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. 2021 Mar 3;116(3):504–506. [Article in Portuguese] doi: 10.36660/abc.20200327
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Comparação entre a Relação Neutrófilo-Linfócito Precoce e Tardia na Predição de Eventos Adversos em Pacientes com IAMCSST submetidos à ICP Primária

Guilherme Pinheiro Machado 1,✉, Gustavo Neves de Araujo 2, Daniele Maltauro 1, Julia Custodio 1, Victoria Milan 3, Marco Wainstein 2
PMCID: PMC8159548  PMID: 33909781

Introdução

A relação neutrófilo-linfócito (NLR) na admissão hospitalar já se mostrou capaz de prever eventos adversos em pacientes com infarto agudo do miocárdio com supra desnível do segmento ST (IAMCSST).1-3 Evidências recentes demonstraram que a NLR continua aumentando no período de 48 a 72 horas nos pacientes que apresentam resultados piores.4 Portanto, nosso objetivo foi comparar a capacidade prognóstica da NLR na admissão e tardia para eventos adversos em pacientes com IAMCSST submetidos à intervenção coronária percutânea primária (ICPp).

Métodos

Este foi um estudo coorte prospectivo com pacientes consecutivos admitidos com IAMCSST que passaram por ICPp e foram acompanhados durante 12 meses. A NLR foi calculada dividindo-se o número de neutrófilos pelo número de linfócitos obtidos da mesma amostra sanguínea. A NLR foi avaliada na admissão e no período de 48 a 72 horas após o procedimento (NLR tardia) como parte do tratamento de rotina. Outros detalhes sobre informações procedimentais, coleta de dados, definições clínicas, critérios de exclusão e diretrizes éticas estão descritos em outros locais.2 A NLR alta foi definida como acima do tercil superior. A análise da curva de característica de operação do receptor (ROC) foi realizada para calcular a área sob a curva (AUC) para a ocorrência de mortalidade em curto e longo prazo e de eventos cardíacos adversos maiores (MACE) Foram realizadas análises multivariadas pela regressão de Poisson com variância robusta para avaliar o valor preditivo independente da NLR tardia. Para o modelo multivariado, os fatores de risco que foram preditores univariados (p <0,05) foram considerados inicialmente como fatores ou covariáveis. As análises de concordância foram comparadas pelo teste de De Long, enquanto os métodos de Kaplan-Meier foram comparados com testes de Log-Rank, realizados utilizando-se o software MedCalc Statistical, versão 14.8.1 (MedCalc Software, Ostend, Bélgica). Todas as demais análises estatísticas foram realizadas utilizando-se o software SPSS Statistics for Windows, v.21.0. (IBM Corp., Armonk, NewYork, EUA).

Resultados

Entre março de 2011 e dezembro de 2018, 864 pacientes compareceram à nossa instituição, diagnosticado com IAMCSST, e 779 deles foram incluídos na análise. A média de idade foi de 60,68 (±12), 66,4% dos pacientes eram do sexo masculino, 62,1% tinham hipertensão e 24% tinham diabetes.

Na análise multivariada, quando ajustada por idade, tempo dor-porta, doença renal crônica prévia, infarto do miocárdio (IM) prévio, hipotensão na admissão, acesso femoral, tempo de fluoroscopia, volume de contraste, classificação de trombose no infarto do miocárdio (TIMI), fração de ejeção do ventrículo esquerdo ≤40% antes da alta, a NLR continuou sendo um preditor independente da mortalidade hospitalar, MACE hospitalar e mortalidade após 1 ano (risco relativo [RR] = 14,9, 95% intervalo de confiança [95% IC]= 3,4 - 80,35, p= 0,001; RR= 3,4, 95% IC= 1,2 – 9,1, p= 0,01; RR= 7,6, 95% IC= 2,9 – 26,1, p= 0,01, respectivamente). O uso da NLR tardia aumentou significativamente a AUC de mortalidade hospitalar de 0,55 para 0,84 (Sensibilidade 81,2%, Especificidade 75,6%, Valor preditivo positivo 24,5 e Valor preditivo negativo 97,7). Os dados discriminados dos demais resultados estão descritos na Figura 1. Ao final de 1 ano de acompanhamento, o índice de mortalidade global foi de 28,6% no grupo de NLR alta, hazard ratio (HR) = 3,07 (95% IC= 1,9 - 4,8); p< 0,0001; Figura 2).

Figura 1. Gráfico de característica de operação do receptor (ROC) mostrando as áreas sob acurva (AUC) da relação neutrófilo-linfócito (NLR) na admissão e NLR tardia para (A) mortalidade hospitalar, (B) eventos cardiovasculares maiores hospitalares (MACE), (C) mortalidade global após 1 ano e (D) MACE após 1 ano.

