at 14 to 18 days (recovery), and at 6 months (stable state) after admission28 (BRAHMS AG; Hennigsdorf Berlin, Germany). The lower detection limit of the assay was 4.3 pmol/L, and its functional sensitivity of the assay (ie, an interassay coefficient of variation , 20%) was 11 pmol/L. The 97.5th percentile in 325 healthy individuals was 163.9 pmol/L, with no difference between women and men.28 Statistical Analysis Discrete variables are expressed as counts (percentages) and continuous variables as means ⫾ SD or median (interquartile range). Comparability of groups was analyzed by x2 test, two-sampled t test, Mann-Whitney U test, Kruskal-Wallis analysis of variance, Wilcoxon matched-pair test, or Friedman test, as appropriate. Cox regression univariate and multivariate analyses were performed to assess the influence of Charlson condition and age-related score, BMI, leukocyte counts, C-reactive protein, FEV1% predicted, Pao2, Paco2, pulmonary hypertension, and MR-proANP levels on admission on 2 years survival. Correlation analyses were performed using Spearman rank. The time to death was analyzed by Kaplan-Meier survival curves and compared by the log-rank tests. Skewed data were logarithmic transformed for regression analyses. All tests were two tailed. Statistical analyses were performed using the SPSS/PC, version 17.0, software package (SPSS Inc; Chicago, Illinois). A statistical significance level of , 0.05 was regarded as significant (P , .05).

Results Baseline characteristics of the 167 patients, including classification according to the GOLD stage at the recovery phase of the disease, are presented in Table 1. Overall, 116 patients (69.5%) had relevant comorbidities. Sputum cultures grew bacteria in 65 cases (38.9%). Echocardiography results were available for 123 patients (73.7%). A total of 38 patients (22.8%) demonstrated clinically relevant pulmonary arterial hypertension. In 12 cases (7.2%), echocardiography showed decreased left ventricular ejection fraction (ⱕ 40%). Median length of hospital stay was 9 (1-15) days, and 16 patients (9.6%) required intensive care. Seventy-three patients (43.7%) required rehospitalization because of exacerbation within 2 years of follow-up. Among patients with recurrence of exacerbation, median time to readmission was 174 (42-395) days. In-hospital mortality was 3.0% (five patients). There were another 32 deaths during the follow-up period. Hence, a total of 37 patients (22.2%) died within 2 years of the initial hospitalization. The main causes of mortality were respiratory conditions (COPDrelated respiratory failure including pneumonia) in 19 patients and cardiovascular disorders in 12 patients. For one patient, the cause of death is unknown. Of the 37 patients who died during the 2-year follow-up, 10 (27%) had concomitant malignancy (bronchial www.chestpubs.org

Table 1—Baseline Characteristics of 167 Patients Requiring Hospitalization for Exacerbation of COPD Values (N 5 167)

Characteristics Male gender Age, y, mean (range) BMI Smoking, pack-years Mean duration of COPD, mo Hospitalization for COPD in previous year Duration of exacerbation, d Cough Increased sputum production Discolored sputum Dyspnea Fever Comorbidities, % Cardiopathy Arterial hypertension Malignancy Diabetes mellitus Renal failure Respiratory medication, % b2-Agonists Anticholinergics Inhaled steroids Oral steroids Theophylline Antibiotics Long-term home oxygen therapy Type of exacerbation, Anthonisen criteria, % 1. Dyspnea, sputum purulence, sputum volume 2. Two of the above 3. One of the above and one minor findinga Severity of COPD, GOLD Stage, % I, FEV1% . 80% predicted II, 50% predicted . FEV1% , 80% predicted III, 30% predicted . FEV1% , 50% predicted IV, FEV1% , 30% predicted Charlson weighted index of comorbidities Charlson condition and age-related scoreb Estimated 10-y survival, % FEV1, L FEV1% predicted Pao2, mm Hg Paco2, mm Hg Leukocyte counts, 3 109/L C-reactive protein, mg/L Ejection fraction,c % Pulmonary arterial pressure,c mm Hg

75 (44.9) 70 (42-91) 24.6 ⫾ 4.8 45 (30-60) 127 ⫾ 86 0.98 ⫾ 1.3 4 (3-7) 142 (85) 113 (67.7) 95 (56.9) 155 (92.8) 68 (40.7) 76 (45.5) 42 (25.1) 24 (14.4) 19 (11.4) 15 (9.0) 142 (85) 86 (52) 120 (72) 55 (33) 16 (10) 37 (22) 23 (14) 80 (47.9) 36 (21.6) 51 (30.5) 14 (8.4) 37 (22.2) 76 (45.5) 40 (24.0) 2 (1-4) 5 (4-7) 21 (0-53) 0.89 ⫾ 0.40 39.9 ⫾ 16.9 62.9 ⫾ 15.7 43.8 ⫾ 11.0 11.27 ⫾ 4.7 26.5 (7.4-60.1) 53.1 ⫾ 17.5 19.1 ⫾ 18

Data are presented as No. (%), mean ⫾ SD, or median (interquartile range), unless indicated otherwise. GOLD 5 Global Initiative for Chronic Obstructive Lung Disease. aLung function values represent postbronchodilator spirometric results obtained during the recovery phase; all other characteristics were assessed on admission. bCharlson condition and age-related score 5 Charlson comorbidity score. cEchocardiography results available for 123 patients.

