402 Original research
The neutrophil-to-lymphocyte ratio is associated with bare-metal stent restenosis in STEMI patients treated with primary PCI Osman Bolcaa, Barış Güngöra, Kazım S. Özcanb, Fatma Ö. Karadeniza, Aylin Sungura, Bayram Köroğlua, Nijad Bakhshyaliyeva, Nizamettin S. Yelgeça, Baran Karataşa, Göktürk İpeka, Hale Yılmaza and Recep Öztürka Background The clinical importance of complete blood count (CBC) parameters such as the neutrophil-tolymphocyte ratio (NLR) has been shown in cardiovascular diseases. Stent restenosis (SR) is a major adverse event after stent implantation. In this study, we aimed to investigate the correlation of CBC parameters with SR rates after primary percutaneous coronary intervention (PCI). Methods Patients who had undergone primary PCI for ST-segment elevation myocardial infarction (STEMI) and control angiography during follow-up were retrospectively recruited. Patients were categorized according to admission NLR tertiles, and clinical, hematological, and angiographic data were compared. Results A total of 404 patients (207 patients with SR and 197 patients without SR) were included in the study. Patients were categorized into three groups according to the tertiles of admission NLRs; the NLR was less than 3.38 in tertile 1 (n = 134), between 3.38 and 6.26 in tertile 2 (n = 135), and greater than 6.26 in tertile 3 (n = 135). During a follow-up period of a median of 14 months (minimum 6 months, maximum 60 months) SR developed in 80 patients of tertile 3 (59%), 74 patients of tertile 2 (55%), and 53 patients of tertile 1 (40%), which were significantly different (P = 0.01). According to multivariate Cox regression analysis, male sex, stent length (odds ratio 1.04, 95% confidence interval 1.01–1.06, P = 0.01), admission
Introduction Primary percutaneous coronary intervention (PCI), including balloon angioplasty and stent implantation, is the preferred and most widely used treatment for STsegment elevation myocardial infarction (STEMI) [1]. However, the inflammatory response and healing process lead to neointimal tissue proliferation and may cause stent restenosis (SR) [2,3]. The rate of SR is about 10%, and it is a major cause of recurrence of symptoms and reintervention [4]. Inflammation has a main role in the pathophysiology of SR [2–4]. The role of inflammation has been shown in cardiovascular diseases including STEMI [5–8]. The neutrophilto-lymphocyte ratio (NLR) is a good indicator of inflammatory status that has prognostic value in STEMI 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
NLRs (odds ratio 1.13, 95% confidence interval 1.08–1.19, P = 0.01), and white blood cell and neutrophil counts remained the independent predictors of SR in the study population. Other CBC parameters and admission C-reactive protein, creatinine, and fasting glucose levels were not independently correlated with SR. On receiver operating curve analysis, admission NLRs higher than 3.84 were found to predict SR with a sensitivity of 73.4% and a specificity of 50.8% (area under the curve 0.604, P = 0.01). Conclusion High NLR levels, white blood cell counts, and neutrophil counts at admission are independently correlated with SR after primary PCI. Coron Artery Dis 26:402–408 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:402–408 Keywords: myocardial infarction, neutrophil-to-lymphocyte ratio, primary percutaneous coronary intervention, restenosis a Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul and bDepartment of Cardiology, Derince Training and Research Hospital, Kocaeli, Turkey
Correspondence to Kazım S. Özcan, MD, İçerenköy mahallesi, Doğanay Sokak, Bayramoğlu apartmanı, Daire:6, Ataşehir, Istanbul, Turkey Tel: + 90 532 6742429, + 90 216 545 47 36; fax: + 90 216 561 38 37; e-mail: [email protected] Received 24 January 2015 Revised 19 March 2015 Accepted 27 March 2015
patients [5–8]. In addition, correlation of the NLR with SR in patients with stable and unstable angina pectoris has been reported [3]. The aim of the present study was to investigate the association of complete blood count (CBC) parameters and especially the NLR with the rate of SR in STEMI patients treated with bare-metal stent (BMS) implantation.
Methods Patient population
Medical records of patients who were admitted to the emergency department of Dr Siyami Ersek Research and Training Hospital with the diagnosis of STEMI and had undergone primary PCI and stent implantation between January 2008 and December 2012 were retrospectively DOI: 10.1097/MCA.0000000000000254
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NLR and bare-metal stent restenosis Bolca et al. 403
collected. Patients were enrolled in the study if they fulfilled the following criteria: (i) presented within 12 h of the onset of symptoms (typical chest pain lasting > 30 min); (ii) had ST-segment elevation of 1 mm or higher in at least two consecutive leads; and (iii) had undergone treatment with BMS deployment. Patients who did not have stent deployment, had undergone surgical revascularization procedures, or had undergone drug eluting stent (DES) implantation were excluded from the study. Initially, 2358 patients were recruited. Medical records were further analyzed to select the patients who had undergone control angiography during the follow-up period. Data on clinical and demographic properties and laboratory parameters were collected from the medical records. Hypertension was defined by a systolic pressure greater than 140 mmHg and/or a diastolic pressure greater than 90 mmHg, or on the basis of whether the individual was taking antihypertensive medications. Diabetes mellitus was defined by a fasting glucose level greater 126 mg/dl and/or on the basis of whether the patient was taking antidiabetic medication. Individuals who reported smoking at least one cigarette per day during the year before the examination were classified as smokers. The study protocol was approved by the local ethics committee. Coronary angiography, primary angioplasty, and stenting, and control angiograms
Angiographic data on primary PCI were obtained from the cardiac catheterization laboratory records and were examined by two independent observers. All patients received chewable aspirin (300 mg, unless contraindicated) and clopidogrel (600 mg, loading dose) before primary PCI. An emergency coronary angiography was performed through a percutaneous femoral approach. In all cases, a nonionic, low-osmolality contrast medium was used. The contralateral artery was first injected. The infarct-related artery was graded according to the Thrombolysis in Myocardial Infarction (TIMI) classification [9]. Heparin (10 000 U) was administered after the coronary anatomy was defined. Coronary artery stenosis of more than 50% was considered clinically significant. Primary coronary interventions, including balloon angioplasty and/or stent implantation, were performed only for the infarct-related artery, according to the lesion anatomy. For each procedure, interventional success at the acute phase was defined by the obstruction and stenosis of the infarct-related artery being reduced to less than 50% stenosis, with a TIMI flow grade of 2 or 3, after primary PCI. After stent placement, clopidogrel was used for more than 1 year and aspirin was used indefinitely. Second coronary angiographies were performed because of clinical indications, including symptoms of angina (stable or unstable) and abnormal noninvasive test results (treadmill exercise test or myocardial perfusion
