Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBC89MLPTCVyBGnh7CBvMbv6gNS0066-782X2016000300218S0066-782X201600500510310.5935/abc.20160021Original ArticlesVery Long-Term Prognostic Role of Admission BNP in Non-ST Segment Elevation Acute Coronary SyndromeBassanFernando12BassanRoberto3EsporcatteRoberto14SantosBraulio5TuraBernardo5Universidade do Estado do Rio de JaneiroRio de JaneiroRJBrazilUniversidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ - BrazilUniversidade do Estado do Rio de JaneiroInstituto Nacional de CardiologiaDepartamento de CoronariopatiaRio de JaneiroRJBrazilDepartamento de Coronariopatia - Instituto Nacional de Cardiologia, Rio de Janeiro, RJ - BrazilPontíficia Universidade Católica do Rio de JaneiroRio de JaneiroRJBrazilPontíficia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ - BrazilPontifícia Universidade Católica do Rio de JaneiroHospital Pró-CardíacoRio de JaneiroRJBrazilHospital Pró-Cardíaco, Rio de Janeiro, RJ - BrazilHospital Pró-CardíacoInstituto Nacional de CardiologiaDepartamento de Pesquisa ClínicaRio de JaneiroRJBrazilDepartamento de Pesquisa Clínica - Instituto Nacional de Cardiologia, Rio de Janeiro, RJ - BrazilMailing Address: Fernando Bassan, Instituto Nacional de Cardiologia - Rua das Laranjeiras, 374. Postal Code 22240-006, Rio de Janeiro, RJ - Brazil. E-mail: fbassan@globo.com
Author contributions
Conception and design of the research, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Bassan F, Bassan R, Esporcatte R; Acquisition of data: Bassan F, Bassan R; Analysis and interpretation of the data and Statistical analysis: Bassan F, Bassan R, Esporcatte R, Santos B, Tura B.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Study Association
This article is part of the thesis of master submitted by Fernando Bassan, from Universidade do Estado do Rio de Janeiro.
02022016320161063218225080620151310201514102015This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractBackground:
BNP has been extensively evaluated to determine short- and intermediate-term prognosis in patients with acute coronary syndrome, but its role in long-term mortality is not known.
Objective:
To determine the very long-term prognostic role of B-type natriuretic peptide (BNP) for all-cause mortality in patients with non-ST segment elevation acute coronary syndrome (NSTEACS).
Methods:
A cohort of 224 consecutive patients with NSTEACS, prospectively seen in the Emergency Department, had BNP measured on arrival to establish prognosis, and underwent a median 9.34-year follow-up for all-cause mortality.
Results:
Unstable angina was diagnosed in 52.2%, and non-ST segment elevation myocardial infarction, in 47.8%. Median admission BNP was 81.9 pg/mL (IQ range = 22.2; 225) and mortality rate was correlated with increasing BNP quartiles: 14.3; 16.1; 48.2; and 73.2% (p < 0.0001). ROC curve disclosed 100 pg/mL as the best BNP cut-off value for mortality prediction (area under the curve = 0.789, 95% CI= 0.723-0.854), being a strong predictor of late mortality: BNP < 100 = 17.3% vs. BNP ≥ 100 = 65.0%, RR = 3.76 (95% CI = 2.49-5.63, p < 0.001). On logistic regression analysis, age >72 years (OR = 3.79, 95% CI = 1.62-8.86, p = 0.002), BNP ≥ 100 pg/mL (OR = 6.24, 95% CI = 2.95-13.23, p < 0.001) and estimated glomerular filtration rate (OR = 0.98, 95% CI = 0.97-0.99, p = 0.049) were independent late-mortality predictors.
Conclusions:
BNP measured at hospital admission in patients with NSTEACS is a strong, independent predictor of very long-term all-cause mortality. This study allows raising the hypothesis that BNP should be measured in all patients with NSTEACS at the index event for long-term risk stratification.
In spite of the large knowledge gathered in the last few decades in identifying clinical and laboratory variables to determine short- and intermediate-term prognosis in patients with acute coronary syndrome (ACS),1-5 their long-term prediction capability remains mostly unknown. B-type natriuretic peptides (BNP) are one of these markers and have been extensively evaluated for this purpose with very good performance,6-10 but no study has dealt with their value in correctly identifying those individuals at high risk of death in the very long-term.
We had the opportunity to prospectively, systematically collect clinical and laboratory data in a cohort of patients examined in the Chest Pain Unit of an Emergency Department, to whom a comprehensive diagnostic and risk-stratification protocol was used.11 Several clinical and laboratory markers were evaluated upon admission to establish the diagnosis of ACS. Patients were then treated accordingly and followed up to determine their long-term natural history. The aim of this study was to determine the prognostic role of the admission BNP level in the 10-year all-cause mortality of those individuals who had a final diagnosis of non-ST segment elevation ACS (NSTEACS).
MethodsStudy population and data collection
We prospectively studied 723 consecutive patients seen in the Emergency Department of the Pró-Cardíaco Hospital, a private, tertiary, cardiology-oriented institution in Rio de Janeiro, Brazil, between January 1st, 2002, and December 31st, 2003. They complained of chest pain or discomfort in the preceding 12 hours due to possible acute cardiac ischemia, and their admission electrocardiogram (ECG) showed no ST-segment elevation. These patients were routinely managed in the Chest Pain Unit with a systematic diagnostic protocol recommending the following: 1) cardiac markers: admission and serial (every 3 hours) creatine kinase-MB mass (CKMB) and/or troponin-I levels; 2) admission and serial ECG; 3) echocardiogram (in many patients); 4) if neither myocardial necrosis nor rest ischemia were detected, a stress test (either treadmill ECG or single-photon emission computed tomographic myocardial scintigraphy). Coronary angiography and revascularization procedure were performed at the discretion of the attending physician. TIMI risk score was calculated in all patients fulfilling the diagnosis of ACS. Based on the above work-up, 237 patients received a final diagnosis of NSTEACS, constituting the initial study population. Of these, 13 individuals were lost sometime during the 10-year follow-up. The remaining 224 patients represent the final study sample.
