Original Research Cardiology 2015;131:116–121 DOI: 10.1159/000375398
Received: October 12, 2014 Accepted after revision: January 16, 2015 Published online: April 21, 2015
Prognostic Value of Serial Brain Natriuretic Peptide Measurements in Patients with Acute Myocardial Infarction Antonio E.P. Pesaro a Marcelo Katz a Adriano Caixeta a Márcia R. Makdisse a Alessandra G. Correia a Carolina Pereira a Marcelo Franken a Anderson N. Fava a Carlos V. Serrano Jr. a, b a Hospital Israelita Albert Einstein, and b Instituto do Coração de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Abstract Objectives: Elevated B-type natriuretic peptide (BNP) levels following acute myocardial infarction (AMI) are associated with adverse outcomes. The role of serial BNP monitoring after AMI has been poorly investigated. We aimed to evaluate the prognostic value of in-hospital serial BNP measurements in AMI patients. Methods: Patients with AMI (n = 1,924) were retrospectively evaluated. We selected patients with at least 2 in-hospital BNP measurements. The association between in-hospital mortality and BNP measurements (earliest, highest follow-up and the variation between measurements) were tested in multivariate models. Results: Serial BNP levels were determined in 176 patients. Compared to the rest of the population, these patients were older and had higher mortality rates. In the adjusted models, only the highest follow-up BNP remained associated with in-hospital death (odds ratio 1.06; 95% confidence interval, CI, 1.01– 1.15; p = 0.014). Receiver-operating characteristic curve analysis demonstrated that the highest follow-up BNP was the best predictor of in-hospital death (area under the
© 2015 S. Karger AG, Basel 0008–6312/15/1312–0116$39.50/0 E-Mail [email protected] www.karger.com/crd
curve = 0.75; 95% CI 0.64–0.86). Conclusions: Serial BNP monitoring was performed in a high-risk subgroup of AMI patients. The highest follow-up BNP was a better predictor of short-term death than the baseline and in-hospital variation values. In AMI patients, a later in-hospital BNP assessment may be more useful than an early measurement. © 2015 S. Karger AG, Basel
Introduction
In patients with acute myocardial infarction (AMI), early risk stratification is based on clinical and laboratory parameters. Biochemical markers of myocardial necrosis are routinely used to perform risk stratification and guide appropriate medical and interventional treatment [1, 2]. In addition, the prognostic value of alternative biomarkers, such as the natriuretic peptides (NPs), has been investigated extensively in AMI patients [3–5]. The B-type natriuretic peptide (BNP) and the aminoterminal portion of the prohormone of this peptide (NTproBNP) have been widely used in clinical practice to assess the differential diagnosis of dyspnea and to diagnose and stratify heart failure patients [6]. In AMI patients, increases in NPs reflect ventricular stretch and remodelAntonio E.P. Pesaro Hospital Israelita Albert Einstein, Programa de Cardiologia Avenida Albert Einstein, 627/701, Pavilhão Vicky e Joseph Safra, Bloco A1, 4° andar São Paulo, SP 05652-901 (Brazil) E-Mail antonioepp @ einstein.br
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/14/2015 8:46:14 AM
Key Words Acute myocardial infarction · B-type natriuretic peptide · Prognostic
Materials and Methods Population Study This study was an observational, retrospective study of data from a single-center registry of consecutively enrolled AMI patients with ST segment elevation and non-ST segment elevation (n = 1,924) that was performed at the Hospital Israelita Albert Einstein (São Paulo, Brazil) from 2004 to 2012. The registry design, the methods and the principal results have been reported previously [14]. AMI was defined according to the criteria described in international guidelines [15]: a typical rise and gradual fall (troponin) or a more rapid rise and fall (muscle and brain creatine kinase) of biochemical markers of myocardial necrosis, with at least 1 of the following parameters: (a) ischemic symptoms; (b) the development of pathologic Q waves on the electrocardiogram; (c) electrocardiogram changes indicative of ischemia (i.e. ST segment elevation or depression), or (d) coronary artery intervention (e.g. coronary angioplasty). A team of research nurses was specifically designated to measure all variables included in this registry. BNP levels were determined for clinical purposes when requested by the attending physician. As part of the present analysis, we included patients with at least 2 BNP measurements. These measurements occurred as follows: (1) in the first week after AMI,
Serial Natriuretic Peptides in Acute Myocardial Infarction
with the earliest BNP value considered the baseline value, and (2) the highest or peak BNP during the 15 days following the baseline measurement, which was considered the highest follow-up BNP. The BNP variation was considered to be the change between the baseline and the highest follow-up measurement. The number of BNP measurements during the analyzed period was also registered. The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Hospital Israelita Albert Einstein under the protocol No. 1991.6813.0000.00071. The study was granted a waiver for informed consent. Measurement of NP Venous blood samples were drawn from the antecubital vein into standard EDTA tubes. The samples were centrifuged, and the plasma was removed and frozen at –70 ° C until the time of analysis. Plasma BNP concentrations were measured quantitatively using the ADVIA Centaur BNP chemiluminescence immunoassay (Siemens Healthcare Diagnostics, Tarrytown, N.Y., USA).