scintigraphy). Data from control coronary angiograms were interpreted by an independent interventional cardiologist who was blinded to patient characteristics. SR was defined as greater than 50% stenosis within or immediately adjacent (within 5 mm) to the implanted stent(s) according to the control angiographic data [10]. Patients who presented with STEMI and had angiographic evidence of a flow-limiting thrombus near a previously placed stent were excluded from the study. Collection of blood samples
Blood samples were drawn by antecubital venipuncture into EDTA-treated or plain tubes according to hospital protocol. CBC testing utilized clinical laboratory methods (Coulter LH 780 Hematology Analyzer; Beckman Coulter Ireland Inc., Mervue, Galway, Ireland) for hemoglobin, red cell distribution width, total white blood cell count, mean corpuscular volume, platelet count, and mean platelet volume. Baseline NLR was measured by dividing the neutrophil count by the lymphocyte count. Two different CBC results were included in the analysis (i) CBC on admission, and (ii) the last available CBC result during hospitalization. High-sensitivity C-reactive protein (CRP) levels were measured on a Cobas Integra analyzer (Roche Diagnostics, Rotkreuz, Switzerland) using the turbidimetric method. Statistical analysis
All data are presented as mean ± SD or median (interquantile range) for parametric variables and as percentages for categorical variables. Continuous variables were checked for the assumption of normal distribution using Kolmogorov–Smirnov statistics. Categorical variables were tested using Pearson’s χ2-test and Fisher’s exact test. Differences between patients and controls were evaluated using the Kolmogorov–Smirnov test or analysis of variance with Tukey’s post-hoc test, as appropriate. Correlations between two continuous variables were assessed using Pearson’s test. Cox regression analyses were used to investigate the univariate and multivariable predictors of SR during follow-up. The Hosmer–Lemeshow statistic was used to assess the goodness-of-fit of the multivariate regression model, and the area under the curve (AUC) was also calculated. Kaplan–Meier estimates and curves were generated, and comparisons were made using log-rank tests. Receiver operating curves (ROC) were analyzed to assess the best cutoff values of NLR to discriminate SR. A P-value of less than 0.05 was considered statistically significant. All statistical studies were carried out using Statistical Package for Social Sciences software (SPSS 16.0 for Windows; SPSS Inc., Chicago, Illinois, USA).
Results A total of 404 patients (207 patients with SR and 197 patients without SR) were included in the study. The patients were categorized into three groups according to the tertiles of admission NLRs: less than 3.38, tertile 1
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Coronary Artery Disease 2015, Vol 26 No 5
Fig. 1
Neutrophil−lymphocyte ratio (NLR)
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Box-plot graph showing the neutrophil-to-lymphocyte ratio (NLR) in tertiles 1, 2, and 3 of NLR. Middle line, median; bottom of box, 25th percentile; top of box, 75th percentile; whiskers, 95th percentiles.
(n = 134); between 3.38 and 6.26, tertile 2 (n = 135); greater than 6.26, tertile 3 (n = 135; Fig. 1). The demographic and clinical properties, and angiographic data of Table 1
the primary PCI are summarized in Table 1. The three groups were comparable, except for the frequency of smokers, which was higher in tertile 3 (P = 0.01). The distribution of culprit arteries was not different between the groups. The frequency of TIMI 0 flow was significantly higher in tertiles 3 and 2 compared with tertile 1 (78 vs. 66 vs. 34%, respectively, P = 0.01). Accordingly, more patients needed percutaneous transluminal coronary angioplasty and stenting in tertile 3 (74%) compared with tertile 2 (63%) and tertile 1 (51%; P = 0.01). However, the post-PCI TIMI 3 flow restoration rate was not different between the groups (P = 0.63). The mean diameter of the stents implanted was not different between the groups, but the mean length of the implanted stents was longer in tertile 3 and 2 patients compared with tertile 1 patients (19.4 ± 6.2 vs. 18.7 ± 6.2 vs. 17.0 ± 6.1 mm, respectively, P = 0.01). During a follow-up period of a median of 14 months (minimum 6 months, maximum 60 months) SR developed in 80 patients in tertile 3 (59%), 74 patients in tertile 2 (55%), and 53 patients in tertile 1 (40%), which were significantly different (P = 0.01). In the SR subgroup, the frequency of male sex (67 vs. 52%, P = 0.01) and smokers (54 vs. 43%, P = 0.05) was higher, whereas the frequency of patients with diabetes mellitus and hypertension, and of those under tirofiban therapy was not different when compared with the no-SR subgroup. The frequencies of patients with pre-PCI TIMI 0 flow (65 vs. 64%, P = 0.87) and post-PCI TIMI 3 flow (96 vs. 95%, P = 0.56) were not different between SR and no-SR subgroups. The mean diameter of the
Demographic, clinical, and angiographic properties of the groups according to the tertiles of the neutrophil–lymphocyte ratio
Age (years) Male [n (%)] Family history of CAD (%) DM [n (%)] Current smoker [n (%)] HT [n (%)] Prior MI [n (%)] Prior PCI [n (%)] Hyperlipidemia [n (%)] Culprit artery LAD [n (%)] CX [n (%)] RCA [n (%)] PTCA + stent implantation [n (%)] Direct stent implantation [n (%)] Pre-TIMI 0 flow [n (%)] Post-TIMI 3 flow [n (%)] Tirofiban infusion [n (%)] Stent diameter (mm) Stent length (mm) Follow-up duration (months) Second CAG indication SAP [n (%)] USAP [n (%)] Stent restenosis [n (%)]
Tertile 1, NLR < 3.38 (n = 134)
Tertile 2, NLR = 3.38–6.26 (n = 135)
Tertile 3, NLR > 6.26 (n = 135)
P
56.4 ± 9.1 88 (66) 17 (13) 29 (22) 48 (36) 60 (45) 49 (37) 41 (31) 48 (36)
54.9 ± 9.7 95 (70) 22 (16) 34 (25) 68 (50) 53 (39) 46 (34) 43 (32) 40 (30)
55.1 ± 9.9 85 (63) 17 (13) 30 (22) 82 (61) 60 (44) 47 (35) 49 (36) 40 (30)
0.39 0.43 0.53 0.63 0.01 0.52 0.87 0.62 0.41
59 (44) 21 (16) 54 (40) 69 (51) 65 (49) 46 (34) 126 (94) 32 (24) 2.94 ± 0.63 17.0 ± 6.1 14 (20)
63 (47) 25 (19) 47 (35) 85 (63) 50 (37) 89 (66) 130 (96) 43 (32) 2.97 ± 0.70 18.7 ± 6.2 14 (25)
77 (57) 19 (14) 39 (29) 100 (74) 35 (26) 105 (78) 130 (96) 47 (35) 3.04 ± 0.51 19.4 ± 6.2 15 (20)
0.01 0.63 0.13 0.36 0.01 0.74
108 (81) 26 (19) 53 (40)
95 (70) 40 (30) 74 (55)
97 (72) 38 (28) 80 (59)
0.12 0.01
0.21 0.01
CAD, coronary artery disease; CAG, coronary angiography; CX, circumflex artery; DM, diabetes mellitus; HT, hypertension; LAD, left anterior descending artery; MI, myocardial infarction; NLR, neutrophil-to-lymphocyte ratio; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery; SAP, stable angina pectoris; TIMI, Thrombolysis in Myocardial Infarction; USAP, unstable angina pectoris.