Patients with suspected (intermediate to high pretest probability) or straightforward admitting diagnosis of life-threatening disorders other than ACS, such as aortic dissection and pulmonary embolism, were also immediately submitted to appropriate imaging tests and, if confirmed, diverted from the above mentioned diagnostic pathway. These patients were excluded from this study.
For this prospective study, plasma BNP was incorporated into the diagnostic protocol and obtained on admission with the purpose of correlating BNP with the final discharge diagnosis and follow-up prognosis. BNP results were available to treating physicians. This study complies with the Declaration of Helsinki and its protocol was approved by the hospital ethics committee. All patients provided written informed consent.
Biochemical analysis
Plasma BNP was immediately analyzed on the same EDTA-anticoagulated blood sample collected on admission for troponin-I, using the quantitative immunofluorescence assay (Biosite, California, USA). The analytic sensitivity of the assay is less than 5 pg/mL and the upper normal limit is considered to be 100 pg/mL. Plasma troponin-I was measured by immunofluorescence assay (Dade-Behring, Marburg, Germany). The analytic sensitivity of the assay is 0.1 ng/mL and any value above this was considered diagnostic of non-ST-segment elevation myocardial infarction (NSTEMI) in this study.12,13 The coefficient of variation of the 99th percentile of the diagnostic value of the assay (0.1 ng/mL) is 10%.
Clinical data and diagnosis on hospital discharge
All demographic and clinical data were prospectively obtained on hospital admission and during Emergency Department and hospital stay until final diagnosis was reached. NSTEMI was diagnosed when a troponin-I level above 0.1 ng/mL in any sample was found during the first 9 post-admission hours with a rise and/or fall pattern afterwards, with or without ST-T changes on ECG, in the absence of any other demonstrable cause for the chest pain. Unstable angina was diagnosed when, in the absence of the above troponin-I pattern, suggestive chest pain was associated with either transient ST-segment depression (≥ 0.1 mV) or T-wave inversion on ECG, pre-discharge ischemic stress test or significant coronary artery disease on angiography. Absence of ACS was diagnosed when complete diagnostic protocol was performed in the Chest Pain Unit and demonstrated neither myocardial necrosis nor ischemia. Patients who showed increased troponin-I levels after undergoing percutaneous coronary angioplasty were not considered to have myocardial infarction. TIMI risk score was calculated upon hospital admission and classified as low (0-2 points), intermediate (3-4 points) and high risk (5-7 points).
Clinical endpoints
After hospital discharge, the patients' clinical status was prospectively determined by programmed telephone calls at 1 month, 1 year and 10 years. When any clinical event was reported by the patient or close relative, the hospital chart was reviewed or the private physician was contacted to establish the type of event or death. The primary endpoint of the study was all-cause death. At 10 years, 13 patients (5.5%) were lost to follow-up.
Statistical analysis
All data analyses were performed using Stata Program 12.1 (StataCorp 2011). Plasma concentrations of BNP are described as median and interquartile (IQ) range. All sample measurements had their 95% confidence interval (CI) calculated according to the maximum likelihood estimation method. For all statistical analyses, a p-value ≤ 0.05 was considered significant.
Differences in proportions were assessed by using the chi-square method. The Mann-Whitney test was used to compare BNP levels between two independent groups (with or without 10-year all-cause death).
The bivariate analysis between BNP level quartiles and clinical variables and mortality was calculated by using the chi-square method for trend or the Fisher exact test.
Receiver operating characteristic (ROC) curves were generated and the area under the curve (and its 95% CI) was calculated to determine the best discriminating BNP level obtained on admission for predicting all-cause mortality.
Sensitivity, specificity, positive and negative predictive values, and 95% CI were calculated in the usual manner. Hazard ratio values were corrected when necessary to avoid calculation bias.
Cumulative 10-year survival was determined by the Kaplan-Meier method. Difference in survival according to BNP level was evaluated with a log-rank test and Cox proportional risk model.
Main effects logistic regression analyses were used to establish the predictive relationship between continuous or dichotomized BNP levels and mortality adjusted for the effects of clinical and laboratory variables. Initially, all significant variables identified on univariate analysis were included in the models. Variables were selected by use of the forward stepwise method guided by likelihood ratio, and respective c-statistics was calculated. Modeling was performed, refusing entry to variables with p > 0.10.
The increased discriminative value after addition of BNP to the established prognostic factors for 10-year mortality was estimated by using the integrated discrimination improvement (IDI) technique.14 IDI was calculated by analyzing the differences in patients' individual estimated probability of mortality after addition of BNP to a model containing the aforementioned established prognostic factors and represents the average improvement in predicted probability. Results were assessed by absolute and relative differences in discrimination values between models.
ResultsPatients characteristics
From this cohort of 224 consecutive NSTEACS patients, 107 (47.8%) had a final diagnosis of myocardial infarction and 117 (52.2%), of unstable angina. Demographic and clinical characteristics are depicted in Table 1. TIMI risk score could be calculated in 202 of the 224 NSTEACS patients, most of whom were classified either as low or intermediate risk.
Baseline clinical and laboratory data of 224 patients with non-ST elevation acute coronary syndrome
Table 2 demonstrates the relationship between BNP quartiles and clinical and laboratory findings in the 224 NSTEACS patients. It is noteworthy that there was a significant univariate direct relationship with admission BNP levels for most of these variables.
