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

Keywords
Myocardial Infarction; Angioplasty; Mortality; Neutrophil-to-lymphocyte Ratio; Inflammation; Risk Factors

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 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

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.

• 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.

Referências

• ¹
  Park JJ, Jang H-J, Oh I-Y, Yoon C-H, Suh J-W, Cho Y-S, et al. Prognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol. 2013;111(5):636–42.
• ²
  Pinheiro Machado G, Araujo GN, Carpes CK, Lech MC, Mariani S, Valle FH, et al. Elevated neutrophil-to-lymphocyte ratio can predict procedural adverse events in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis . 2019;30(11):20-5.
• ³
  Machado GP, Araujo GN, Carpes CK, Lech M, Mariani S, Valle FH, et al. Comparison of neutrophil-to-lymphocyte ratio and mean platelet volume in the prediction of adverse events after primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction. Atherosclerosis. 2018;274:212-7.
• ⁴
  Machado GP, Araujo GN, Carpes CK, Niches M, Fracasso JF, Custodio JL, et al. Temporal pattern of neutrophil-to-lymphocyte ratio in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019 Dec;30(8):631–3.
• ⁵
  Forget P, Khalifa C, Defour J-P, Latinne D, Van Pel M-C, De Kock M. What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Res Notes. 2017;10(1):12.
• ⁶
  Kim S, Eliot M, DC K, Wu W, KT K. Association of neutrophil-to-lymphocyte ratio with mortality and cardiovascular disease in the jackson heart study and modification by the duffy antigen variant. JAMA Cardiol
• ⁷
  Tanriverdi Z, Colluoglu T, Dursun H, Kaya D. The Relationship between neutrophil-to-lymphocyte ratio and fragmented QRS in acute STEMI patients treated with primary PCI. J Electrocardiol. 2017 Nov;50(6):876–83.
• ⁸
  Arruda-Olson AM, Reeder GS, Bell MR, Weston SA, Roger VL. Neutrophilia predicts death and heart failure after myocardial infarction: A community-based study. Circ Cardiovasc Qual Outcomes. 2009;2(6):656–62.
• ⁹
  Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol. 2004 Nov;44(10):1945–56.
• ¹⁰
  Narducci ML, Grasselli A, Biasucci LM, Farsetti A, Mule A, Liuzzo G, et al. High telomerase activity in neutrophils from unstable coronary plaques. J Am Coll Cardiol. 2007 Dec;50(25):2369–74.
• ¹¹
  Nunez J, Sanchis J, Bodi V, Nunez E, Mainar L, Heatta AM, et al. Relationship between low lymphocyte count and major cardiac events in patients with acute chest pain, a non-diagnostic electrocardiogram and normal troponin levels. Atherosclerosis. 2009 Sep;206(1):251–7.
• ¹²
  Onsrud M, Thorsby E. Influence of in vivo hydrocortisone on some human blood lymphocyte subpopulations. I. Effect on natural killer cell activity. Scand J Immunol. 1981;13(6):573–9.

Publication Dates

• Publication in this collection
  23 Apr 2021
• Date of issue
  Mar 2021

History

• Received
  14 Apr 2020
• Reviewed
  16 Aug 2020
• Accepted
  09 Sept 2020