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NLR and bare-metal stent restenosis Bolca et al. 405
Table 2
Comparison of the laboratory parameters between the groups of tertiles of the neutrophil-to-lymphocyte ratio
Hemoglobin (g/dl) Platelet (103/μl) MPV (fl) WBC (103/μl) Neutrophil (103/μl) Lymphocyte (103/μl) NLR (admission) NLR (discharge) NLR (mean) RDW (%) MCV (fl) Fasting glucose (mg/dl) Creatinine (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) CRP (admission) (mg/l) Peak CK-MB (IU/l)
Tertile 1, NLR < 3.38 (n = 134)
Tertile 2, NLR = 3.38–6.26 (n = 135)
Tertile 3, NLR > 6.26 (n = 135)
P
14.5 ± 1.2 231 ± 61 8.78 ± 1.04 9.3 ± 2.9 5.65 ± 2.12 2.64 ± 0.78 2.25 ± 0.64 2.15 ± 0.99 2.21 ± 0.69 13.52 ± 0.91 89.9 ± 4.69 116 ± 42 0.91 ± 0.22 190 ± 41 112 ± 36 40.3 ± 10.9 4.02 (2.1) 88 (107)
14.6 ± 1.2 245 ± 54 8.72 ± 0.9 11.5 ± 3.7 8.91 ± 3.0 1.97 ± 0.62 4.64 ± 0.77 2.30 ± 1.13 3.45 ± 0.75 13.61 ± 1.12 89.05 ± 5.65 112 ± 56 0.93 ± 0.78 192 ± 50 118 ± 41 38.1 ± 9.9 6.30 (6.17) 108 (170)
14.4 ± 1.1 247 ± 70 8.62 ± 1.27 14.6 ± 3.4 12.2 ± 2.6 1.46 ± 0.39 9.0 ± 2.19 2.67 ± 1.1 6.51 ± 2.66 13.58 ± 0.98 89.50 ± 4.70 120 ± 55 0.87 ± 0.29 181 ± 46 113 ± 38 37.9 ± 10.8 7.80 (6.0) 172 (185)
0.61 0.11 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.87 0.41 0.64 0.55 0.13 0.45 0.14 0.01 0.01
CK-MB, creatinine kinase MB fraction; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MPV, mean platelet volume; NLR, neutrophil-to-lymphocyte ratio; RDW, red cell distribution width; WBC, white blood cell.
implanted stents was not higher in the SR group (3.03 ± 0.39 vs. 2.93 ± 0.77 mm, P = 0.12), but the mean length of the implanted stents was higher (19.45 ± 6.08 vs. 17.27 ± 6.18 mm, P = 0.01) in the SR subgroup. In the ROC curve analysis, admission NLRs higher than 3.84 predicted SR with a sensitivity of 73.4% and a specificity of 50.8% (AUC 0.604, P = 0.01; Table 2). Univariate and multivariate Cox regression analyses were carried out to investigate the possible predictors of SR in the study population (Table 3). On univariate regression analysis, male sex, presence of pre-PCI TIMI 0 flow, stent length, admission white blood cell count, neutrophil count, NLR, and creatinine and CRP levels were found to be correlated with SR. On multivariate Cox regression analysis, using a model adjusted for sex, the presence of pre-PCI TIMI 0 flow, stent length, admission creatinine and CRP levels, increased NLRs (odds ratio 1.13, 95% confidence interval 1.08–1.19, P = 0.01), and sex were found to independently predict SR. The patients in tertile 3 had a 2.09 times higher risk for SR compared with patients in tertile 1. White blood cell and neutrophil counts and NLRs were analyzed separately in the multivariate regression model to prevent multicollinearity. White blood cell and neutrophil counts were also independently correlated with SR (Table 3). The Hosmer–Lemeshow test statistic was 5.44 (d.f. = 8; P = 0.71), which indicates good model of fit of the regression model. The AUC for the multivariate regression model was 0.649 (95% confidence interval 0.572–0.720). The Kaplan–Meier curve showed a significant difference in the SR rates between the NLR tertile groups (Fig. 2).