Relationship of clinical and laboratory data, final diagnosis and all-cause mortality rate with quartiles of BNP levels (in pg/mL)
1st quartile
2nd quartile
3rd quartile
4th quartile
(BNP < 22.2) n = 56
(BNP 22.2-81.9) n = 56
(BNP 82.0-225) n = 56
(BNP > 225)n = 56
p-value
Age (years) (IQ range)
60.5 (51.5; 71.5)
68.5 (58.5; 75)
73.0 (68; 81)
80.0 (73; 84)
p < 0.0001
Previous MI (%)
10 (17.9)
15 (26.8)
21 (37.5)
23 (41.1)
p = 0.0037
Previous use of aspirin (%)
16 (28.6)
23 (41.1)
29 (51.8)
19 (33.9)
p = 0.3594
Admission LV failure (%)
4 (7.3)
2 (3.6)
4 (7.1)
16 (28.6)
p = 0.0004
Admission ST-segment depression (%)
7.1 (4)
10.7 (6)
16.1 (9)
16.1 (9)
p = 0.1050
Admission TIMI Risk Score
Low Risk (TIMI 0-2) (%)
31 (58.5)
19 (38.8)
11 (22.9)
15 (28.8)
Intermediate Risk (TIMI 3-4) (%)
20 (37.7)
25 (51.0)
28 (58.3)
29 (55.8)
p = 0.0002
High Risk (TIMI 5-7) (%)
2 (3.8)
5 (10.2)
9 (18.8)
8 (15.4)
LV dysfunction on Echo (%)
9 (16.4)
16 (30.2)
21 (38.2)
36 (64.3)
p < 0.0001
Final diagnosis
Unstable angina (%)
60.7
64.3
55.4
28.6
p = 0.0004
NSTEMI (%)
39.3
35.7
44.6
71.4
p = 0.0004
All-cause death (%)
8 (14.3)
9 (16.1)
27 (48.2)
41 (73.2)
p < 0.0001
BNP- B: type natriuretic peptide; IQ: interquartile; MI: myocardial infarction; LV: left ventricle; Echo: echocardiogram; NSTEMI: non-ST elevation myocardial infarction.
During follow-up, 85 patients (37.9%) died in 10 years. Mortality rate increased progressively according to BNP quartiles levels, as depicted in Table 2. Patients who died were older at the index ACS event (79 vs 66 years, p < 0.001), had a worse mean estimated glomerular filtration rate (49.1 vs 80.5 mL/min, p < 0.001), presented more frequently with heart failure on admission (21.2 vs 5.8%, p = 0.001), had more frequently myocardial infarction on admission (61.2 vs 39.6%, p = 0.002) and had higher levels of admission BNP (220 vs 44.7 pg/mL, p < 0.001) than patients who survived.
Prognostic accuracy of BNP levels measured on admission
ROC curve analysis disclosed 100 pg/mL as the best prognostic cut-off value of BNP for 10-year all-cause mortality (area under the curve = 0.789, 95% CI = 0.723 - 0.854). Patients with BNP ≥ 100 pg/mL had a mortality rate of 65% vs 17.3% of those with BNP < 100 pg/mL (relative risk = 3.76, p < 0.001). Sensitivity, specificity, and positive and negative predictive values for mortality were 74.1%, 75.5%, 64.9% and 82.7%, respectively.
The median 10-year survival, as determined by use of the Kaplan-Meier method, was 5.80 years (IQ range = 2.55-9.44) for patients with admission BNP ≥ 100 pg/mL vs 9.63 years (IQ range = 9.04-10.13) for those with BNP < 100 pg/mL (p < 0.0001).
On a multivariate stepwise logistic regression analysis adjusted for all demographic and clinical variables known to be predictors of cardiac death or related to an elevated BNP level (including all variables from Tables 1 and 2), a BNP level of 100 pg/mL obtained upon Emergency Department admission was an independent predictor of 10-year death (Table 3).
Independent predictors of 10-year all-cause death by multivariate stepwise logistic regression analysis in patients with non-ST segment elevation acute coronary syndrome
Finally, when using the IDI technique, the addition of BNP information to the traditional risk variables improved prediction and produced an absolute discriminatory increase rate of 3.06% for 10-year mortality (Table 4). The relative discrimination improvement was 10% greater for 10-year mortality with the knowledge and use of BNP information as compared to no use.
Comparison of average risk and discrimination improvement using the traditional risk model and the B-type natriuretic peptide (BNP)-added model for 10-year mortality between patients who died (cases) and who survived (controls)
Information of BNP level further improved risk stratification of the 10-year mortality rate in all three levels of the TIMI risk score, as depicted in Figure 1. The Kaplan-Meier 10-year survival curves of the two levels of BNP value and the three levels of TIMI risk score are depicted in Figures 2 and 3, and clearly disclose a much better discriminative prognostic performance of BNP.
10-year all-cause mortality rates of non-ST segment elevation acute coronary syndrome patients according to the TIMI risk score levels (low = 0-2 points, intermediate = 3-4 points, high= 5-7 points) stratified by optimal C-statistics B-type natriuretic peptide (BNP) cut-off value (in pg/mL).
Kaplan-Meier survival curves of 224 patients with non-ST segment elevation acute coronary syndrome according to admission B-type natriuretic peptide (BNP) level.
Kaplan-Meier survival curves of 202 patients with non-ST segment elevation acute coronary syndrome according to TIMI risk score levels (low = 0-2 points, intermediate = 3-4 points, high = 5-7 points).
Discussion
Several cardiac biomarkers have been proposed and used in the last few decades for prognostic stratification of patients with ACS. The most used are the necrosis markers, specially troponins.4,5,15,16
Since the year 2000, the immediate- and short-term risk evaluation of cardiovascular outcomes in patients with ACS has been done with the TIMI1 and the GRACE17 risk scores as they are relatively easy to calculate at the bedside. It is important to remember that the TIMI risk score was originally tested for a 14-day follow-up; however, several authors have extrapolated its use for longer periods.18-20 Unfortunately these aggregates of risk factors lack good accuracy for 1-year follow-up as evaluated by the C-statistics of 0.5818 to 0.6919 for the TIMI and 0.7118 to 0.7919 for the GRACE risk scores. This knowledge has instigated the search for novel and more accurate markers of mortality prediction.10,21-25
BNP was initially found to be a very early and accurate biochemical marker of acute cardiac contractile dysfunction26-28 and has been also extensively studied in patients with myocardial ischemia and infarction.29-31 Its blood concentration increases immediately and rapidly after the beginning of cardiac hypoxia and correlates directly with the extension of myocardial ischemia.11,32,33 Lately, it has been found to be an excellent prognostic marker of cardiac outcomes in patients with ACS.6,8,9,34-38 However, most of these studies followed their patients for 1 year, and few of them did it for up to 4 years.36,39-40
The present study is the first to demonstrate that BNP measured on arrival at the Emergency Department is a strong and independent marker of all-cause death in patients with NSTEACS up to 10 years after the index event, even when compared to the TIMI Risk Score. Our population comes from a consecutive series of patients seen at the Emergency Department with acute chest pain to whom a systematic, careful, comprehensive diagnostic protocol for cardiac ischemia was applied, including the serial measurement of myocardial necrosis markers and ECG, as well as a single BNP sample obtained on admission. Patient's management was left at their private physicians discretion, but most of those with ACS were submitted to coronary angiography and revascularization if found necessary.
