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Vol. 41. Núm. 2.
Páginas 87-95 (fevereiro 2022)
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Vol. 41. Núm. 2.
Páginas 87-95 (fevereiro 2022)
Original Article
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Prognostic value of brain natriuretic peptide in ST-elevation myocardial infarction patients: A Portuguese registry
Valor prognóstico do BNP no enfarte agudo do miocárdio com supradesnivelamento de ST: um registo português
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Inês Almeidaa,
Autor para correspondência
inesalmeida91@gmail.com

Corresponding author.
, Joana China, Hélder Santosa, Hugo Mirandaa, Mariana Santosa, Catarina Sáa, Samuel Almeidaa, Catarina Sousaa,b, Lurdes Almeidaa, National Cardiology Data Collection Center, Portuguese Society of Cardiology, Coimbra, Portugal, National Register of Acute Coronary Syndromes Investigators
a Serviço de Cardiologia, Centro Hospitalar Barreiro-Montijo, Barreiro, Portugal
b Centro Cardiovascular de Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
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Table 1. Baseline characteristics of patients admitted with ST-elevation myocardial infarction according to brain natriuretic peptide levels.
Table 2. Clinical presentation and laboratory and echocardiographic findings.
Table 3. Characterization of coronary anatomy and planned revascularization and other therapeutic interventions.
Table 4. Adverse outcomes during hospitalization.
Table 5. In-hospital and discharge medication.
Table 6. Influence of brain natriuretic peptide on the primary endpoint, a composite of all-cause mortality and rehospitalization for cardiovascular causes at one year.
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Abstract
Introduction

Brain natriuretic peptide (BNP) is a highly sensitive and specific biomarker for the extent of myocardial infarction that is strongly related to short- and long-term prognosis in patients with acute coronary syndromes.

Objective

To assess the prognostic value of BNP levels in a Portuguese cohort of ST-elevation myocardial infarction (STEMI) patients.

Methods

We performed a retrospective analysis of patients admitted with STEMI included in the Portuguese Registry of Acute Coronary Syndromes (ProACS) between 2010 and 2019. Patients were divided into three groups according to BNP level (<100 pg/ml, 100-399 pg/ml and ≥400 pg/ml) and compared. Independent predictors of a composite of all-cause mortality and rehospitalization for cardiovascular causes were assessed by multivariate logistic regression. For sample homogenization, propensity score matching and pairwise matching with a tolerance level of 0.005 were performed.

Results

A total of 1650 patients were included, of whom 21.5% presented high BNP levels (≥400 pg/ml). These were older and had more comorbidities, lower admission systolic blood pressure and hemoglobin, higher heart rate, Killip class and creatinine, worse left ventricular systolic function and severe coronary anatomy. Higher BNP was associated with more in-hospital complications, in-hospital mortality and adverse outcomes at one year.

Conclusion

BNP levels during the index hospitalization were a powerful prognostic biomarker for all-cause mortality and major adverse cardiac events in patients admitted with STEMI to Portuguese hospitals.

Keywords:
Brain natriuretic peptide
ST-elevation myocardial infarction
Mortality
Prognosis
Myocardial infarction
Resumo
Introdução

O peptídeo natriurético cerebral (BNP) é um biomarcador de elevada sensibilidade e especificidade relativamente à extensão do enfarte do miocárdio, estando fortemente relacionado com o prognóstico a curto e longo prazo em doentes com síndrome coronária aguda.

Objetivo

Avaliar o valor diagnóstico e prognóstico dos níveis de BNP numa coorte portuguesa de doentes com enfarte do miocárdio com elevação de ST (STEMI).

Métodos

Realizámos uma análise retrospectiva de pacientes admitidos com STEMI incluídos no Registo Português de Síndromes Coronarianas Agudas (ProACS) entre 2010 e 2019. Os pacientes foram divididos em três grupos de acordo com o nível BNP (<100 pg/ml, 100-399 pg/ml e ≥400 pg/ml) e comparados. Preditores independentes de um composto de mortalidade por todas as causas e re-hospitalização para causas cardiovasculares foram avaliados por regressão logística multivariada. Para a homogeneização da amostra, foi realizada uma correspondência de propensão e uma correspondência em pares com um nível de tolerância de 0,005.