Figura 1

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Figura 2. Curvas tempo-evento para mortalidade global após 1 ano de relação neutrófilo-linfócito (NLR). Os índices de eventos foram calculados utilizando-se os métodos de Kaplan-Meier, e comparados com uso do teste Log-rank.

Figura 2

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Discussão

No presente estudo coorte de pacientes de IAMCSST que passaram por ICPp, a NLR tardia foi fortemente associada à mortalidade no curto e no longo prazo e aos MACE. Além disso, a NLR tardia aumenta a capacidade da NLR na admissão de eventos adversos nesses pacientes. Até onde sabemos, esta foi a primeira vez em que a NLR tardia foi avaliada consistentemente nesse cenário.

A distribuição normal da NLR ainda exige debates. Forget et al.,5 estudaram indivíduos saudáveis, e os valores variaram entre 0,78 e 3,5, permanecendo estáveis após 48 horas. Recentemente, Kim et al.,6 observaram que a NLR aumenta ao longo do tempo em indivíduos com doença cardiovascular, atingindo os valores de pico próximo ao momento de um evento adverso. Um estudo recente demonstrou que os pacientes que experimentaram resultados adversos durante o período de acompanhamento tiveram um aumento agudo dos valores de NLR 48 horas após o procedimento.4 Esses resultados corroboram os achados de Kim et al.,6 descritos acima.

No presente estudo, quando os valores de NLR tardia foram usados para avaliar a capacidade de prever eventos adversos, houve um aumento significativo na AUC quando comparada à NLR na admissão. Isso pode ser explicado porque os neutrófilos são os primeiros leucócitos a infiltrarem o miocárdio infartado, liberando uma variedade enzimas proteolíticas que causam ruptura de placa, expansão do infarto, ativação da via da coagulação, e instabilidade elétrica cardíaca.7–9 Além disso, há evidências do prolongamento da vida de neutrófilos em placas instáveis.10 Em contraste com o aumento de neutrófilos nas áreas lesionadas do miocárdio, houve redução dos linfócitos devido ao aumento dos níveis de cortisol, catecolaminas e citocinas pró-inflamatórias no IAMCSST.11,12 Isso sugere que a resposta inflamatória exacerbada após o evento define os piores resultados para esses pacientes.

Na prática clínica da maioria dos centros mundiais, a contagem de leucócitos é realizada rotineiramente durante a hospitalização por evento coronário agudo. No presente estudo, uma medição de NLR no período de 48 a 72 horas foi um preditor forte dos resultados adversos, o que destaca a possível aplicação desses marcadores inflamatórios acessíveis e prontamente disponíveis para a estratificação de risco após o infarto do miocárdio.

Footnotes

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é parte de tese de Doutorado de Guilherme Pinheiro Machado pela Universidade Federal do Rio Grande do Sul.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética do Hospital de Clinicas de Porto Alegre sob o número de protocolo 2018/0436. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo

Referências

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Arq Bras Cardiol. 2021 Mar 3;116(3):504–506. [Article in English]

Early vs. Late Neutrophil-To-Lymphocyte Ratio for the Prediction of Adverse Outcomes in Patients with STEMI Undergoing Primary PCI

Guilherme Pinheiro Machado 1,✉, Gustavo Neves de Araujo 2, Daniele Maltauro 1, Julia Custodio 1, Victoria Milan 3, Marco Wainstein 2

Introduction

Admission neutrophil-to-lymphocyte ratio (NLR) has proven to predict adverse events in patients with ST-elevation Myocardial Infarction (STEMI).1–3 New evidence has shown that NLR continues to increase within 48-72 hours in patients who develop worse outcomes.4 Therefore, this study sought to compare the prognostic capacity of admission and late NLR for adverse events in patients with STEMI undergoing primary percutaneous coronary intervention (pPCI).

Methods

This was a prospective cohort study with consecutive patients admitted with STEMI, who underwent pPCI and were followed up for 12 months. NLR was calculated by dividing the neutrophil count by the lymphocyte count obtained from the same blood sample. NLR was assessed at admission and 48-72 hours post-procedure (late NLR), as a part of routine care. Other details about procedural information, data collection, clinical definitions, exclusion criteria, and ethical guidelines are described elsewhere.2 High NLR was defined as above upper tertile. Receiver operating characteristic (ROC) curve analysis was performed to calculate the area under the curve(AUC) for the occurrence of short and long-term mortality and major adverse cardiovascular events (MACE). Multivariate analysis was performed by Poisson robust regression to evaluate the independent predictive value of late NLR. For the multivariate model, risk factors that were univariate predictors (at p <0.05) were initially considered factors or covariates. C-statistic analyses were compared with the De Long test, while Kaplan–Meier methods were compared with log-rank tests, performed using the MedCalc Statistical Software version 14.8.1 (MedCalc Software, Ostend, Belgium). All remaining statistical analyses were conducted using SPSS Statistics for Windows, v.21.0. (IBM Corp., Armonk, NewYork, USA).