BNP was found to remain a powerful and independent marker of all-cause death in the long run in our NSTEACS study sample. BNP also had discriminatory power adding significant prognostic information beyond traditional risk variables for 10-year mortality as seen with the C-statistics. This was confirmed by use of the IDI tool that evaluates the absolute difference between predicted and observed outcome rates, thus representing predictive model's efficiency and consequently allowing comparison of two models. For 10-year mortality, IDI significantly improved outcome discrimination when BNP was used in the model as compared to not used (Table 4), allowing one more patient to obtain a correct outcome classification in a group of 33 individuals.
BNP added significant prognostic information to the TIMI Risk Score of these patients identifying lower and higher risk subgroups (Figure 1). Similar findings were previously demonstrated on a 6-month follow-up study by Bazzino et al.6 Contrary to BNP, the TIMI Risk Score itself could not accurately stratify patients for long-term mortality in our study (Figure 3).
Why an elevated BNP measured at an index ACS episode remains as a risk factor of all-cause mortality up to 10 years later is a matter of discussion. As BNP blood levels are not particularly predictive of recurrent fatal and nonfatal myocardial infarction,6,41 it seems unlikely that late mortality can be explained by a new episode of ACS. It may be speculated that its elevation represents a summation of two well-known prognostic markers in coronary artery disease, that is, the presence and extension of left ventricular ischemia and dysfunction.7,42,43 The findings of our study could be useful in treatment strategy decision as some authors have suggested that BNP-therapy-guided interventions might improve mortality after ACS.44,45
Limitations of the study
The present study sample is relatively small in comparison with other cited multicenter studies and originates from a single, private, cardiology-oriented institution. This study does not address the possible value of serial BNP measurements. The troponin assay used in this patient sample is of an older generation (non-high sensitive), although many institutions around the world still use it. It must be remembered that the biochemical diagnostic criteria of myocardial infarction have changed at least twice in the last decade.46,47
Conclusions
BNP measured on hospital admission in patients with NSTEACS remains a strong, independent predictor of very long-term all-cause mortality, corroborating its excellent risk-stratification capability seen in short- and intermediate-term follow-up studies. This study allows raising the hypothesis that BNP should be measured in all patients with NSTEACS at the index event for long-term risk stratification.
Acknowledgement
This study was partially funded by Hospital Pró-Cardíaco, Rio de Janeiro, Brazil, from where all the data were collected. This manuscript is part of the Master's thesis in Science of Fernando Bassan at the Cardiology Chair, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Brazil.
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Sources of Funding
There were no external funding sources for this study.
Artigos OriginaisPapel Prognóstico a Muito Longo Prazo do BNP de Admissão na Síndrome Coronariana Aguda sem Elevação do Segmento STBassanFernando12BassanRoberto3EsporcatteRoberto14SantosBraulio5TuraBernardo5Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ - BrasilDepartamento de Coronariopatia - Instituto Nacional de Cardiologia, Rio de Janeiro, RJ - BrasilPontíficia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ - BrasilHospital Pró-Cardíaco, Rio de Janeiro, RJ - BrasilDepartamento de Pesquisa Clínica - Instituto Nacional de Cardiologia, Rio de Janeiro, RJ - BrasilCorrespondência: Fernando Bassan, Instituto Nacional de Cardiologia - Rua das Laranjeiras, 374. Rio de Janeiro - RJ. CEP 22240-006, Rio de Janeiro, RJ - Brasil. E-mail: fbassan@globo.com
Contribuição dos autores
Concepção e desenho da pesquisa, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Bassan F, Bassan R, Esporcatte R; Obtenção de dados: Bassan F, Bassan R; Análise e interpretação dos dados e Análise estatística: Bassan F, Bassan R, Esporcatte R, Santos B, Tura B.
Potencial conflito de interesse
Declaro não haver conflito de interesses pertinentes.
Vinculação acadêmica
Este artigo é parte de Dissertação de Mestrado de Fernando Bassan pela Universidade do Estado do Rio de Janeiro.
ResumoFundamento:
O BNP foi exaustivamente avaliado para a determinação do prognóstico em curto e médio prazo em pacientes com síndrome coronariana aguda, mas o seu papel para a mortalidade a longo prazo é incerta.
Objetivo:
Determinar o papel prognóstico a muito longo prazo do peptídeo natriurético do tipo B (BNP) para a mortalidade por todas as causas em pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST (SCASSST).
Métodos:
Coorte de 224 pacientes consecutivos com SCASSST, prospectivamente atendidos no setor de emergência, em que se mediu o BNP na chegada para estabelecer o prognóstico ao longo do seguimento mediano de 9,34 anos para a mortalidade por todas as causas.
Resultados:
Diagnosticou-se angina instável em 52,2% e infarto do miocárdio sem supradesnivelamento do segmento ST em 47,8%. A mediana do BNP da admissão foi de 81,9 pg/mL (intervalo IQ = 22,2; 225) e a taxa de mortalidade correlacionou-se com quartis crescentes de BNP: 14,3; 16,1; 48,2; e 73,2% (p < 0,0001). A curva ROC revelou 100 pg/mL como o melhor ponto de corte de BNP para a predição de mortalidade (área sob a curva = 0,789, 95% CI = 0,723-0,854) sendo um forte preditor de mortalidade tardia: BNP < 100 = 17,3% vs. BNP ≥ 100 = 65,0%, RR = 3,76 (IC 95% = 2,49-5,63, p < 0,001). Na análise de regressão logística, idade>72 anos (OR = 3,79, IC 95% = 1,62-8,86, p = 0,002), BNP ≥ 100 pg/mL (OR = 6,24, IC 95% = 2,95-13,23, p < 0,001) e taxa de filtração glomerular estimada (OR = 0,98, IC 95% = 0,97-0,99, p = 0,049) foram preditores independentes de mortalidade tardia.