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or cardiovascular disease (bronchial carcinoma in one, colon diverticulitis in two, ischemic colitis in one, and Staphylococcus aureus endocarditis in one). MR-proANP Plasma Levels at Exacerbation, Recovery, and Stable Phase and Correlation to Patient’s Characteristics MR-proANP plasma levels at exacerbation, recovery, and stable phase were 95.9 pmol/L (52.5-166.3), 80.0 pmol/L (53.7-130.5), and 81.5 pmol/L (58.5-116.8), respectively (Fig 1). Compared with the recovery and stable phase, MR-proANP was significantly elevated on admission (P5 .004 for the comparison among all time points). MR-proANP levels in the recovery phase and in the stable phase were similar (P 5 .539). Spearman correlation coefficients for patients’ characteristics and MR-proANP levels on hospital admission are shown in Table 2. MR-proANP on admission correlated significantly with Charlson comorbidity score, C-reactive protein, FEV1% predicted, and left ventricular ejection fraction. Moreover, the presence of cardiopathy and renal failure was significantly associated with higher MR-proANP values at admission (P , .0001 for both). MR-proANP Plasma Levels and the Need for ICU on Admission and Recurrence of Exacerbation Requiring Hospital Admission Within 2 Years Median MR-proANP values in patients requiring intensive care did not differ significantly from those in patients treated in the medical ward (146.5 pmol/L [88-296.5] vs 101 pmol/L [59.4-180 pmol/L], P5 .086). Patients presenting a recurrence of severe exacerba-

tion and those remaining recurrence free within 2 years of the initial exacerbation had similar median MR-proANP values on admission (102 pmol/L [52.3-147] vs 101 pmol/L [55.3-197], P 5 .603). MR-proANP Plasma Levels on Admission and Probability of 2-Year Survival MR-proANP levels on hospital admission for exacerbation were significantly higher in long-term nonsurvivors compared with long-term survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001) (Fig 2). This difference was also significant for patients who died within 6 months of exacerbation (189.5 pmol/L [125.8-169.8] vs 101 pmol/L [52.4-172], P5 .001). The probability of survival across MR-proANP quartiles on admission was estimated with the Kaplan-Meier method. Mortality differed significantly across MR-proANP quartiles (log rank P , .0001) (Fig 3). Using a univariate Cox regression model, we evaluated the prognostic value of MR-proANP and clinical and laboratory parameters on hospital admission to predict 2-year survival following hospitalization for exacerbation (Table 3). Charlson condition and age-related score, Paco2, and MR-proANP levels on admission were associated with 2-year survival, whereas no association was found for BMI, Pao2, leukocyte counts, C-reactive protein, FEV1% predicted, and presence of pulmonary hypertension. In the multivariate Cox regression model analysis, both MR-proANP and Paco2 remained independent predictors of 2-year survival (Table 4). Discussion

Figure 1. Log MR-proANP at exacerbation, recovery, and stable state of the disease. At exacerbation, MR-proANP plasma levels were significantly elevated (95.9 pmol/L [52.5-166.3]) compared with the recovery (80.0 pmol/L [53.7-130.5]) and stable phase (81.5 pmol/L [58.5-116.8], P 5 .004 for the comparison among all time points). Levels in the recovery phase and in the stable phase were similar (P 5 .539). 䊉 5 outliners, *5 extreme values. MR-proANP 5 midregional proatrial natriuretic peptide.

In this study, we report three major findings: First, MR-proANP plasma levels are elevated in patients hospitalized for exacerbation of COPD compared with during the recovery and the stable phase of the disease. Second, MR-proANP levels at exacerbation are increased in long-term nonsurvivors compared with survivors, and the probability of survival markedly differs across MR-proANP quartiles. Third, MR-proANP and Paco2 are independent predictors of 2-year survival in patients with COPD. Several clinical and laboratory parameters have been proposed as prognostic markers of morbidity and mortality at exacerbation but their predictive value has varied across studies. A growing number of reports have shown that ANP levels are elevated in patients hospitalized with inflammatory and infectious conditions29-32 and lower respiratory tract infections.16,29,33-35 To the best of our knowledge, the current study is the first to report on the prognostic value of MR-proANP in the exacerbation of COPD.