Statistical Analysis and End Point Clinical characteristics, in-hospital death and length of hospital stay were compared between patients with and without serial BNP measurements. Among the subgroup with serial BNP measurements, clinical characteristics were compared between survivors and nonsurvivors. Continuous variables are described as the mean ± standard deviation or the median with the interquartile range (IQR). Categorical variables are described according to absolute and relative frequencies. Student’s t test and the Mann-Whitney test were used to compare numerical variables as appropriate, and the χ2 test was used to compare categorical variables. The following variables were selected for the present analysis: the lowest in-hospital left ventricular ejection fraction (LVEF), the lowest in-hospital creatinine levels and the baseline Killip classification measured in the first 24 h of admission for AMI. Adjusted logistic regression models (i.e. adjusted for age, peak troponin levels, LVEF and creatinine) were used to test the association between each BNP measurement (i.e. baseline, highest follow-up and variation) and inhospital death. The variables used in the adjusted model were selected based on statistical and clinical criteria. Receiver-operating characteristic curves were used to assess the predictive accuracy of the baseline BNP, the highest follow-up BNP and the variation in BNP. All statistical tests were 2-sided, and the criterion for statistical significance was a value of p < 0.05. All statistical analyses were performed using the SPSS statistical software (version 20.0; SPSS Inc., Chicago, Ill., USA).
Results
Serial BNP levels were determined in 176 patients (57% men, 78 ± 12 years of age, 32% ST elevation), which represented 9.2% of the entire population. Compared to the subgroup without serial BNP measurements, patients with serial BNP measurements were older (67 ± 15 vs. 78 ± 12 years; p < 0.001), less often male (72 vs. 57%; p < Cardiology 2015;131:116–121 DOI: 10.1159/000375398
117
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/14/2015 8:46:14 AM
ing related to necrosis and are associated with short- and long-term adverse outcomes [3, 4]. Conversely, the importance of serial NP monitoring remains a subject of debate in several clinical settings. In acute and chronic heart failure patients, serial NP measurements may identify clinical refractoriness and poor prognosis [7]. However, whether serial NP measurement may also guide therapeutic management and drug titration in patients with heart failure remains controversial [8, 9]. In AMI patients, the value of serial NP measurements has been poorly investigated, particularly in real world cohorts. A few small trials investigated the role of serial NP monitoring after hospital discharge and demonstrated associations between NP levels and ventricular remodeling and adverse outcomes [10, 11]. Two larger studies reported that in AMI patients with non-ST segment elevation, the absence of an early decrease (i.e.
Received: October 12, 2014 Accepted after revision: January 16, 2015 Published online: April 21, 2015
Prognostic Value of Serial Brain Natriuretic Peptide Measurements in Patients with Acute Myocardial Infarction Antonio E.P. Pesaro a Marcelo Katz a Adriano Caixeta a Márcia R. Makdisse a Alessandra G. Correia a Carolina Pereira a Marcelo Franken a Anderson N. Fava a Carlos V. Serrano Jr. a, b a Hospital Israelita Albert Einstein, and b Instituto do Coração de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Abstract Objectives: Elevated B-type natriuretic peptide (BNP) levels following acute myocardial infarction (AMI) are associated with adverse outcomes. The role of serial BNP monitoring after AMI has been poorly investigated. We aimed to evaluate the prognostic value of in-hospital serial BNP measurements in AMI patients. Methods: Patients with AMI (n = 1,924) were retrospectively evaluated. We selected patients with at least 2 in-hospital BNP measurements. The association between in-hospital mortality and BNP measurements (earliest, highest follow-up and the variation between measurements) were tested in multivariate models. Results: Serial BNP levels were determined in 176 patients. Compared to the rest of the population, these patients were older and had higher mortality rates. In the adjusted models, only the highest follow-up BNP remained associated with in-hospital death (odds ratio 1.06; 95% confidence interval, CI, 1.01– 1.15; p = 0.014). Receiver-operating characteristic curve analysis demonstrated that the highest follow-up BNP was the best predictor of in-hospital death (area under the
© 2015 S. Karger AG, Basel 0008–6312/15/1312–0116$39.50/0 E-Mail [email protected] www.karger.com/crd
curve = 0.75; 95% CI 0.64–0.86). Conclusions: Serial BNP monitoring was performed in a high-risk subgroup of AMI patients. The highest follow-up BNP was a better predictor of short-term death than the baseline and in-hospital variation values. In AMI patients, a later in-hospital BNP assessment may be more useful than an early measurement. © 2015 S. Karger AG, Basel
Introduction
In patients with acute myocardial infarction (AMI), early risk stratification is based on clinical and laboratory parameters. Biochemical markers of myocardial necrosis are routinely used to perform risk stratification and guide appropriate medical and interventional treatment [1, 2]. In addition, the prognostic value of alternative biomarkers, such as the natriuretic peptides (NPs), has been investigated extensively in AMI patients [3–5]. The B-type natriuretic peptide (BNP) and the aminoterminal portion of the prohormone of this peptide (NTproBNP) have been widely used in clinical practice to assess the differential diagnosis of dyspnea and to diagnose and stratify heart failure patients [6]. In AMI patients, increases in NPs reflect ventricular stretch and remodelAntonio E.P. Pesaro Hospital Israelita Albert Einstein, Programa de Cardiologia Avenida Albert Einstein, 627/701, Pavilhão Vicky e Joseph Safra, Bloco A1, 4° andar São Paulo, SP 05652-901 (Brazil) E-Mail antonioepp @ einstein.br