Conclusões:
O BNP medido na admissão hospitalar em pacientes com SCASSST é um forte preditor independente de mortalidade por todas as causas de muito longo prazo. Este estudo permite que se levante a hipótese de que o BNP deva ser medido em todos os pacientes com SCASSST no evento-índice para a estratificação de risco a longo prazo.
Palavras-chave:Peptídeo Natriurético Tipo B / mortalidadePrognósticoSíndrome Coronariana AgudaIsquemia MiocárdicaIntrodução
A despeito de todo o conhecimento acumulado nas últimas décadas sobre a identificação de variáveis clínicas e laboratoriais para a determinação de prognóstico a curto e médio prazo em pacientes com síndrome coronariana aguda (SCA),1-5 sua capacidade de predição a longo prazo permanece desconhecida. O peptídeo natriurético do tipo B (BNP) é um desses marcadores e mostrou muito bom desempenho na extensa avaliação para aquele propósito,6-10 embora nenhum estudo tenha investigado seu valor para a correta identificação daqueles indivíduos com alto risco de morte em muito longo prazo.
Este estudo coletou prospectiva e sistematicamente dados clínicos e laboratoriais em uma coorte de pacientes examinados na Unidade de Dor Torácica de um setor de emergência, tendo-se utilizado um protocolo abrangente de diagnóstico e estratificação de risco.11 Vários marcadores clínicos e laboratoriais foram avaliados quando da admissão para o diagnóstico de SCA. Os pacientes foram então tratados adequadamente e seguidos para a determinação de sua história natural a longo prazo. Este estudo teve por objetivo determinar o papel prognóstico do nível de BNP à admissão para a mortalidade em 10 anos por todas as causas desses indivíduos com diagnóstico final de SCA sem supradesnivelamento do segmento ST (SCASSST).
MétodosPopulação do estudo e coleta de dados
Este estudo avaliou prospectivamente 723 pacientes consecutivos atendidos no setor de emergência do Hospital Pró-Cardíaco, uma instituição privada, terciária, com foco em cardiologia, no Rio de Janeiro, Brasil, entre 1 de janeiro de 2002 e 31 de dezembro de 2003. Queixavam-se de desconforto ou dor torácica nas 12 horas anteriores, devida a provável isquemia cardíaca aguda, e, ao eletrocardiograma (ECG) de admissão, não apresentavam elevação do segmento ST. Esses pacientes foram tratados rotineiramente na Unidade de Dor Torácica com um protocolo sistemático de diagnóstico que recomendava o seguinte: 1) marcadores cardíacos: níveis admissionais e seriados (a cada 3 horas) de creatina quinase-MB massa (CKMB) e/ou troponina I; 2) ECG admissional e seriado; 3) ecocardiograma (em muitos pacientes); 4) caso não se detectem necrose miocárdica nem isquemia de repouso, realizar teste de esforço (ECG na esteira ou cintilografia miocárdica). Realizaram-se angiografia coronariana e revascularização a critério do médico assistente. Calculou-se o escore de risco TIMI para todos aqueles que atendessem aos critérios de diagnóstico de SCA. Com base nisso, 237 pacientes receberam o diagnóstico final de SCASSST, constituindo a população inicial do estudo. Desses, 13 foram perdidos nos 10 anos de seguimento. Os outros 224 pacientes representaram a amostra final do estudo.
Os pacientes com suspeita (de intermediária a alta probabilidade pré-teste) ou diagnóstico claro na admissão de distúrbio com ameaça de morte outro que não SCA, como dissecção aórtica e embolia pulmonar, foram imediatamente submetidos a exames de imagem adequados e, caso confirmado, foram desviados da via diagnóstica acima mencionada. Tais pacientes foram excluídos deste estudo.
Para este estudo prospectivo, a medida do BNP plasmático foi incorporada ao protocolo de diagnóstico e realizada na admissão com o propósito de correlacionar o BNP com o diagnóstico final de alta e prognóstico de seguimento. Os resultados de BNP foram disponibilizados para os médicos assistentes. Este estudo está de acordo com a Declaração de Helsinki, tendo seu protocolo sido aprovado pelo comitê de ética do hospital. Todos os pacientes assinaram o termo de consentimento livre e informado.
Análise bioquímica
O BNP plasmático foi imediatamente analisado na mesma amostra de sangue anticoagulado com EDTA colhido na admissão para troponina I, usando o ensaio quantitativo de imunofluorescência (Biosite, Califórnia, EUA). A sensibilidade analítica do teste é inferior a 5 pg/mL, sendo o limite superior de normalidade considerado 100 pg/mL. Mediu-se a troponina I plasmática através de imunofluorescência (Dade-Behring, Marburg, Alemanha). A sensibilidade analítica do teste é 0,1 ng/mL, sendo qualquer valor acima desse considerado diagnóstico de infarto do miocárdio sem supradesnivelamento de segmento ST (IMSSST) neste estudo.12,13 O coeficiente de variação do percentil 99 do valor diagnóstico do teste (0,1 ng/mL) é 10%.
Dados clínicos e diagnóstico na alta hospitalar
Todos os dados demográficos e clínicos foram obtidos prospectivamente na admissão hospitalar e durante permanência no setor de emergência e hospital até o estabelecimento do diagnóstico final. Diagnosticou-se IMSSST quando o nível de troponina I excedeu 0,1 ng/mL em alguma amostra nas primeiras 9 horas após a admissão, seguido de uma elevação e/ou queda, com ou sem alteração ST-T no ECG, na ausência de qualquer outra causa demonstrável para dor torácica. Diagnosticou-se angina instável quando, na ausência do padrão de troponina I já mencionado, dor torácica sugestiva associou-se a depressão transitória do segmento ST (≥ 0,1 mV) ou a inversão da onda T no ECG, ou a teste de esforço isquêmico antes da alta ou a significativa doença arterial coronariana na angiografia. Diagnosticou-se ausência de SCA quando o protocolo diagnóstico completo realizado na Unidade de Dor Torácica não demonstrou necrose nem isquemia miocárdica. Os pacientes que apresentaram elevação nos níveis de troponina I após angioplastia coronariana percutânea não foram considerados como tendo infarto do miocárdio. Calculou-se o escore de risco TIMI na admissão hospitalar, com a seguinte classificação: risco baixo, 0-2 pontos; intermediário, 3-4 pontos; e alto, 5-7 pontos.