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Table 2—Spearman’s r Correlation Between Clinical and Laboratory Markers and Plasma MR-proANP on Hospital Admission r Coefficient

Parameter Charlson condition and age-related score Pack-years Duration of COPD, mo Body temperature, °C Heart rate, beats/min Respiratory rate, breaths/min Pao2, mm Hg Paco2, mm Hg Leukocytes, 3 109 C-reactive protein, 3 109/L FEV1, % predicted LVEF, % Pulmonary artery pressure, mm Hg

P Value

0.641

, .0001

20.061 0.084 0.055 0.001 0.07 0.091 0.12 0.087 0.162 0.248 20.313 0.125

.435 .283 .478 .987 .368 .306 .177 .267 .037 .004 , .0001 .168

LVEF 5 left ventricular ejection fraction; MR-proANP 5 midregional proatrial natriuretic peptide.

The stimuli leading to increased MR-proANP levels in exacerbation of COPD might be manifold. IL-6 is suggested as representing an important link between ANP release and COPD-related conditions, such as infection and aggravation of pulmonary hypertension.35 In bacterial infection, IL-6 correlated strongly with plasma ANP, and IL-6 infusion increased ANP gene expression in cardiac myocytes.32,36,37 Patients with pulmonary hypertension related to COPD have increased plasma IL-6 values.38 In this context, experimental data demonstrated that ANP has pulmonary

Figure 2. MR-proANP values at exacerbation of COPD in 2-year survivors and nonsurvivors. MR-proANP levels at exacerbation were significantly higher in long-term nonsurvivors compared with long-term survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001). See Figure 1 legend for expansion of abbreviation. www.chestpubs.org

vasorelaxant activity.39 IV ANP application has led to acute, partial reversibility of increased pulmonary vascular resistance and a reduction in pulmonary arterial pressures in patients with COPD.15 Thus, we postulate that ANP secretion could be stimulated by IL-6 release from the human pulmonary artery smooth muscle cells to counteract the pulmonary artery vasoconstriction related to the exacerbation of COPD. Distension of the right atrium, a typical feature of pulmonary hypertension, is aggravated by hypoxia and leads to an increase in plasma ANP levels.22 In contrast, in patients with chronic lung disease but normal pulmonary hemodynamics, plasma ANP concentrations remain low despite chronic hypoxia.22 This suggests that hypoxia itself does not influence ANP release. Accordingly, we did not find a significant correlation between MR-proANP and Pao2 in exacerbation of COPD. It is worth noting that hypoxia induced by exercise leads to increased ANP levels in healthy subjects, suggesting different links among hypoxia, pulmonary artery vasoconstriction, and an increase in ANP between healthy subjects and patients with COPD.22 Interestingly, hypoxemia did not remain an independent predictor of hospitalization in the Cox proportional-hazards model in a study assessing predictors of hospitalization for exacerbation in patients with COPD.40 According to recent data from the Towards a Revolution in COPD Health (TORCH) study, which investigated cause-specific mortality in a large cohort of patients with COPD, 30% of deaths were attributable to cardiac causes and 40% of deaths were related to COPD.41 Similarly, in our study, 84% of the patients who died during the follow-up of 2 years died from a respiratory (51%) or cardiovascular disorder (32%). These data underline the significance of cardiovascular disease in patients with COPD and suggest well-recognized prognostic biomarkers of heart disease (eg, BNP) as potential prognostic biomarkers in a COPD population. We demonstrated that BNP plasma levels were significantly elevated during exacerbation compared with recovery, and accurately predicted the need for ICU care, but failed to predict short- and long-term mortality in patients with exacerbation of COPD.42 Although BNP summarizes the extent of left ventricular systolic and diastolic impairment, ANP seems to be more specific for assessing right-sided heart, and particularly atrial, dysfunction. The results of our study suggest that MR-proANP plasma levels correlate better with the pulmonary vascular changes that characterize COPD. Interestingly, and in contrast to BNP, MR-proANP values in patients requiring ICU care for exacerbation were similar to those in patients treated in the medical ward. It is possible to hypothesize that patients with manifested left-sided heart failure in CHEST / 140 / 1 / JULY, 2011

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Figure 3. Kaplan-Meier probability of survival over 720 days after admission across MR-proANP quartiles. ProANP 5 proatrial natriuretic peptide. See Figure 1 legend for expansion of the other abbreviation.

addition to COPD have been admitted to the ICU more often; however, this discrepancy should be analyzed in further studies. Table 3—Univariate Cox Regression Analysis for the Association Between Clinical and Laboratory Parameters on Hospital Admission and 2-y Mortality in Patients Hospitalized for Exacerbation of COPD Characteristics Charlson condition and age-related score Male gender BMI Pack-years Exacerbation in previous year, No. History of cardiopathy Antibiotics use current exacerbation Anthonisen criteria Leukocytes, 3 109 C-reactive protein 3 109/L FEV1% predicted LVEF , 40% PAP . 35 mm Hg Log Pao2, mm Hg Log Paco2, mm Hg Log MR-proANP, pmol/L