Resultados

Foram incluídos 1650 doentes; 21,5% apresentaram níveis elevados de BNP (≥400 pg/ml). Estes doentes eram mais velhos; apresentavam mais comorbilidades; menor pressão arterial sistólica e hemoglobina à admissão; frequência cardíaca, classe Killip e creatinina mais elevados; pior função sistólica ventricular esquerda e anatomia coronária mais grave. A elevação de BNP associou-se a maior taxa de complicações intra-hospitalares, mortalidade intra-hospitalar e outcomes adversos a ano.

Conclusão

Os níveis de BNP durante a hospitalização index foram um poderoso biomarcador prognóstico para mortalidade por todas as causas e eventos cardíacos adversos major (MACE) em doentes com STEMI.

Palavras-chave:
BNP
SCA com supradesnivelamento ST
Mortalidade
Prognóstico
Enfarte do miocárdio
Texto Completo
Introduction

ST-elevation myocardial infarction (STEMI) remains an important cause of death, especially in developed countries, despite significant advances in its prevention and management.1 Primary percutaneous coronary intervention (PCI) has been shown to reduce death, reinfarction and stroke in STEMI patients.2 Accurate risk stratification plays an important role in appropriate therapeutic decision-making for these patients. The Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores are helpful in the identification of high-risk patients, however they require complex calculation methods that are not easily applicable before hospital admission or in the emergency department, and are therefore not widely used in clinical practice.

Brain natriuretic peptide (BNP) measurement is a simple tool that has been proposed to assist in risk stratification. BNP is secreted in response to cardiac hemodynamic stress mediated by volume and pressure overload.1 The inflammatory response that is triggered leads to myocyte necrosis and apoptosis, collagen deposition, fibrosis, hypertrophy and dilatation, resulting in left ventricular (LV) systolic dysfunction.1,3 Exogenous BNP infusion has proved to have a cardioprotective effect, preventing unfavorable LV remodeling through generation of 3′,5′-cyclic guanosine monophosphate and nitric oxide synthase, leading to reduced myocardial oxygen consumption, enhancement of myocardial relaxation, retardation of adrenergic activation, induction of vascular regeneration, and inhibition of cardiac fibroblast collagen synthesis and proliferation.3,4

BNP is a highly sensitive and specific indicator of the extent of myocardial infarction (MI) and remodeling that is strongly related to short-term (LV systolic dysfunction, ventricular arrhythmias, LV aneurysm) and long-term clinical outcomes, including heart failure (HF) and mortality.2,5–8 BNP's prognostic value is due to the fact that it is the sum of different risk markers. Detection of LV dysfunction during the early phase of MI through elevated plasma BNP levels should prompt close clinical follow-up and imaging studies to guide the therapeutic strategy needed in order to improve the long-term clinical outcome.5 After MI, BNP levels rise rapidly, reaching a peak after 16-18 hours, and usually fall over the next 2-3 days in a monophasic pattern. However, a biphasic pattern, with BNP levels rising once more within five days of MI, is observed in about half of patients and predicts worsening cardiac function and clinical HF.9 With the advent of primary PCI, the importance of remodeling has decreased significantly, however a significant proportion of STEMI patients still suffer impaired LV function, and rates of mortality and progression to HF remain high.3

The current guidelines recommend the use of BNP as a biomarker to provide additional prognostic information in patients with non-STEMI; however, no European or universal risk model has incorporated it for use in STEMI patients.1 To the best of our knowledge, there has been a single Dutch study evaluating a multimarker approach that includes BNP to improve mortality prognostication in STEMI patients.10 There is no evidence on this issue in the Portuguese population, despite its significant impact on clinical practice. The present study aims to assess the added prognostic value of BNP levels in a Portuguese cohort of STEMI patients regarding all-cause mortality and major adverse cardiac events (MACE).

Methods

The Portuguese Registry of Acute Coronary Syndromes (ProACS) is a national multicenter voluntary registry of patients admitted with acute coronary syndromes. Baseline demographic data, cardiovascular risk factors and other relevant personal background, clinical, laboratory, echocardiographic and angiographic data, and medications of all patients are recorded. The present analysis is a retrospective cohort study, but all data were collected prospectively during the index hospitalization. Fifteen Portuguese centers contributed to this study (four in the North region, four in the Center region, three in the Greater Lisbon area and four in the Lower Alentejo). Primary PCI was performed using standard techniques according to the institution's protocol and European guidelines for the management of patients with STEMI. The use of antiplatelet agents, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), statins or inotropic drug support was left at the clinician's discretion according to clinical protocols.