Desfechos clínicos
Após a alta hospitalar, o status clínico dos pacientes foi prospectivamente determinado através de ligações telefônicas com 1 mês, 1 ano e 10 anos. Quando algum evento clínico foi relatado pelo paciente ou parente próximo, o prontuário médico foi revisto ou o médico particular contatado para estabelecer o tipo de evento ou morte. O desfecho primário do estudo foi morte por todas as causas. Após 10 anos, 13 pacientes (5,5%) foram perdidos no seguimento.
Análise estatística
Todas as análises de dados foram realizadas com o programa Stata 12.1 (StataCorp 2011). As concentrações plasmáticas de BNP foram descritas como mediana e intervalo interquartil (IQ). Para todas as medidas da amostra, calculou-se o intervalo de confiança (IC) a 95% de acordo com o método de estimativa da probabilidade máxima. Para todas as análises estatísticas, um valor de p ≤ 0,05 foi considerado significativo.
Diferenças nas proporções foram avaliadas usando-se o método do qui-quadrado. O teste de Mann-Whitney foi usado para comparar níveis de BNP entre dois grupos independentes (com ou sem morte por todas as causas em 10 anos).
Calculou-se a análise bivariada entre os quartis dos níveis de BNP e as variáveis clínicas e mortalidade, usando-se o teste do qui-quadrado para tendência ou o teste exato de Fisher.
Curvas receiver operating characteristic (ROC) foram geradas e a área sob a curva (e seu IC 95%) calculada para determinar o melhor nível discriminante de BNP obtido na admissão para predição de mortalidade por todas as causas.
Sensibilidade, especificidade, valores preditivos positivo e negativo e IC 95% foram calculados da maneira usual. Os valores de hazard ratio foram corrigidos quando necessário para evitar viés de cálculo.
A sobrevida acumulada de 10 anos foi determinada pelo método de Kaplan-Meier. A diferença na sobrevida de acordo com o nível de BNP foi avaliada usando-se teste de log-rank e modelo de riscos proporcionais de Cox.
Análises de regressão logística foram usadas para estabelecer a relação preditiva entre níveis de BNP contínuos ou dicotomizados e mortalidade ajustada para os efeitos de variáveis clínicas e laboratoriais. Inicialmente, todas as variáveis significativas identificadas na análise univariada foram incluídas nos modelos. As variáveis foram selecionadas usando-se o método forward stepwise guiado pelo teste de verossimilhança, calculando-se a respectiva estatística C. Realizou-se modelamento, recusando-se a entrada de variáveis com p > 0,10.
Estimou-se o valor discriminativo aumentado após adição do BNP para se estabelecerem os fatores prognósticos de mortalidade em 10 anos usando-se a técnica de melhoria da discriminação integrada (IDI).14 A IDI foi calculada analisando-se as diferenças na probabilidade estimada de mortalidade individual após a adição do BNP ao modelo contendo os fatores prognósticos estabelecidos e mencionados, e representa a melhoria média na probabilidade prevista. Os resultados foram avaliados pelas diferenças absolutas e relativas nos valores de discriminação entre os modelos.
ResultadosCaracterísticas dos pacientes
Desta coorte de 224 pacientes consecutivos com SCASSST, 107 (47,8%) tiveram um diagnóstico final de infarto do miocárdio e 117 (52,2%), de angina instável. A Tabela 1 mostra as características demográficas e clínicas. O escore de risco TIMI pôde ser calculado em 202 daqueles 224 pacientes, a maioria dos quais foi classificada como de risco baixo ou intermediário.
Características clínicas e laboratoriais basais de 224 pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST
Características clínicas
n = 224
Idade (anos) (intervalo IQ)
71,5 (60,5; 79)
Sexo masculino
141 (62,9%)
Diabetes mellitus
53 (23,7%)
Tabagismo
36 (16,1%)
IM prévio
69 (30,8%)
Uso prévio de aspirina
87 (38,8%)
ECG Normal (admissão)
157 (70,1%)
Depressão do segmento ST (admissão)
28 (12,5%)
Insuficiência ventricular esquerda (admissão)
26 (11,7%)
Escore de risco TIMI baixo (TIMI 0-2)
76 (37,6%)
Escore de risco TIMI intermediário (TIMI 3-4)
102 (50,5%)
Escore de risco TIMI alto (TIMI 5-7)
24 (11,9%)
TFGe (mL/min) (intervalo IQ)
69,3 (46,7; 92,3)
BNP (pg/mL) (admissão) (intervalo IQ)
81,9 (22,2; 225)
Diagnóstico final
Angina instável
117 (52,2%)
IMSSST
107 (47,8%)
IM: infarto do miocárdio; BNP: peptídeo natriurético do tipo B; TFGe: taxa de filtração glomerular estimada; IQ: interquartil; IMSSST: infarto do miocárdio sem supradesnivelamento do segmento ST; ECG: Eletrocardiograma.
A Tabela 2 demonstra a relação entre quartis de BNP e achados clínicos e laboratoriais nos 224 pacientes com SCASSST. É importante notar que a maioria dessas variáveis apresentou uma significativa relação univariada direta com os níveis de BNP na admissão.