Discussion The main finding of the present study was that the elevated preprocedural NLR was an independent predictor of SR in patients with STEMI treated with primary PCI
and BMS implantation. Patients in the highest NLR tertile group had a 2.39 times higher risk for SR compared with patients in the lowest NLR tertile group. The stent length but not the stent diameter was found to be correlated with SR in our study. PCI is the most widely used method for coronary revascularization in patients with stable and unstable angina pectoris. Stent implantation has many advantages when compared with balloon angioplasty such as prevention of recoiling and early reocclusion [9,11]. The major problems with the use of stents are stent thrombosis and SR. Effective antiplatelet therapies have decreased the rates of stent thrombosis and led to a decrease in mortality, especially after STEMI [9]. The development of DESs led to a marked decrease in SR rates when compared with BMSs [9]. However, SR is still the most important cause for recurrence of symptoms and reintervention [4,9, 12,13]. The underlying mechanism of SR is complex and includes biological and mechanical factors. Local and systemic inflammatory responses, neointimal proliferation, and matrix remodeling are the major pathophysiological mechanisms of SR [4,12,13]. In addition, incomplete stent expansion, stent malapposition, and barotrauma to unstented segments may cause SR [4,9,12, 13]. Inflammation probably has the most important role of all the known biological risk factors in the development of coronary restenosis [13]. The correlation of inflammatory markers with adverse events after stent implantation has been shown in various trials. Preprocedurally, elevated levels of CRP are associated with SR, especially in patients with unstable angina [14]. In addition, a postprocedural increase in CRP predicts SR after BMS deployment [15]. Park et al. [16] showed that baseline CRP levels were associated with an increased risk of death, myocardial infarction, and stent thrombosis after DES implantation. However, in
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Table 3
Univariate and multivariate Cox regression analysis for the possible predictors of stent restenosis in the study population
Variables
Unadjusted OR (95% CI)
Age, 1 − SD increase Male sex Hypertension Smoking Pre-PCI TIMI 0 flow PTCA + stenting vs. direct stenting Tirofiban infusion Stent diameter, 1 − SD increase Stent length, 1 − SD increase Fasting glucose, 1 − SD increase Creatinine, 1 − SD increase Peak CK-MB, 1 − SD increase Total cholesterol, 1 − SD increase LDL cholesterol, 1 − SD increase HDL cholesterol, 1 − SD decrease Triglycerides, 1 − SD increase Hemoglobin, 1 − SD decrease Platelet count, 1 − SD increase MPV, 1 − SD increase MCV, 1 − SD increase RDW, 1 − SD increase WBC, 1 − SD increasea Neutrophil count, 1 − SD increasea Lymphocyte count, 1 − SD decrease NLR (admission) tertilesa Tertile 1 Tertile 2 Tertile 3 NLR (admission), 1 − SD increasea CRP, 1 − SD increase
0.99 1.51 0.88 1.04 1.39 1.29 1.25 1.29 1.06 1.01 0.57 1.01 1.0 1.003 0.99 0.99 0.93 1.002 0.91 1.02 0.98 1.05 1.07 1.09
(0.98–1.01) (1.12–2.01) (0.67–1.16) (0.16–7.41) (1.04–1.85) (0.97–1.72) (0.92–1.68) (0.98–1.71) (1.04–1.09) (0.99–1.02) (0.33–1.01) (0.99–1.003) (0.99–1.01) (1.0–1.007) (0.98–1.01) (0.98–1.01) (0.83–1.05) (0.99–1.004) (0.79–1.06) (0.99–1.05) (0.86–1.12) (1.02–1.09) (1.04–1.11) (0.91–1.31)
Reference 1.47 (1.04–2.11) 1.81 (1.27–2.56) 1.12 (1.07–1.16) 1.02 (1.01–1.05)
P 0.19 0.01 0.38 0.95 0.03 0.08 0.15 0.07 0.01 0.54 0.05 0.21 0.74 0.07 0.82 0.51 0.26 0.14 0.23 0.17 0.86 0.01 0.01 0.31 – 0.03 0.01 0.01 0.04
Adjusted OR (95% CI)* 1.85
1.02 1.02 1.03 1.04 0.66
1.003
1.06 1.08
1.44 2.09 1.13 1.004
P
– (1.33–2.55) – – (0.69–1.49) (0.69–1.49) – (074–1.44) (1.01–1.06) – (0.37–1.21) – – (0.99–1.007) – – – – – – – (1.02–1.10) (1.04–1.13) –
– 0.01 – – 0.92 0.93 – 0.85 0.01 – 0.18 – – 0.12 – – – – – – – 0.01 0.01 –
– (0.96–2.17) (1.35–3.24) (1.08–1.19) (0.98–1.03)
– 0.07 0.01 0.01 0.77
CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MPV, mean platelet volume; NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RDW, red cell distribution width; TIMI, Thrombolysis in Myocardial Infarction; WBC, white blood cell. a White blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio (tertiles and as a continuous variable) were entered into the multivariate model separately to prevent multicollinearity. *Parameters with P < 0.10 in the univariate model were entered into multivariate regression analysis.
contrast to BMS deployment, preprocedural serum CRP levels do not appear to predict SR after DES deployment [17]. Other inflammatory biomarkers such as fibrinogen, interleukin-1β, interleukin-6, interleukin-10, complement components, and the vitamin D receptor may also provide additional information on the preprocedural inflammatory state and anticipation of SR [18–22]. NLR is a marker of systemic inflammation that has been shown to predict adverse cardiovascular events. Elevated neutrophil levels have been shown to be associated with worse angiographic outcomes, larger infarct sizes, and worse prognosis in STEMI [23–25]. Neutrophils mediate the inflammatory response to acute myocardial injury through numerous biochemical mechanisms, resulting in further tissue damage. These include the release of arachidonic acid metabolites and platelet-aggravating factors, cytotoxic oxygen-derived free radicals, myeloperoxidase, elastase, and various hydrolytic enzymes, such as acid phosphatases [26–29]. The relative lymphopenia observed in patients with acute myocardial infarction is considered to be a stress response mediated by the increased endogenous cortisol level and is shown to be an early marker of acute myocardial infarction [30,31]. For interventional and surgical cardiac procedures, a high preprocedural NLR is a powerful and independent predictor of mortality
among patients undergoing coronary angiography and PCI [32,33]. A high preprocedural NLR is directly correlated with myocardial infarct size and left ventricular function in patients with STEMI undergoing primary PCI [34]. Kurtul et al. [35] reported that STEMI patients with higher NLRs are at a higher risk of having TIMI 0/1 flow in the culprit artery during primary PCI. In concordance with this finding, we found that the frequency of preprocedural TIMI 0 flow was significantly higher in tertiles 3 and 2 compared with tertile 1. However, the presence of TIMI 0 flow was not independently correlated with SR. Sen et al. [36] reported that an elevated admission NLR was correlated with both the no-reflow phenomenon and the long-term prognosis. However, we did not find a significant difference in TIMI 3 flow restoration rates between NLR tertiles. In another study, it was demonstrated that the NLR at 24 h was an independent predictor of mortality after STEMI, increasing the risk by ∼ 5% for every unit increase [37]. The correlation of NLR with SR on BMS deployment was investigated previously by Turak and colleagues in patients with stable (70%) and unstable angina pectoris (30%). They found that higher NLRs (especially NLR > 2.73) were independently associated with SR. In our study, ROC curve analysis revealed NLR greater
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NLR and bare-metal stent restenosis Bolca et al. 407
generalizable to STEMI patients treated with DES implantation.
Fig. 2
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Acknowledgements Conflicts of interest
Event-free survival
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There are no conflicts of interest.
References
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Kaplan–Meier curve showing the correlation between tertiles of the neutrophil-to-lymphocyte ratio (NLR) and stent restenosis in the study population.