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/14/2015 8:46:14 AM
Key Words Acute myocardial infarction · B-type natriuretic peptide · Prognostic
Materials and Methods Population Study This study was an observational, retrospective study of data from a single-center registry of consecutively enrolled AMI patients with ST segment elevation and non-ST segment elevation (n = 1,924) that was performed at the Hospital Israelita Albert Einstein (São Paulo, Brazil) from 2004 to 2012. The registry design, the methods and the principal results have been reported previously [14]. AMI was defined according to the criteria described in international guidelines [15]: a typical rise and gradual fall (troponin) or a more rapid rise and fall (muscle and brain creatine kinase) of biochemical markers of myocardial necrosis, with at least 1 of the following parameters: (a) ischemic symptoms; (b) the development of pathologic Q waves on the electrocardiogram; (c) electrocardiogram changes indicative of ischemia (i.e. ST segment elevation or depression), or (d) coronary artery intervention (e.g. coronary angioplasty). A team of research nurses was specifically designated to measure all variables included in this registry. BNP levels were determined for clinical purposes when requested by the attending physician. As part of the present analysis, we included patients with at least 2 BNP measurements. These measurements occurred as follows: (1) in the first week after AMI,
Serial Natriuretic Peptides in Acute Myocardial Infarction
with the earliest BNP value considered the baseline value, and (2) the highest or peak BNP during the 15 days following the baseline measurement, which was considered the highest follow-up BNP. The BNP variation was considered to be the change between the baseline and the highest follow-up measurement. The number of BNP measurements during the analyzed period was also registered. The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Hospital Israelita Albert Einstein under the protocol No. 1991.6813.0000.00071. The study was granted a waiver for informed consent. Measurement of NP Venous blood samples were drawn from the antecubital vein into standard EDTA tubes. The samples were centrifuged, and the plasma was removed and frozen at –70 ° C until the time of analysis. Plasma BNP concentrations were measured quantitatively using the ADVIA Centaur BNP chemiluminescence immunoassay (Siemens Healthcare Diagnostics, Tarrytown, N.Y., USA).
Statistical Analysis and End Point Clinical characteristics, in-hospital death and length of hospital stay were compared between patients with and without serial BNP measurements. Among the subgroup with serial BNP measurements, clinical characteristics were compared between survivors and nonsurvivors. Continuous variables are described as the mean ± standard deviation or the median with the interquartile range (IQR). Categorical variables are described according to absolute and relative frequencies. Student’s t test and the Mann-Whitney test were used to compare numerical variables as appropriate, and the χ2 test was used to compare categorical variables. The following variables were selected for the present analysis: the lowest in-hospital left ventricular ejection fraction (LVEF), the lowest in-hospital creatinine levels and the baseline Killip classification measured in the first 24 h of admission for AMI. Adjusted logistic regression models (i.e. adjusted for age, peak troponin levels, LVEF and creatinine) were used to test the association between each BNP measurement (i.e. baseline, highest follow-up and variation) and inhospital death. The variables used in the adjusted model were selected based on statistical and clinical criteria. Receiver-operating characteristic curves were used to assess the predictive accuracy of the baseline BNP, the highest follow-up BNP and the variation in BNP. All statistical tests were 2-sided, and the criterion for statistical significance was a value of p < 0.05. All statistical analyses were performed using the SPSS statistical software (version 20.0; SPSS Inc., Chicago, Ill., USA).
Results
Serial BNP levels were determined in 176 patients (57% men, 78 ± 12 years of age, 32% ST elevation), which represented 9.2% of the entire population. Compared to the subgroup without serial BNP measurements, patients with serial BNP measurements were older (67 ± 15 vs. 78 ± 12 years; p < 0.001), less often male (72 vs. 57%; p < Cardiology 2015;131:116–121 DOI: 10.1159/000375398
117
Downloaded by: Freie Universität Berlin 130.133.8.114 - 5/14/2015 8:46:14 AM
ing related to necrosis and are associated with short- and long-term adverse outcomes [3, 4]. Conversely, the importance of serial NP monitoring remains a subject of debate in several clinical settings. In acute and chronic heart failure patients, serial NP measurements may identify clinical refractoriness and poor prognosis [7]. However, whether serial NP measurement may also guide therapeutic management and drug titration in patients with heart failure remains controversial [8, 9]. In AMI patients, the value of serial NP measurements has been poorly investigated, particularly in real world cohorts. A few small trials investigated the role of serial NP monitoring after hospital discharge and demonstrated associations between NP levels and ventricular remodeling and adverse outcomes [10, 11]. Two larger studies reported that in AMI patients with non-ST segment elevation, the absence of an early decrease (i.e.