Relação das características clínicas e laboratoriais, diagnóstico final e taxa de mortalidade por todas as causas com os quartis de BNP (pg/mL)
1° quartil
2° quartil
3° quartil
4° quartil
(BNP < 22,2) n = 56
(BNP 22,2-81,9) n = 56
(BNP 82,0-225) n = 56
(BNP > 225)n = 56
valor de p
Idade (anos) (intervalo IQ)
60,5 (51,5; 71,5)
68,5 (58,5; 75)
73,0 (68; 81)
80,0 (73; 84)
p < 0,0001
IM prévio (%)
10 (17,9)
15 (26,8)
21 (37,5)
23 (41,1)
p = 0,0037
Uso prévio de aspirina (%)
16 (28,6)
23 (41,1)
29 (51,8)
19 (33,9)
p = 0,3594
Insuficiência ventricular esquerda (admissão) (%)
4 (7,3)
2 (3,6)
4 (7,1)
16 (28,6)
p = 0,0004
Depressão do segmento ST (admissão) (%)
7,1 (4)
10,7 (6)
16,1 (9)
16,1 (9)
p = 0,1050
Escore de risco TIMI (admissão)
Risco baixo (TIMI 0-2) (%)
31 (58,5)
19 (38,8)
11 (22,9)
15 (28,8)
Risco intermediário (TIMI 3-4) (%)
20 (37,7)
25 (51,0)
28 (58,3)
29 (55,8)
p = 0,0002
Risco alto (TIMI 5-7) (%)
2 (3,8)
5 (10,2)
9 (18,8)
8 (15,4)
Disfunção ventricular esquerda no ECO (%)
9 (16,4)
16 (30,2)
21 (38,2)
36 (64,3)
p < 0,0001
Diagnóstico final
Angina instável (%)
60,7
64,3
55,4
28,6
p = 0,0004
IMSSST, %
39,3
35,7
44,6
71,4
p = 0,0004
Morte por todas as causas (%)
8 (14,3)
9 (16,1)
27 (48,2)
41 (73,2)
p < 0,0001
IQ: interquartil; IM: infarto do miocárdio; BNP: peptídeo natriurético do tipo B; ECO: ecocardiograma; IMSSST: infarto do miocárdio sem supradesnivelamento do segmento ST.
Durante o seguimento de 10 anos, 85 pacientes (37,9%) morreram. A taxa de mortalidade aumentou progressivamente de acordo com os quartis de BNP (Tabela 2). Os pacientes que morreram quando comparados aos que sobreviveram eram mais idosos na ocasião do evento-índice SCA (79 vs 66 anos, p < 0,001), apresentavam pior taxa de filtração glomerular estimada média (49,1 vs 80,5 mL/min, p < 0,001), apresentavam-se mais frequentemente com insuficiência cardíaca na admissão (21,2 vs 5,8%, p = 0,001), apresentavam mais frequentemente infarto do miocárdio na admissão (61,2 vs 39,6%, p = 0,002) e tinham níveis mais elevados de BNP na admissão (220 vs 44,7 pg/mL, p < 0,001).
Acurácia prognóstica dos níveis de BNP medidos na admissão
A análise da curva ROC revelou 100 pg/mL como sendo o ponto de corte de BNP de melhor prognóstico para mortalidade por todas as causas em 10 anos (área sob a curva = 0,789, IC 95% = 0,723 - 0,854). Pacientes com BNP ≥ 100 pg/mL apresentaram taxa de mortalidade de 65% versus 17,3% para aqueles com BNP < 100 pg/mL (risco relativo = 3,76, p < 0,001). Sensibilidade, especificidade e valores preditivos positivo e negativo para mortalidade foram 74,1%, 75,5%, 64,9% e 82,7%, respectivamente.
A mediana da sobrevida em 10 anos, determinada pelo método de Kaplan-Meier, foi de 5,80 anos (intervalo IQ = 2,55-9,44) para pacientes com BNP na admissão ≥ 100 pg/mL versus 9,63 anos (intervalo IQ = 9,04-10,13) para aqueles com BNP <100 pg/mL (p < 0,0001).
Na análise multivariada stepwise de regressão logística ajustada para todas as variáveis demográficas e clínicas conhecidas como preditoras de morte cardíaca ou relacionadas com um nível de BNP elevado (incluindo todas as variáveis da Tabelas 1 e 2), um nível de BNP de 100 pg/mL obtido na admissão ao setor de emergência foi um preditor independente de morte em 10 anos (Tabela 3).
Preditores independentes de morte por todas as causas em 10 anos por análise multivariada com regressão logística em pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST
Preditores independentes de mortalidade
Variáveis
OR (IC 95%)
valor de p
Idade > 72 anos
3,79 (1,62-8,86)
p = 0,002
BNP ≥ 100pg/mL
6,24 (2,95-13,23)
p < 0,001
TFGe (para cada incremento ml/min)
0,98 (0,97-0,99)
p = 0,049
BNP: peptídeo natriurético do tipo B; TFGe: taxa de filtração glomerular estimada; IC: intervalo de confiança; OR: odds ratio.
Por fim, ao usar a técnica de IDI, a adição de informação sobre o BNP às variáveis tradicionais de risco melhorou a predição e produziu um aumento no índice de discriminação absoluta de 3,06% para mortalidade em 10 anos (Tabela 4). A melhoria na discriminação relativa foi 10% maior para mortalidade em 10 anos com o conhecimento e uso de informação sobre BNP do que sem ele.
Comparação do risco médio e melhoria da discriminação usando o modelo tradicional de risco e o modelo com adição do peptídeo natriurético do tipo B (BNP) para mortalidade em 10 anos entre pacientes que morreram (casos) e que sobreviveram (controles)
Melhoria da discriminação relativa: 37,615/34,557 = 1,088
Escore de risco TIMI e níveis de BNP
Conhecer o nível de BNP melhorou mais a estratificação de risco para mortalidade em 10 anos em todos os três níveis do escore de risco TIMI (Figura 1). As curvas de sobrevida em 10 anos de Kaplan-Meier dos dois níveis do valor de BNP e três níveis do escore de risco TIMI são mostradas nas Figuras 2 e 3 e claramente revelam o desempenho prognóstico discriminativo muito melhor do BNP.
Taxas de mortalidade por todas as causas em 10 anos de pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST de acordo com o escore de risco TIMI (baixo = 0-2 pontos, intermediário = 3-4 pontos, alto = 5-7 pontos), estratificados conforme o valor de corte ótimo por estatística C do peptídeo natriurético do tipo B (BNP) em pg/mL.
Curvas de sobrevida de Kaplan-Meier de 224 pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST conforme o nível do peptídeo natriurético do tipo B (BNP) à admissão.