A total of 8036 consecutive STEMI patients were enrolled in this registry between October 2010 and January 2019. Of these, 2695 patients were excluded due to lack of information related to LV systolic function and coronary artery disease characterization, 22 due to lack of follow-up data and 3669 due to lack of BNP quantification. The remaining patients were stratified according to BNP levels: <100 pg/ml, 100-399 pg/ml and ≥400 pg/ml. These cut-off values were established in accordance with the upper limit of normal values in an acute setting set out in the European guidelines on heart failure.

The population was thus composed of 1650 subjects, of whom 1287 (78%) were followed for at least one year after the index hospitalization. Follow-up data were obtained by reviewing medical records or through telephone interviews with patients. The clinical outcomes analyzed were in-hospital adverse events and mortality and a composite of all-cause mortality and rehospitalization for cardiovascular causes at one year after discharge.

Statistical analysis

Continuous variables were expressed as means±standard deviation and categorical variables as percentages. Categorical data were analyzed by the chi-square test and continuous data by the Kruskal-Wallis test. Two-sided p-values <0.05 were considered statistically significant. Logistic regression models were used to assess independent predictors of the clinical outcomes. Propensity score matching and pairwise matching with a tolerance level of 0.005 were performed. The patients were paired taking in account the following characteristics: age, body mass index (BMI), gender, LV ejection fraction (LVEF), previous myocardial infarction, chronic kidney disease (CKD), previous HF, creatinine level, atrial fibrillation at admission, Killip class and admission blood pressure (BP). The final matched groups (n=351 patients, 21.3% of the total population) were as follows: BNP <100 pg/ml (n=116, 7.0%); 100-399 pg/ml (n=117, 7.1%) and BNP ≥400 pg/ml (n=118, 7.2%).

Ethical considerations

Patient identities were anonymized at all times, and the registry was authorized by the national authorities and registered on the clinicaltrials.gov site (NCT01642329). All ethical requirements in the Helsinki Declaration of 1975 were met for studies not involving human and/or animal experimentation. Written informed consent for the introduction of patient data into the registry has been available since 2010 and was applied after approval by the ethics committee of each center.

ResultsClinical and demographic characterization

The population was composed of 1650 patients, mean age 64±13 years, mostly male (75.4%). There was a high prevalence of cardiovascular risk factors, particularly hypertension (61.7%), dyslipidemia (50.9%) and smoking (36.0%). BNP levels were <100 pg/ml in 39.0% (n=643), 100-399 pg/ml in 39.5% (n=652) and ≥400 pg/ml in 21.5% (n=355). Baseline characteristics differed substantially between groups (Table 1). Patients with higher BNP levels were significantly older and had more classic cardiovascular risk factors, except for smoking status and family history of premature cardiovascular disease. BMI did not differ significantly between groups. A previous history of cardiovascular disease (coronary, cerebrovascular and peripheral arterial disease), CKD, chronic obstructive pulmonary disease (COPD) and cancer was more common in patients with higher BNP, and before hospitalization, they were more medicated for cardiovascular risk factors and disease.

Table 1.

Baseline characteristics of patients admitted with ST-elevation myocardial infarction according to brain natriuretic peptide levels.