than 3.84 as a cutoff value for SR. In our study, we only included patients with STEMI and searched for the development of angiographic SR rather than adverse cardiovascular events during the follow-up period. For the first time in the literature, we have shown that admission NLR is an independent and powerful predictor of SR after BMS implantation in patients with STEMI. The NLR levels decreased markedly during hospitalization, and we found that predischarge NLRs were not associated with SR. In conclusion, high preprocedural NLR is an important predictor of SR among patients treated with BMS implantation after STEMI. Further studies are needed to confirm and reveal the clinical implications of our findings. Limitations
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Our study has several limitations. This study was conducted on a retrospective basis, and represents a singlecenter experience. The definition of stenosis was based on visual inspection, not on quantitative measurements. The use of a single blood sample during the preoperational period does not allow the anticipation of the persistence of NLR over time, and we could not investigate the impact of medications on NLRs during hospitalization. In addition, our findings may not be
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The neutrophil-to-lymphocyte ratio is associated with bare-metal stent restenosis in STEMI patients treated with primary PCI Osman Bolcaa, Barış Güngöra, Kazım S. Özcanb, Fatma Ö. Karadeniza, Aylin Sungura, Bayram Köroğlua, Nijad Bakhshyaliyeva, Nizamettin S. Yelgeça, Baran Karataşa, Göktürk İpeka, Hale Yılmaza and Recep Öztürka Background The clinical importance of complete blood count (CBC) parameters such as the neutrophil-tolymphocyte ratio (NLR) has been shown in cardiovascular diseases. Stent restenosis (SR) is a major adverse event after stent implantation. In this study, we aimed to investigate the correlation of CBC parameters with SR rates after primary percutaneous coronary intervention (PCI). Methods Patients who had undergone primary PCI for ST-segment elevation myocardial infarction (STEMI) and control angiography during follow-up were retrospectively recruited. Patients were categorized according to admission NLR tertiles, and clinical, hematological, and angiographic data were compared. Results A total of 404 patients (207 patients with SR and 197 patients without SR) were included in the study. Patients were categorized into three groups according to the tertiles of admission NLRs; the NLR was less than 3.38 in tertile 1 (n = 134), between 3.38 and 6.26 in tertile 2 (n = 135), and greater than 6.26 in tertile 3 (n = 135). During a follow-up period of a median of 14 months (minimum 6 months, maximum 60 months) SR developed in 80 patients of tertile 3 (59%), 74 patients of tertile 2 (55%), and 53 patients of tertile 1 (40%), which were significantly different (P = 0.01). According to multivariate Cox regression analysis, male sex, stent length (odds ratio 1.04, 95% confidence interval 1.01–1.06, P = 0.01), admission
Introduction Primary percutaneous coronary intervention (PCI), including balloon angioplasty and stent implantation, is the preferred and most widely used treatment for STsegment elevation myocardial infarction (STEMI) [1]. However, the inflammatory response and healing process lead to neointimal tissue proliferation and may cause stent restenosis (SR) [2,3]. The rate of SR is about 10%, and it is a major cause of recurrence of symptoms and reintervention [4]. Inflammation has a main role in the pathophysiology of SR [2–4]. The role of inflammation has been shown in cardiovascular diseases including STEMI [5–8]. The neutrophilto-lymphocyte ratio (NLR) is a good indicator of inflammatory status that has prognostic value in STEMI 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
NLRs (odds ratio 1.13, 95% confidence interval 1.08–1.19, P = 0.01), and white blood cell and neutrophil counts remained the independent predictors of SR in the study population. Other CBC parameters and admission C-reactive protein, creatinine, and fasting glucose levels were not independently correlated with SR. On receiver operating curve analysis, admission NLRs higher than 3.84 were found to predict SR with a sensitivity of 73.4% and a specificity of 50.8% (area under the curve 0.604, P = 0.01). Conclusion High NLR levels, white blood cell counts, and neutrophil counts at admission are independently correlated with SR after primary PCI. Coron Artery Dis 26:402–408 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:402–408 Keywords: myocardial infarction, neutrophil-to-lymphocyte ratio, primary percutaneous coronary intervention, restenosis a Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul and bDepartment of Cardiology, Derince Training and Research Hospital, Kocaeli, Turkey
Correspondence to Kazım S. Özcan, MD, İçerenköy mahallesi, Doğanay Sokak, Bayramoğlu apartmanı, Daire:6, Ataşehir, Istanbul, Turkey Tel: + 90 532 6742429, + 90 216 545 47 36; fax: + 90 216 561 38 37; e-mail: [email protected] Received 24 January 2015 Revised 19 March 2015 Accepted 27 March 2015
patients [5–8]. In addition, correlation of the NLR with SR in patients with stable and unstable angina pectoris has been reported [3]. The aim of the present study was to investigate the association of complete blood count (CBC) parameters and especially the NLR with the rate of SR in STEMI patients treated with bare-metal stent (BMS) implantation.
Methods Patient population
Medical records of patients who were admitted to the emergency department of Dr Siyami Ersek Research and Training Hospital with the diagnosis of STEMI and had undergone primary PCI and stent implantation between January 2008 and December 2012 were retrospectively DOI: 10.1097/MCA.0000000000000254
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NLR and bare-metal stent restenosis Bolca et al. 403
collected. Patients were enrolled in the study if they fulfilled the following criteria: (i) presented within 12 h of the onset of symptoms (typical chest pain lasting > 30 min); (ii) had ST-segment elevation of 1 mm or higher in at least two consecutive leads; and (iii) had undergone treatment with BMS deployment. Patients who did not have stent deployment, had undergone surgical revascularization procedures, or had undergone drug eluting stent (DES) implantation were excluded from the study. Initially, 2358 patients were recruited. Medical records were further analyzed to select the patients who had undergone control angiography during the follow-up period. Data on clinical and demographic properties and laboratory parameters were collected from the medical records. Hypertension was defined by a systolic pressure greater than 140 mmHg and/or a diastolic pressure greater than 90 mmHg, or on the basis of whether the individual was taking antihypertensive medications. Diabetes mellitus was defined by a fasting glucose level greater 126 mg/dl and/or on the basis of whether the patient was taking antidiabetic medication. Individuals who reported smoking at least one cigarette per day during the year before the examination were classified as smokers. The study protocol was approved by the local ethics committee. Coronary angiography, primary angioplasty, and stenting, and control angiograms