Curvas de sobrevida de Kaplan-Meier de 202 pacientes com síndrome coronariana aguda sem supradesnivelamento do segmento ST conforme o escore de risco TIMI (baixo = 0-2 pontos, intermediário = 3-4 pontos, alto = 5-7 pontos).
Discussão
Vários biomarcadores cardíacos foram propostos e usados nas últimas décadas para a estratificação prognóstica de pacientes com SCA, os mais comuns sendo os marcadores de necrose, especialmente as troponinas.4,5,15,16
Desde o ano 2000, a avaliação de risco imediato e de curto prazo de desfechos cardiovasculares em pacientes com SCA vem sendo feita com os escores de risco TIMI1 e GRACE17, cujo cálculo à beira do leito é relativamente fácil. É importante lembrar que o escore de risco TIMI foi originalmente testado para seguimento de 14 dias; entretanto, vários autores extrapolaram seu uso para períodos mais longos.18-20 Infelizmente esses agregados de fatores de risco não apresentam boa acurácia para o seguimento de 1 ano, como avaliado pela estatística C de 0,5818 a 0,6919 para o TIMI e de 0,7118 a 0,7919 para o GRACE. Isso incentivou a busca por novos e mais precisos marcadores de predição de mortalidade.10,21-25
A princípio, descobriu-se que o BNP era um marcador bioquímico muito precoce e preciso de disfunção contrátil cardíaca aguda,26-28 tendo sido exaustivamente estudado em pacientes com isquemia miocárdica e infarto.29-31 Sua concentração sanguínea aumenta de maneira imediata e rápida após o início da hipóxia cardíaca, correlacionando-se de forma direta com a extensão da isquemia miocárdica.11,32,33 Mais recentemente, descobriu-se ser o BNP um excelente marcador prognóstico de desfecho cardíaco em pacientes com SCA.6,8,9,34-38 No entanto, na maioria desses estudos, o seguimento foi de 1 ano, e, em poucos deles, de até 4 anos.36,39-40
O presente estudo é o primeiro a demonstrar que o BNP medido na chegada ao setor de emergência é um marcador forte e independente de morte por todas as causas em pacientes com SCASSST até 10 anos após o evento índice, mesmo quando comparado ao escore de risco TIMI. A população deste estudo vem de uma série consecutiva de portadores de dor torácica aguda atendidos no setor de emergência, para os quais utilizou-se um protocolo diagnóstico sistemático, cuidadoso e abrangente de isquemia cardíaca, incluindo a medida seriada de marcadores de necrose miocárdica e ECG, além de uma única amostra de BNP obtida na admissão. A conduta foi deixada a critério dos médicos assistentes privados, mas a maioria dos pacientes com SCA foi submetida a angiografia coronariana e revascularização, se necessária.
Descobriu-se que o BNP permanece um forte marcador independente de morte por todas as causas em longo prazo na amostra deste estudo sobre SCASSST. O BNP também apresentou poder discriminatório, fornecendo significativa informação prognóstica além das tradicionais variáveis de risco para mortalidade em 10 anos, como visto na estatística C. Isso foi confirmado pelo uso da ferramenta de IDI, que avalia a diferença absoluta entre as taxas de desfecho previsto e observado, representando assim a eficiência do modelo preditivo e permitindo a comparação de dois modelos. Para a mortalidade em 10 anos, a IDI melhorou significativamente a discriminação do desfecho quando o BNP foi usado no modelo em comparação a quando não foi (Tabela 4), permitindo que mais um paciente obtivesse uma correta classificação de desfecho em um grupo de 33 indivíduos.
O BNP adicionou significativa informação prognóstica ao escore de risco TIMI desses pacientes, identificando subgrupos de risco mais baixo e mais alto (Figura 1). Achados semelhantes foram previamente demonstrados em estudo com seguimento de 6 meses por Bazzino et al.6 Ao contrário do BNP, o escore de risco TIMI por si só não pôde estratificar com precisão pacientes para mortalidade a longo prazo no nosso estudo (Figura 3).
O motivo pelo qual o BNP medido em um episódio-índice de SCA permanece como um fator de risco para mortalidade por todas as causas em até 10 anos é assunto de discussão. Como os níveis sanguíneos de BNP não são particularmente preditivos de infarto do miocárdio recorrente fatal e não fatal,6,41 parece improvável que a mortalidade tardia possa ser explicada por um novo episódio de SCA. Pode-se especular que sua elevação represente a soma de dois marcadores prognósticos bem conhecidos de doença arterial coronariana, isso é, presença e extensão de isquemia e disfunção ventricular esquerda.7,42,43 Os achados deste estudo podem ajudar na decisão da estratégia de tratamento, pois alguns autores sugeriram que intervenções de tratamento guiadas pelo BNP podem melhorar a mortalidade após SCA.44,45
Limitações do estudo
A amostra do presente estudo é relativamente pequena em comparação às de outros estudos multicêntricos, além de originar-se em uma única instituição privada com foco em cardiologia. Este estudo não avalia o possível valor de medidas seriadas de BNP. O teste de troponina usado nestes pacientes é de uma geração mais antiga (não 'ultra sensível'), ainda que usado em muitas instituições pelo mundo afora. É importante lembrar que os critérios bioquímicos de diagnóstico de infarto do miocárdio mudaram pelo menos duas vezes na última década.46,47
Conclusões
A medida do BNP na admissão hospitalar em pacientes com SCASSST permanece um forte preditor independente de mortalidade por todas as causas em muito longo prazo, corroborando sua excelente capacidade para estratificação de risco relatada em estudos com seguimento curto e médio. Este estudo permite que se levante a hipótese de que o BNP deva ser medido em todos os pacientes com SCASSST no evento-índice para estratificação de risco a longo prazo.
Agradecimentos
Este estudo foi parcialmente financiado pelo Hospital Pró-Cardíaco, Rio de Janeiro, Brasil, onde todos os dados foram coletados. Este artigo é parte da dissertação de Mestrado em Ciências, Cadeira de Cardiologia, de Fernando Bassan, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Brasil.
Fontes de financiamento
O presente estudo não teve fontes de financiamento externas.