  All (n=1650)  BNP <100 pg/ml(n=643)  BNP 100-399 pg/ml(n=652)  BNP ≥400 pg/ml(n=355) 
Demographic
Age, years  64±13 (1649/1650)  58±11 (643/643)  66±13 (651/652)  72±12 (355/355)  <0.001 
Male, %  75.4 (1244/1650)  85.2 (548/643)  71.6 (467/652)  64.5 (229/355)  <0.001 
BMI, kg/m2  27.2±4.4 (1487/1650)  27.5±4.4 (610/643)  27.1±4.4 (572/652)  26.8±4.4 (305/355)  0.039 
CV risk factors
Smoking, %  36.0 (592/1643)  49.1 (314/639)  31.6 (206/651)  20.4 (72/355)  <0.001 
Hypertension, %  61.7 (997/1615)  54.7 (343/627)  63.4 (405/639)  71.3 (249/349)  <0.001 
Diabetes, %  25.6 (411/1603)  21.4 (134/625)  25.8 (162/629)  33.0 (115/349)  <0.001 
Dyslipidemia, %  50.9 (787/1547)  56.1 (342/610)  46.5 (282/607)  49.4 (163/330)  0.003 
Family history of CAD, %  9.3 (140/1504)  12.9 (80/618)  8.4 (49/583)  3.6 (11/303)  <0.001 
Previous history
Angina, %  19.6 (322/1642)  19.4 (124/640)  19.4 (126/649)  20.4 (72/353)  0.915 
MI, %  12.1 (199/1642)  13.9 (89/640)  9.9 (64/648)  13.0 (46/354)  0.073 
PCI, %  10.5 (173/1647)  12.6 (81/642)  8.6 (56/651)  10.2 (36/354)  0.061 
CABG, %  1.3 (21/1648)  0.9 (6/642)  0.8 (5/651)  2.8 (10/355)  0.013 
HF, %  2.2 (36/1647)  0.5 (3/642)  1.8 (12/651)  5.9 (21/354)  <0.001 
Stroke/TIA, %  5.6 (92/1648)  3.4 (22/642)  5.2 (34/651)  10.1 (36/355)  <0.001 
CKD, %  3.1 (51/1631)  1.3 (8/638)  2.5 (16/647)  7.8 (27/346)  <0.001 
PAD, %  4.2 (68/1634)  2.0 (13/637)  4.6 (30/649)  7.2 (25/348)  <0.001 
COPD, %  4.2 (69/1639)  2.8 (18/637)  4.5 (29/649)  6.2 (22/353)  0.035 
Cancer, %  3.9 (64/1638)  2.5 (16/639)  3.4 (22/649)  7.4 (26/350)  <0.001 

BMI: body mass index; BNP: brain natriuretic peptide; CABG: coronary artery bypass grafting; CAD: coronary artery disease; CCB: calcium channel blocker; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CV: cardiovascular; HF: heart failure; MI: myocardial infarction; PAD: peripheral arterial disease; PCI: percutaneous coronary intervention; TIA: transient ischemic attack.

Clinical, laboratory, echocardiographic and angiographic characteristics

Anterior STEMI was the most frequent location of STEMI for all groups. Patients with higher levels of BNP presented with lower systolic BP and higher heart rate and Killip class. They also presented the highest creatinine levels and the lowest hemoglobin levels at admission and during hospitalization. Mean LVEF was lower in patients with higher BNP, and a higher proportion of these patients had severely compromised LVEF (Table 2).

Table 2.

Clinical presentation and laboratory and echocardiographic findings.

  All (n=1650)  BNP <100 pg/ml(n=643)  BNP 100-399 pg/ml(n=652)  BNP ≥400 pg/ml(n=355) 
STEMI location
Anterior, %  51.1 (843/1650)  46.2 (297/643)  49.5 (323/652)  62.8 (223/355)  <0.001 
Inferior, %  48.2 (796/1650)  53.5 (344/643)  50.0 (326/652)  35.5 (126/355)  <0.001 
New-onset LBBB, %  0.7 (11/1650)  0.3 (2/643)  0.5 (3/652)  1.7 (6/355)  0.029 
Vital signs
HR, bpm  78±20 (1650/1650)  76±17 (643/643)  77±19 (652/652)  84±26 (355/355)  <0.001 
SBP, mmHg  136±30 (1649/1650)  136±30 (643/643)  140±31 (651/652)  131±28 (355/355)  <0.001 
DBP, mmHg  80±18 (1650/1650)  81±19 (643/643)  81±18 (652/652)  77±18 (355/355)  0.007 
Killip class >I, %  12.1 (1648/1650)  5.6 (642/643)  9.5 (651/652)  28.5 (355/355)  <0.001 
Laboratory findings
Cr (admission), mg/dl  1±0.5 (1643/1650)  0.9±0.4 (641/643)  1±0.4 (649/652)  1.2±0.7 (353/355)  <0.001 
Cr (maximum), mg/dl  1.2±0.8 (1354/1650)  1±0.5 (572/643)  1.2±0.9 (499/652)  1.5±1 (283/355)  <0.001 
Hb (admission), g/dl  14.1±1.8 (1639/1650)  14.5±1.5 (639/643)  14.1±1.8 (648/652)  13.5±2 (352/355)  <0.001 
Hb (minimum), g/dl  12.8±2 (1357/1650)  13.5±1.6 (584/643)  12.6±1.9 (501/652)  11.7±2.1 (272/355)  <0.001 
LVEF
Mean, %  53±13 (1650/1650)  58±11 (643/643)  53±12 (652/652)  44±13 (353/355)  <0.001 
>50%, %  63.2 (1043/1650)  81.2 (522/643)  61.5 (401/652)  33.8 (120/355)  <0.001 
40-49%, %  21.2 (350/1650)  13.1 (84/643)  23.9 (156/652)  31.0 (110/355)  <0.001 
30-39%, %  11.8 (195/1650)  5.1 (33/643)  12.4 (81/652)  22.8 (81/355)  <0.001 
<30%, %  3.8 (62/1650)  0.6 (4/643)  2.1 (14/652)  12.4 (44/355)  <0.001 