Angiographic data on primary PCI were obtained from the cardiac catheterization laboratory records and were examined by two independent observers. All patients received chewable aspirin (300 mg, unless contraindicated) and clopidogrel (600 mg, loading dose) before primary PCI. An emergency coronary angiography was performed through a percutaneous femoral approach. In all cases, a nonionic, low-osmolality contrast medium was used. The contralateral artery was first injected. The infarct-related artery was graded according to the Thrombolysis in Myocardial Infarction (TIMI) classification [9]. Heparin (10 000 U) was administered after the coronary anatomy was defined. Coronary artery stenosis of more than 50% was considered clinically significant. Primary coronary interventions, including balloon angioplasty and/or stent implantation, were performed only for the infarct-related artery, according to the lesion anatomy. For each procedure, interventional success at the acute phase was defined by the obstruction and stenosis of the infarct-related artery being reduced to less than 50% stenosis, with a TIMI flow grade of 2 or 3, after primary PCI. After stent placement, clopidogrel was used for more than 1 year and aspirin was used indefinitely. Second coronary angiographies were performed because of clinical indications, including symptoms of angina (stable or unstable) and abnormal noninvasive test results (treadmill exercise test or myocardial perfusion
scintigraphy). Data from control coronary angiograms were interpreted by an independent interventional cardiologist who was blinded to patient characteristics. SR was defined as greater than 50% stenosis within or immediately adjacent (within 5 mm) to the implanted stent(s) according to the control angiographic data [10]. Patients who presented with STEMI and had angiographic evidence of a flow-limiting thrombus near a previously placed stent were excluded from the study. Collection of blood samples
Blood samples were drawn by antecubital venipuncture into EDTA-treated or plain tubes according to hospital protocol. CBC testing utilized clinical laboratory methods (Coulter LH 780 Hematology Analyzer; Beckman Coulter Ireland Inc., Mervue, Galway, Ireland) for hemoglobin, red cell distribution width, total white blood cell count, mean corpuscular volume, platelet count, and mean platelet volume. Baseline NLR was measured by dividing the neutrophil count by the lymphocyte count. Two different CBC results were included in the analysis (i) CBC on admission, and (ii) the last available CBC result during hospitalization. High-sensitivity C-reactive protein (CRP) levels were measured on a Cobas Integra analyzer (Roche Diagnostics, Rotkreuz, Switzerland) using the turbidimetric method. Statistical analysis
All data are presented as mean ± SD or median (interquantile range) for parametric variables and as percentages for categorical variables. Continuous variables were checked for the assumption of normal distribution using Kolmogorov–Smirnov statistics. Categorical variables were tested using Pearson’s χ2-test and Fisher’s exact test. Differences between patients and controls were evaluated using the Kolmogorov–Smirnov test or analysis of variance with Tukey’s post-hoc test, as appropriate. Correlations between two continuous variables were assessed using Pearson’s test. Cox regression analyses were used to investigate the univariate and multivariable predictors of SR during follow-up. The Hosmer–Lemeshow statistic was used to assess the goodness-of-fit of the multivariate regression model, and the area under the curve (AUC) was also calculated. Kaplan–Meier estimates and curves were generated, and comparisons were made using log-rank tests. Receiver operating curves (ROC) were analyzed to assess the best cutoff values of NLR to discriminate SR. A P-value of less than 0.05 was considered statistically significant. All statistical studies were carried out using Statistical Package for Social Sciences software (SPSS 16.0 for Windows; SPSS Inc., Chicago, Illinois, USA).
Results A total of 404 patients (207 patients with SR and 197 patients without SR) were included in the study. The patients were categorized into three groups according to the tertiles of admission NLRs: less than 3.38, tertile 1
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Fig. 1
Neutrophil−lymphocyte ratio (NLR)
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Box-plot graph showing the neutrophil-to-lymphocyte ratio (NLR) in tertiles 1, 2, and 3 of NLR. Middle line, median; bottom of box, 25th percentile; top of box, 75th percentile; whiskers, 95th percentiles.
(n = 134); between 3.38 and 6.26, tertile 2 (n = 135); greater than 6.26, tertile 3 (n = 135; Fig. 1). The demographic and clinical properties, and angiographic data of Table 1
the primary PCI are summarized in Table 1. The three groups were comparable, except for the frequency of smokers, which was higher in tertile 3 (P = 0.01). The distribution of culprit arteries was not different between the groups. The frequency of TIMI 0 flow was significantly higher in tertiles 3 and 2 compared with tertile 1 (78 vs. 66 vs. 34%, respectively, P = 0.01). Accordingly, more patients needed percutaneous transluminal coronary angioplasty and stenting in tertile 3 (74%) compared with tertile 2 (63%) and tertile 1 (51%; P = 0.01). However, the post-PCI TIMI 3 flow restoration rate was not different between the groups (P = 0.63). The mean diameter of the stents implanted was not different between the groups, but the mean length of the implanted stents was longer in tertile 3 and 2 patients compared with tertile 1 patients (19.4 ± 6.2 vs. 18.7 ± 6.2 vs. 17.0 ± 6.1 mm, respectively, P = 0.01). During a follow-up period of a median of 14 months (minimum 6 months, maximum 60 months) SR developed in 80 patients in tertile 3 (59%), 74 patients in tertile 2 (55%), and 53 patients in tertile 1 (40%), which were significantly different (P = 0.01). In the SR subgroup, the frequency of male sex (67 vs. 52%, P = 0.01) and smokers (54 vs. 43%, P = 0.05) was higher, whereas the frequency of patients with diabetes mellitus and hypertension, and of those under tirofiban therapy was not different when compared with the no-SR subgroup. The frequencies of patients with pre-PCI TIMI 0 flow (65 vs. 64%, P = 0.87) and post-PCI TIMI 3 flow (96 vs. 95%, P = 0.56) were not different between SR and no-SR subgroups. The mean diameter of the
Demographic, clinical, and angiographic properties of the groups according to the tertiles of the neutrophil–lymphocyte ratio
Age (years) Male [n (%)] Family history of CAD (%) DM [n (%)] Current smoker [n (%)] HT [n (%)] Prior MI [n (%)] Prior PCI [n (%)] Hyperlipidemia [n (%)] Culprit artery LAD [n (%)] CX [n (%)] RCA [n (%)] PTCA + stent implantation [n (%)] Direct stent implantation [n (%)] Pre-TIMI 0 flow [n (%)] Post-TIMI 3 flow [n (%)] Tirofiban infusion [n (%)] Stent diameter (mm) Stent length (mm) Follow-up duration (months) Second CAG indication SAP [n (%)] USAP [n (%)] Stent restenosis [n (%)]
Tertile 1, NLR < 3.38 (n = 134)
Tertile 2, NLR = 3.38–6.26 (n = 135)
Tertile 3, NLR > 6.26 (n = 135)
P
56.4 ± 9.1 88 (66) 17 (13) 29 (22) 48 (36) 60 (45) 49 (37) 41 (31) 48 (36)
54.9 ± 9.7 95 (70) 22 (16) 34 (25) 68 (50) 53 (39) 46 (34) 43 (32) 40 (30)
55.1 ± 9.9 85 (63) 17 (13) 30 (22) 82 (61) 60 (44) 47 (35) 49 (36) 40 (30)
0.39 0.43 0.53 0.63 0.01 0.52 0.87 0.62 0.41
59 (44) 21 (16) 54 (40) 69 (51) 65 (49) 46 (34) 126 (94) 32 (24) 2.94 ± 0.63 17.0 ± 6.1 14 (20)
63 (47) 25 (19) 47 (35) 85 (63) 50 (37) 89 (66) 130 (96) 43 (32) 2.97 ± 0.70 18.7 ± 6.2 14 (25)
77 (57) 19 (14) 39 (29) 100 (74) 35 (26) 105 (78) 130 (96) 47 (35) 3.04 ± 0.51 19.4 ± 6.2 15 (20)
0.01 0.63 0.13 0.36 0.01 0.74
108 (81) 26 (19) 53 (40)
95 (70) 40 (30) 74 (55)
97 (72) 38 (28) 80 (59)
0.12 0.01
0.21 0.01
CAD, coronary artery disease; CAG, coronary angiography; CX, circumflex artery; DM, diabetes mellitus; HT, hypertension; LAD, left anterior descending artery; MI, myocardial infarction; NLR, neutrophil-to-lymphocyte ratio; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery; SAP, stable angina pectoris; TIMI, Thrombolysis in Myocardial Infarction; USAP, unstable angina pectoris.