Results

Between March 2011 and December 2018, 864 patients were admitted to our institution, diagnosed with STEMI, and 779 were included in the analysis. Mean age was 60.68 (±12), 66.4% were male, 62.1% had hypertension, and 24% had diabetes.

In a multivariate analysis, when adjusted by age, pain-to-door time, previous chronic kidney disease, previous myocardial infarction (MI), hypotension at admission, femoral access, fluoroscopy time, contrast volume thrombolysis in myocardial infarction (TIMI) score, left ventricle ejection fraction ≤40% before discharge, late NLR remained an independent predictor of in-hospital death, in-hospital MACE, and one-year mortality (relative risk[RR] = 14.9, 95% confidence interval [95% CI]= 3.4 - 80.35, p= 0.001; RR= 3.4, 95% CI= 1.2 – 9.1, p = 0.01; RR= 7.6, 95% CI= 2.9 – 26.1, p= 0.01, respectively). The use of late NLR increased significantly the AUC of in-hospital mortality from 0.55 to 0.84 (Sensitivity 81.2%, Specificity 75.6%, Positive Predictive Value 24.5, and Negative Predictive Value 97.7). Discriminative data of other outcomes are described in Figure 1. At the end of a one-year follow-up, the rate of death from any cause was 28.6% in the high late NLR group, hazard ratio [HR] = 3.07 (95% CI = 1.9 - 4.8); p < 0.0001; Figure 2).

Figure 1. Receiver operator characteristic (ROC) graph showing areas under the curve (AUC) of admission neutrophil–to–lymphocyte ratio (NLR) and late NLR for (A) in-hospital death, (B) in-hospital major cardiovascular outcomes (MACE), (C) one-year all-cause mortality, and (D) one-year MACE.

Figure 1

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Figure 2. Time-to-Event Curves for one-year all-cause mortality for late neutrophil–to–lymphocyte ratio (NLR). Event rates were calculated by means of Kaplan–Meier methods and compared with the use of the log-rank test.

Figure 2

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Discussion

In this present cohort-based study of STEMI patients undergoing pPCI, late NLR was strongly associated with short and long-term mortality and MACE. Moreover, late NLR increased the admission NLR's prognostic capacity for adverse events in these patients. To the best of our knowledge, this was the first time late NLR was consistently evaluated in this setting.

Normal distribution of NLR is still a matter of debate. Forget et al.5 have studied healthy individuals and values ranged between 0.78 and 3.5, remaining stable after 48 hours. Recently, Kim et al.6 observed that NLR increases over time in individuals with cardiovascular disease, reaching peak values around the time of an adverse event. A recent study showed that patients who experienced adverse outcomes during follow-up had an acute increase in NLR values 48h after the procedure.4 These results support the findings of Kim et al.6 described above.

In the present study, when late NLR values were used to assess the ability to predict adverse events, there was a significant increase in AUC when compared to admission NLR. This might be explained because neutrophils are the first leukocytes to infiltrate the infarcted myocardium, releasing a variety of proteolytic enzymes which cause plaque rupture, infarct expansion, coagulation pathway activation, and cardiac electrical instability.7–9 In addition, there is evidence of the prolongation of the lifespan of neutrophils in unstable plaques.10 In contrast to increased neutrophils in the damaged myocardial area, lymphocytes decrease due to increased levels of cortisol, catecholamines, and proinflammatory cytokines in acute STEMI.11,12 This suggests that the exacerbated inflammatory response after the event defines the worse outcome for these patients.

In the clinical practice of most centers worldwide, white blood counts are routinely obtained during hospitalization for an acute coronary event. In the present study, a measurement of 48-72h NLR was a strong predictor of adverse outcomes, which highlights a potential application of this inexpensive and readily available inflammatory marker for risk stratification of post-myocardial infarction.

Footnotes

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of Doctoral submitted by Guilherme Pinheiro Machado, from Universidade Federal do Rio Grande do Sul.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Hospital de Clinicas de Porto Alegre under the protocol number 2018/0436. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

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