BNP: brain natriuretic peptide; bpm: beats per min; Cr: creatinine; DBP: diastolic blood pressure; Hb: hemoglobin; HR: heart rate; LBBB: left bundle branch block; LVEF: left ventricular ejection fraction; SBP: systolic blood pressure; TG: triglycerides.

Table 3 summarizes the coronary anatomy in the BNP stratification groups. Multivessel disease was more common in patients with higher BNP. In this group, a higher proportion of patients were proposed for medical therapy. In the patients proposed for revascularization, there was a trend towards surgical revascularization or a hybrid approach, although this was not statistically significant. These patients also more frequently required advanced therapeutic devices and ventilatory support.

Table 3.

Characterization of coronary anatomy and planned revascularization and other therapeutic interventions.

  All (n=1650)  BNP <100 pg/ml(n=643)  BNP 100-399 pg/ml(n=652)  BNP ≥400 pg/ml(n=355) 
No. of diseased vessels
1.0 (16/1650)  1.2 (8/643)  0.8 (6/652)  0.8 (3/355)  0.657 
56.7 (936/1650)  63.9 (411/643)  54.4 (355/652)  47.9 (170/355)  <0.001 
28.5 (470/1650)  25.0 (161/643)  30.5 (199/652)  31.0 (110/355)  0.046 
13.8 (228/1650)  9.8 (63/643)  14.3 (93/652)  20.3 (72/355)  <0.001 
Multivessel (2-3) disease  42.3 (698/1650)  34.8 (224/643)  44.8 (292/652)  51.3 (182/355)  <0.001 
Planned revascularization
None (%)  4.3 (71/1650)  2.8 (18/643)  3.5 (23/652)  8.5 (30/355)  <0.001 
PCI (%)  93.0 (1535/1650)  95.8 (616/643)  93.7 (611/652)  86.8 (308/355)  <0.001 
CABG (%)  1.2 (20/1650)  0.3 (2/643)  1.5 (10/652)  2.3 (8/355)  0.017 
PCI+CABG (%)  1.5 (24/1650)  1.1 (7/643)  1.2 (8/652)  2.5 (9/355)  0.155 
Other interventions
Swan-Ganz (%)  1.5 (24/1650)  0.0 (0/643)  0.6 (4/652)  5.6 (20/355)  <0.001 
IABP (%)  0.5 (9/1650)  0.3 (2/643)  0.8 (5/652)  0.6 (2/355)  0.556 
IMV  4.0 (66/1650)  3.7 (24/643)  3.2 (21/652)  5.9 (21/355)  0.103 
NIMV  2.1 (34/1650)  0.2 (1/643)  1.4 (9/652)  6.8 (24/355)  <0.001 
Temporary PM  3.8 (63/1650)  2.2 (14/643)  3.8 (25/652)  6.8 (24/355)  0.001 
Ventricular assistance  0.0 (0/1650)  0.0 (0/643)  0.0 (0/652)  0.0 (0/355)  – 

BNP: brain natriuretic peptide; CABG: coronary artery bypass grafting; IABP: intra-aortic balloon pump; IMV: invasive mechanical ventilation; LAD: left anterior descending; LCX: left circumflex; LM: left main; NIMV: non-invasive mechanical ventilation; PCI: percutaneous coronary intervention; PM: pacemaker.

In-hospital outcomes and medication

Table 4 shows that in-hospital complications, especially HF (mean 18.9% vs. 45.4%, p<0.001), were more frequent in patients with higher BNP levels. Atrial fibrillation (AF) and cardiogenic shock were the second and third most observed complications. Sustained ventricular tachycardia was also frequent in patients with higher BNP. In-hospital mortality was seven times greater in the higher BNP group than in the lower BNP group (1.2% vs. 8.5%, p<0.001).

Table 4.

Adverse outcomes during hospitalization.