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NLR and bare-metal stent restenosis Bolca et al. 405
Table 2
Comparison of the laboratory parameters between the groups of tertiles of the neutrophil-to-lymphocyte ratio
Hemoglobin (g/dl) Platelet (103/μl) MPV (fl) WBC (103/μl) Neutrophil (103/μl) Lymphocyte (103/μl) NLR (admission) NLR (discharge) NLR (mean) RDW (%) MCV (fl) Fasting glucose (mg/dl) Creatinine (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) CRP (admission) (mg/l) Peak CK-MB (IU/l)
Tertile 1, NLR < 3.38 (n = 134)
Tertile 2, NLR = 3.38–6.26 (n = 135)
Tertile 3, NLR > 6.26 (n = 135)
P
14.5 ± 1.2 231 ± 61 8.78 ± 1.04 9.3 ± 2.9 5.65 ± 2.12 2.64 ± 0.78 2.25 ± 0.64 2.15 ± 0.99 2.21 ± 0.69 13.52 ± 0.91 89.9 ± 4.69 116 ± 42 0.91 ± 0.22 190 ± 41 112 ± 36 40.3 ± 10.9 4.02 (2.1) 88 (107)
14.6 ± 1.2 245 ± 54 8.72 ± 0.9 11.5 ± 3.7 8.91 ± 3.0 1.97 ± 0.62 4.64 ± 0.77 2.30 ± 1.13 3.45 ± 0.75 13.61 ± 1.12 89.05 ± 5.65 112 ± 56 0.93 ± 0.78 192 ± 50 118 ± 41 38.1 ± 9.9 6.30 (6.17) 108 (170)
14.4 ± 1.1 247 ± 70 8.62 ± 1.27 14.6 ± 3.4 12.2 ± 2.6 1.46 ± 0.39 9.0 ± 2.19 2.67 ± 1.1 6.51 ± 2.66 13.58 ± 0.98 89.50 ± 4.70 120 ± 55 0.87 ± 0.29 181 ± 46 113 ± 38 37.9 ± 10.8 7.80 (6.0) 172 (185)
0.61 0.11 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.87 0.41 0.64 0.55 0.13 0.45 0.14 0.01 0.01
CK-MB, creatinine kinase MB fraction; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MPV, mean platelet volume; NLR, neutrophil-to-lymphocyte ratio; RDW, red cell distribution width; WBC, white blood cell.
implanted stents was not higher in the SR group (3.03 ± 0.39 vs. 2.93 ± 0.77 mm, P = 0.12), but the mean length of the implanted stents was higher (19.45 ± 6.08 vs. 17.27 ± 6.18 mm, P = 0.01) in the SR subgroup. In the ROC curve analysis, admission NLRs higher than 3.84 predicted SR with a sensitivity of 73.4% and a specificity of 50.8% (AUC 0.604, P = 0.01; Table 2). Univariate and multivariate Cox regression analyses were carried out to investigate the possible predictors of SR in the study population (Table 3). On univariate regression analysis, male sex, presence of pre-PCI TIMI 0 flow, stent length, admission white blood cell count, neutrophil count, NLR, and creatinine and CRP levels were found to be correlated with SR. On multivariate Cox regression analysis, using a model adjusted for sex, the presence of pre-PCI TIMI 0 flow, stent length, admission creatinine and CRP levels, increased NLRs (odds ratio 1.13, 95% confidence interval 1.08–1.19, P = 0.01), and sex were found to independently predict SR. The patients in tertile 3 had a 2.09 times higher risk for SR compared with patients in tertile 1. White blood cell and neutrophil counts and NLRs were analyzed separately in the multivariate regression model to prevent multicollinearity. White blood cell and neutrophil counts were also independently correlated with SR (Table 3). The Hosmer–Lemeshow test statistic was 5.44 (d.f. = 8; P = 0.71), which indicates good model of fit of the regression model. The AUC for the multivariate regression model was 0.649 (95% confidence interval 0.572–0.720). The Kaplan–Meier curve showed a significant difference in the SR rates between the NLR tertile groups (Fig. 2).
Discussion The main finding of the present study was that the elevated preprocedural NLR was an independent predictor of SR in patients with STEMI treated with primary PCI
and BMS implantation. Patients in the highest NLR tertile group had a 2.39 times higher risk for SR compared with patients in the lowest NLR tertile group. The stent length but not the stent diameter was found to be correlated with SR in our study. PCI is the most widely used method for coronary revascularization in patients with stable and unstable angina pectoris. Stent implantation has many advantages when compared with balloon angioplasty such as prevention of recoiling and early reocclusion [9,11]. The major problems with the use of stents are stent thrombosis and SR. Effective antiplatelet therapies have decreased the rates of stent thrombosis and led to a decrease in mortality, especially after STEMI [9]. The development of DESs led to a marked decrease in SR rates when compared with BMSs [9]. However, SR is still the most important cause for recurrence of symptoms and reintervention [4,9, 12,13]. The underlying mechanism of SR is complex and includes biological and mechanical factors. Local and systemic inflammatory responses, neointimal proliferation, and matrix remodeling are the major pathophysiological mechanisms of SR [4,12,13]. In addition, incomplete stent expansion, stent malapposition, and barotrauma to unstented segments may cause SR [4,9,12, 13]. Inflammation probably has the most important role of all the known biological risk factors in the development of coronary restenosis [13]. The correlation of inflammatory markers with adverse events after stent implantation has been shown in various trials. Preprocedurally, elevated levels of CRP are associated with SR, especially in patients with unstable angina [14]. In addition, a postprocedural increase in CRP predicts SR after BMS deployment [15]. Park et al. [16] showed that baseline CRP levels were associated with an increased risk of death, myocardial infarction, and stent thrombosis after DES implantation. However, in
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Table 3
Univariate and multivariate Cox regression analysis for the possible predictors of stent restenosis in the study population
Variables
Unadjusted OR (95% CI)
Age, 1 − SD increase Male sex Hypertension Smoking Pre-PCI TIMI 0 flow PTCA + stenting vs. direct stenting Tirofiban infusion Stent diameter, 1 − SD increase Stent length, 1 − SD increase Fasting glucose, 1 − SD increase Creatinine, 1 − SD increase Peak CK-MB, 1 − SD increase Total cholesterol, 1 − SD increase LDL cholesterol, 1 − SD increase HDL cholesterol, 1 − SD decrease Triglycerides, 1 − SD increase Hemoglobin, 1 − SD decrease Platelet count, 1 − SD increase MPV, 1 − SD increase MCV, 1 − SD increase RDW, 1 − SD increase WBC, 1 − SD increasea Neutrophil count, 1 − SD increasea Lymphocyte count, 1 − SD decrease NLR (admission) tertilesa Tertile 1 Tertile 2 Tertile 3 NLR (admission), 1 − SD increasea CRP, 1 − SD increase