Hazard Ratio

95% CI

P Value

1.289

1.175-1.414

.001

0.824 0.998 1.006 1.155

0.428-1.519 0.932-1.068 0.995-1.117 0.988-1.351

.564 .944 .277 .071

1.605 1.806

0.837-3.076 0.892-3.656

.154 .100

1.089 0.96 0.998 0.985 0.261 0.907 0.276 22.591 2.385

0.754-1.074 .649 0.885-1.043 .336 0.001-1.005 .547 0.966-1.005 .141 0.036-1.917 .187 0.371-2.219 .831 0.049-1.564 .146 5.296-96.360 , .0001 1.642-3.464 .001

PAP 5 pulmonary arterial pressure. See Tables 1 and 2 for expansion of other abbreviations.

In the multivariate Cox regression analysis, Paco2 and MR-proANP were independent predictors of 2-year mortality in patients with exacerbation of COPD. Short- and long-term respiratory failure with rise of Paco2 was shown previously to be an important prognostic factor following severe exacerbation of COPD.8,40,43,44 Kessler et al40 reported Paco2 and pulmonary arterial pressure to be independent predictors of short-term hospitalization in a cohort of 64 patients with moderate to severe COPD at exacerbation. Of note, even moderate hypercapnia appeared to be associated with a higher reexacerbation risk. In line with these findings, short- and long-term mortality was significantly higher in patients with Paco2 . 50 mm Hg (P5 .025 and P , .0001, respectively) in the present cohort, in which hypercapnia was moderate in most patients (range, 28-96 mm Hg). Moderate hypercapnia at exacerbation, suggestive of ventilation-perfusion mismatch with or without alveolar hypoventilation, might identify patients who easily downplay their respiratory conditions and therefore develop acute respiratory failure.40 Unfortunately, we cannot infer whether the prognosis differs between patients who remain hypercapnic after resolution of the short-term episode and those with reversible hypercapnic respiratory failure, because blood gas analyses were obtained at exacerbation only.45 In contrast to previous studies evaluating patients with severe COPD, our study did

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Table 4—Multivariate Cox Regression Analysis for the Association Between Clinical and Laboratory Parameters on Hospital Admission and 2-y Mortality in Patients Hospitalized for Exacerbation of COPD Characteristics

Hazard Ratio

Charlson condition and age-related score Log Paco2 Log MR-proANP

95% CI

P Value

1.122

0.994-1.266

.063

11.537 1.681

2.434-54.694 1.037-2.726

.002 .035

See Table 2 for expansion of abbreviations.

not demonstrate that pulmonary hypertension is associated with mortality following severe exacerbation.40,46,47 However, in the current study, pulmonary arterial pressures were assessed solely by echocardiography, whereas in the series by Kessler et al,40 all patients underwent right-sided heart catheterization both at rest and during a steady-state exercise at exacerbation. It may be hypothesized that an invasive evaluation could have produced similar results in the present cohort. Some limitations should be considered in interpreting our results. First, this is an observational study and, therefore, hypothesis generating. The data were collected in a single center and only in patients who were hospitalized consecutively. The demographics of our COPD cohort are comparable to those of previously published studies analyzing patients with severe exacerbation of COPD.8,43,48 The mortality rate reported in this study fits well in the lower range of the one described previously.49-51 However, the results might not be applicable to patients with exacerbation treated as outpatients. The representative study population and the long observational period lasting until 2 years after the initial hospitalization are advantages of our study.

Conclusions In conclusion, our results support the long-term prognostic value of MR-proANP plasma level on hospital admission in patients with exacerbation of COPD. Studies are needed to evaluate whether an MR-proANP guided-approach is able to influence survival in the COPD population.

Acknowledgments Author contributions: All authors reviewed and approved the final manuscript. Dr Bernasconi: contributed to data analysis and writing of the manuscript. Dr Tamm: contributed to the study concept, study design, data analysis, and drafting the manuscript for important intellectual content. www.chestpubs.org

Dr Bingisser: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Miedinger: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Leuppi: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Müller: contributed to data collection and drafting the manuscript for important intellectual content. Dr Christ-Crain: contributed to data collection drafting the manuscript for important intellectual content. Dr Stolz: contributed to the study concept, study design, data analysis, and drafting the manuscript for important intellectual content. 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 sponsors of this investigator-initiated project had no involvement in design and conduct of the study, collection, management, analysis, and interpretation of the data, nor in the preparation, review, and approval of the manuscript or decision to submit the manuscript.

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