  All (n=1650)  BNP <100 pg/ml(n=643)  BNP 100-399 pg/ml(n=652)  BNP ≥400 pg/ml(n=355) 
Reinfarction, %  0.7  0.5  0.6  1.1  0.447 
HF, %  18.9  6.5  16.7  45.4  <0.001 
Shock, %  6.9  3.3  5.1  16.9  <0.001 
AF, %  7.5  3.0  6.4  17.5  <0.001 
Mechanical complication, %  0.6  0.2  0.3  2.0  0.001 
AV block, %  5.0  3.3  5.1  7.9  0.006 
SVT, %  3.5  1.6  3.7  6.8  <0.001 
Cardiac arrest, %  7.9  9.8  6.3  7.3  0.058 
Stroke, %  0.8  0.5  0.6  2.0  0.032 
Major bleeding, %  2.8  1.6  2.6  5.4  0.002 
Blood transfusion, %  1.9  0.3  1.8  5.1  <0.001 
Death, %  3.3  1.2  2.6  8.5  <0.001 

AF: atrial fibrillation; AV: atrioventricular; BNP: brain natriuretic peptide; HF: heart failure; SVT: sustained ventricular tachycardia.

Although HF was the most frequent complication in patients with higher BNP levels, during hospitalization they were less medicated with standard HF therapies (except aldosterone antagonists) but more often received diuretic therapy. As AF was the most prevalent condition in this group, a higher percentage received anticoagulant and antiarrhythmic drugs. Medication at discharge also followed these tendencies (Table 5).

Table 5.

In-hospital and discharge medication.

  All (n=1650)  BNP <100 pg/ml(n=643)  BNP 100-399 pg/ml(n=652)  BNP ≥400 pg/ml(n=355) 
In-hospital medication, %
Aspirin  98.8 (1631/1650)  99.4 (639/643)  98.2 (640/652)  99.2 (352/355)  0.100 
Clopidogrel  83.9 (1384/1650)  83.4 (536/642)  84.4 (550/652)  83.9 (298/355)  0.887 
Ticagrelor  25.4 (321/1264)  27.1 (136/502)  24.2 (121/499)  24.3 (64/263)  0.531 
Glycoprotein inhibitor  56.3 (928/1649)  74.5 (479/643)  49.0 (319/651)  36.6 (130/355)  <0.001 
UFH  33.0 (544/1646)  20.6 (132/642)  38.9 (253/651)  44.9 (159/354)  <0.001 
LMWH  39.0 (643/1647)  19.0 (122/642)  47.9 (312/651)  59.0 (209/354)  <0.001 
ACEI/ARB  85.2 (1405/1649)  83.8 (539/643)  89.7 (585/652)  79.4 (281/354)  <0.001 
Beta-blocker  76.8 (1268/1650)  80.7 (519/643)  76.2 (497/652)  71.0 (252/355)  0.002 
Aldosterone antagonist  14.9 (246/1650)  11.4 (73/643)  14.3 (93/652)  22.5 (80/355)  <0.001 
Statin  95.1 (1569/1650)  95.5 (614/643)  95.2 (621/652)  94.1 (334/355)  0.600 
VKA  3.0 (49/1650)  1.4 (9/643)  3.4 (22/652)  5.1 (18/355)  0.004 
Other OAC  1.7 (19/1650)  0.9 (6/643)  2.3 (7/652)  1.7 (6/355)  0.576 
Amiodarone  9.1 (150/1650)  3.7 (24/643)  8.7 (57/652)  19.4 (69/355)  <0.001 
Digoxin  1.6 (26/1650)  0.2 (1/643)  29.0 (9/652)  32.7 (16/355)  <0.001 
Nitrate  26.7 (441/1649)  21.2 (136/643)  31.4 (189/651)  4.5 (116/355)  <0.001 
CCB  3.8 (63/1650)  2.8 (18/643)  4.1 (27/652)  5.1 (18/355)  0.172 
Diuretic  445/1647 (27.0)  12.5 (80/642)  25.2 (16/651)  56.8 (201/354)  <0.001 
Inotropic support  143/1650 (8.7)  3.3 (21/643)  6.6 (43/652)  22.3 (79/355)  <0.001 
Levosimendan  6/1650 (0.4)  0.0 (0/643)  0.0 (0/652)  1.7 (6/355)  <0.001 
Discharge medication, %
Aspirin  96.1 (1502/1563)  97.6 (615/630)  97.1 (600/618)  91.1 (287/315)  <0.001 
Clopidogrel  77.3 (1208/1563)  75.9 (478/630)  79.8 (493/618)  75.2 (237/315)  0.161 
Ticagrelor  24.0 (289/1205)  28.0 (138/493)  22.9 (109/475)  17.7 (42/237)  0.008 
ACEI/ARB  85.0 (1329/1564)  84.2 (531/631)  88.4 (547/619)  79.9 (251/314)  0.002 
Beta-blocker  76.8 (1399/1562)  79.5 (501/630)  75.7 (467/617)  73.3 (231/315)  0.075 
Aldosterone antagonist  12.7 (198/1562)  7.3 (46/630)  13.5 (83/617)  21.9 (69/315)  <0.001 
Statin  95.8 (1499/1565)  97.3 (614/631)  96.1 (595/619)  92.1 (290/315)  <0.001 
VKA  3.7 (58/1563)  1.7 (11/631)  3.7 (23/617)  7.6 (24/315)  <0.001 
Other OAC  4.4 (45/1563)  1.9 (11/631)  3.6 (12/617)  7.7 (22/315)  <0.001 
Amiodarone  3.6 (56/1562)  1.6 (10/630)  3.4 (21/617)  7.9 (25/315)  <0.001 
Digoxin  0.8 (12/1562)  0.0 (0/630)  0.8 (5/617)  2.2 (7/315)  0.001 
Nitrate  7.9 (124/1562)  8.6 (54/630)  6.2 (38/617)  10.2 (32/315)  0.076 
CCB  4.8 (75/1562)  2.4 (15/630)  6.8 (42/617)  5.7 (18/315)  <0.001 
Diuretic  21.2 (331/1563)  9.0 (57/630)  20.1 (124/618)  47.6 (150/315)  <0.001 