0.99 1.51 0.88 1.04 1.39 1.29 1.25 1.29 1.06 1.01 0.57 1.01 1.0 1.003 0.99 0.99 0.93 1.002 0.91 1.02 0.98 1.05 1.07 1.09
(0.98–1.01) (1.12–2.01) (0.67–1.16) (0.16–7.41) (1.04–1.85) (0.97–1.72) (0.92–1.68) (0.98–1.71) (1.04–1.09) (0.99–1.02) (0.33–1.01) (0.99–1.003) (0.99–1.01) (1.0–1.007) (0.98–1.01) (0.98–1.01) (0.83–1.05) (0.99–1.004) (0.79–1.06) (0.99–1.05) (0.86–1.12) (1.02–1.09) (1.04–1.11) (0.91–1.31)
Reference 1.47 (1.04–2.11) 1.81 (1.27–2.56) 1.12 (1.07–1.16) 1.02 (1.01–1.05)
P 0.19 0.01 0.38 0.95 0.03 0.08 0.15 0.07 0.01 0.54 0.05 0.21 0.74 0.07 0.82 0.51 0.26 0.14 0.23 0.17 0.86 0.01 0.01 0.31 – 0.03 0.01 0.01 0.04
Adjusted OR (95% CI)* 1.85
1.02 1.02 1.03 1.04 0.66
1.003
1.06 1.08
1.44 2.09 1.13 1.004
P
– (1.33–2.55) – – (0.69–1.49) (0.69–1.49) – (074–1.44) (1.01–1.06) – (0.37–1.21) – – (0.99–1.007) – – – – – – – (1.02–1.10) (1.04–1.13) –
– 0.01 – – 0.92 0.93 – 0.85 0.01 – 0.18 – – 0.12 – – – – – – – 0.01 0.01 –
– (0.96–2.17) (1.35–3.24) (1.08–1.19) (0.98–1.03)
– 0.07 0.01 0.01 0.77
CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MPV, mean platelet volume; NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RDW, red cell distribution width; TIMI, Thrombolysis in Myocardial Infarction; WBC, white blood cell. a White blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio (tertiles and as a continuous variable) were entered into the multivariate model separately to prevent multicollinearity. *Parameters with P < 0.10 in the univariate model were entered into multivariate regression analysis.
contrast to BMS deployment, preprocedural serum CRP levels do not appear to predict SR after DES deployment [17]. Other inflammatory biomarkers such as fibrinogen, interleukin-1β, interleukin-6, interleukin-10, complement components, and the vitamin D receptor may also provide additional information on the preprocedural inflammatory state and anticipation of SR [18–22]. NLR is a marker of systemic inflammation that has been shown to predict adverse cardiovascular events. Elevated neutrophil levels have been shown to be associated with worse angiographic outcomes, larger infarct sizes, and worse prognosis in STEMI [23–25]. Neutrophils mediate the inflammatory response to acute myocardial injury through numerous biochemical mechanisms, resulting in further tissue damage. These include the release of arachidonic acid metabolites and platelet-aggravating factors, cytotoxic oxygen-derived free radicals, myeloperoxidase, elastase, and various hydrolytic enzymes, such as acid phosphatases [26–29]. The relative lymphopenia observed in patients with acute myocardial infarction is considered to be a stress response mediated by the increased endogenous cortisol level and is shown to be an early marker of acute myocardial infarction [30,31]. For interventional and surgical cardiac procedures, a high preprocedural NLR is a powerful and independent predictor of mortality
among patients undergoing coronary angiography and PCI [32,33]. A high preprocedural NLR is directly correlated with myocardial infarct size and left ventricular function in patients with STEMI undergoing primary PCI [34]. Kurtul et al. [35] reported that STEMI patients with higher NLRs are at a higher risk of having TIMI 0/1 flow in the culprit artery during primary PCI. In concordance with this finding, we found that the frequency of preprocedural TIMI 0 flow was significantly higher in tertiles 3 and 2 compared with tertile 1. However, the presence of TIMI 0 flow was not independently correlated with SR. Sen et al. [36] reported that an elevated admission NLR was correlated with both the no-reflow phenomenon and the long-term prognosis. However, we did not find a significant difference in TIMI 3 flow restoration rates between NLR tertiles. In another study, it was demonstrated that the NLR at 24 h was an independent predictor of mortality after STEMI, increasing the risk by ∼ 5% for every unit increase [37]. The correlation of NLR with SR on BMS deployment was investigated previously by Turak and colleagues in patients with stable (70%) and unstable angina pectoris (30%). They found that higher NLRs (especially NLR > 2.73) were independently associated with SR. In our study, ROC curve analysis revealed NLR greater
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NLR and bare-metal stent restenosis Bolca et al. 407
generalizable to STEMI patients treated with DES implantation.
Fig. 2
1.0
Acknowledgements Conflicts of interest
Event-free survival
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There are no conflicts of interest.
References
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P = 0.01 (log-rank test)
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Kaplan–Meier curve showing the correlation between tertiles of the neutrophil-to-lymphocyte ratio (NLR) and stent restenosis in the study population.
than 3.84 as a cutoff value for SR. In our study, we only included patients with STEMI and searched for the development of angiographic SR rather than adverse cardiovascular events during the follow-up period. For the first time in the literature, we have shown that admission NLR is an independent and powerful predictor of SR after BMS implantation in patients with STEMI. The NLR levels decreased markedly during hospitalization, and we found that predischarge NLRs were not associated with SR. In conclusion, high preprocedural NLR is an important predictor of SR among patients treated with BMS implantation after STEMI. Further studies are needed to confirm and reveal the clinical implications of our findings. Limitations
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Our study has several limitations. This study was conducted on a retrospective basis, and represents a singlecenter experience. The definition of stenosis was based on visual inspection, not on quantitative measurements. The use of a single blood sample during the preoperational period does not allow the anticipation of the persistence of NLR over time, and we could not investigate the impact of medications on NLRs during hospitalization. In addition, our findings may not be
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