ACEI/ARB: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BNP: brain natriuretic peptide; CCB: calcium channel blocker; LMWH: low molecular weight heparin; OAC: oral anticoagulation; UFH: unfractionated heparin; VKA: vitamin K antagonist.

One-year outcomes

Higher BNP was associated with higher rates of one-year mortality and rehospitalization due to cardiovascular disease (p=0.001) (Figure 1). One-year mortality was 4.6% and the rate of rehospitalization for cardiovascular causes was 9.0%. The composite endpoint of one-year mortality and cardiovascular rehospitalization occurred in 12%. After propensity score matching for sample homogenization, the one-year endpoint of total mortality and cardiovascular rehospitalization occurred in 20.3%.

Figure 1.

Kaplan-Meier curve for one-year all-cause mortality and rehospitalization for cardiovascular causes.

Time discharge - death/CV rehospitalization.

p value of Log-Rank test 0.001.

(0,1MB).

Factors predicting the endpoint, assessed through Cox multivariate regression (Table 6), were previous HF, multivessel disease, LVEF <30% and the use of nitrates and aldosterone antagonists. The use of aspirin was a protective factor.

Table 6.

Influence of brain natriuretic peptide on the primary endpoint, a composite of all-cause mortality and rehospitalization for cardiovascular causes at one year.

Predictor  Beta-coefficient  Statistical significance  HR  95% CI 
BNP ≥400 vs. BNP <100 pg/ml  0.730  0.400  0.007  2.07  0.95-4.54 
Previous HF  1.740  0.437  <0.001  5.69  2.42-13.42 
Multivessel disease  0.850  0.326  0.009  0.43  0.23-0.81 
LVEF <30%  1.561  0.594  0.009  4.76  1.49-15.25 
Discharge medication: nitrates  2.575  0.749  0.001  13.13  3.02-56.98 
Discharge medication: aldosterone antagonists  2.180  0.572  <0.001  8.85  2.89-27.14 
Discharge medication: aspirin  −1.923  0.391  <0.001  0.15  0.07-0.31 

BNP: brain natriuretic peptide; CI: confidence interval; HF: heart failure; HR: hazard ratio; LVEF: left ventricular ejection fraction.

Discussion

We observed higher BNP levels in elderly patients and in those with classic cardiovascular risk factors and previous history of cardiovascular disease, CKD, COPD and cancer. Patients with higher BNP levels had lower systolic BP at admission, higher heart rate and Killip class, and higher creatinine and lower hemoglobin levels, which are known predictors of worse outcome. Their coronary anatomy was more complex, with multivessel disease, left main and left anterior descending lesions, also features associated with a worse prognosis. A higher proportion of these patients were proposed for medical therapy, probably reflecting significant surgical risk and frailty. In patients referred for revascularization, there was a trend, albeit not statistically significant, toward coronary artery bypass grafting or a hybrid approach, probably reflecting more severe coronary disease. These features were also in accordance with the more frequent need for advanced therapeutic devices and ventilatory support in this group.

BNP is a polypeptide secreted by the ventricles in response to excessive stretching of cardiomyocytes, and increased BNP may represent a greater extent of myocardial ischemic territory, which would explain the positive correlation between elevated BNP and MACE in MI patients.5 In our study, patients with high BNP levels had lower LVEF. Previous studies have shown an association between elevated BNP level and multivessel disease, independently of LV systolic dysfunction and congestive HF.4

Higher BNP is associated with short-term complications, including HF, ventricular arrhythmias and LV aneurysm formation, which is in accordance with our results, although we did not specifically assess the presence of LV aneurysms.11 HF was the most frequent in-hospital complication, followed by AF and cardiogenic shock. In-hospital mortality was more than seven times higher in the highest than in the lowest BNP group. At discharge, patients with higher BNP were more likely to be prescribed drugs to control cardiovascular risk factors (aspirin and statins) and for AF control and anticoagulation. The rate of neurohormonal therapy was lower in the high BNP group, except for aldosterone antagonists, probably as a result of their in-hospital clinical course requiring greater use of inotropes and levosimendan, which could have limited the use of neurohormonal HF drugs. The 30-day mortality of patients with STEMI treated with PCI ranges between 5.3 and 7.3%, and is higher in patients with HF (16.5%).12 Although overall mortality in our study was low, it proved that high BNP was associated not only with worse in-hospital outcomes but also with one-year outcomes, which is in line with previous studies.13 BNP levels probably represent the sum of well-known prognostic markers in coronary artery disease, the presence and extent of LV ischemia and dysfunction, suggesting that BNP therapy-guided interventions might improve mortality after STEMI.14 Furthermore, in patients with type 2 diabetes and renal dysfunction, independently of glomerular filtration rate, BNP is an important predictor of mortality, cardiovascular death, MI, HF, and stroke.15 In survivors, patients’ quality of life after hospital discharge is affected primarily by the development of HF, recurrence of ischemic events, and death. Close monitoring of STEMI patients enables the identification of high-risk patients who might benefit from more regular attention and long-term follow-up.12 One-year mortality in our study was 4.6% and 9.0% were hospitalized for cardiovascular causes.

The results of our study are supported by the findings of previous studies aiming to identify STEMI patients at high risk of poor clinical outcomes. Accurate, comprehensive and simple risk assessment plays an important role in appropriate therapeutic decision-making for these patients. Higher-intensity treatments may be appropriate in patients with higher risk scores; however, their inappropriate use in low-risk patients may expose them to adverse effects. Although existing risk scores present good predictive value, their use is limited due to their complexity, the need to carry out various calculations, and the effect of procedure-related variables. BNP can be rapidly measured during admission and is increasingly shown to be predictive of short- and long-term outcomes following STEMI, independently of the presence of clinical HF during hospitalization, providing significant prognostic information in addition to that of Killip class and TIMI risk score in STEMI patients.16–18

Our study presents some limitations. First, it was a retrospective observational study and thus susceptible to inherent limitations, including selection bias. Since this is a voluntary registry, it does not represent all the cardiology centers in Portugal and, even in the centers that did participate, we cannot guarantee that all STEMI patients are included. Also, STEMI patients suffering out-of-hospital death were probably not included. Second, BNP was collected for clinical reasons and this decision was made at the discretion of the attending physician, thus there was only one measurement, which does not allow an analysis of BNP kinetics, and the timing of the measurements was variable. BNP values may have been determined at admission, reflecting the baseline severity of the population, during hospitalization, or at discharge, reflecting the evolution of STEMI itself and implemented therapies. Thirdly, there were no data regarding adherence to medical treatment after discharge.

Conclusion

Patients with higher BNP levels were significantly older, had more cardiovascular risk factors and comorbidities, more severe clinical presentation and complications, and needed more aggressive treatment. These differences might explain their higher in-hospital and one-year mortality and adverse outcomes. Importantly, BNP levels during the index hospitalization were a powerful prognostic biomarker for one-year all-cause mortality and MACE in patients with STEMI, which may indicate a need for more regular monitoring of these patients at follow-up.

Conflicts of interest

The authors have no conflicts of interest to declare.

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