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Lymphocyte Ratio in Patients Undergoing Noncardiac Surgery After Coronary Stent Implantation
ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 1 10
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Original Article
Neutrophil/Lymphocyte Ratio in Patients Undergoing Noncardiac Surgery After Coronary Stent Implantation Jaeyeon Chung, MD, Jinyoung Bae, MD, Yongsuk Kwon, MD, Hyun-Kyu Yoon, MD, Seokha Yoo, MD, Ho-Jim Lee, MD, Sun-Kyung Park, MD, PhD, Jin-Tae Kim, MD, PhD, 1 Won Ho Kim, MD, PhD Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Objective: Perioperative cell count associated predictors, including the neutrophil/lymphocyte ratio (N/LR) and platelet/lymphocyte ratio (P/LR), are associated with poor clinical outcomes including myocardial injury. Study investigators aimed to examine the association among the perioperative N/LR, P/LR, and postoperative major adverse cardiovascular and cerebral events (MACCE) after noncardiac surgery in patients with drug-eluting stent (DES) insertion. Design: Retrospective and observational. Setting: Single university hospital. Participants: The study comprised 965 patients who underwent noncardiac surgery within 6 months after DES implantation. Interventions: None. Measurements and Main Results: Baseline perioperative clinical parameters, including N/LR and P/LR measured before surgery, immediately after surgery, and on postoperative day (POD) 1, were obtained. MACCE was defined as a composite of nonfatal myocardial infarction, coronary revascularization, nonhemorrhagic stroke, and pulmonary embolism within 1 month after surgery. Multivariate logistic regression analysis and propensity score matching were used to identify predictors of MACCE after surgery. MACCE occurred in 67 patients (6.9%) and was more common in patients with N/LR on POD 1 >4.3 (multivariable-adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040 and as a continuous N/LR [OR 1.17, 95% CI 1.08-1.27; p < 0.001]). This association was consistent after propensity score matching and was stronger when the antiplatelet agent was stopped before surgery (OR 3.02, 95% CI 2.14-4.48; p = 0.006 for stopping dual antiplatelet therapy). Conclusions: In patients undergoing noncardiac surgery within 6 months after DES implantation, elevated N/LR on POD 1 is independently associated with postoperative MACCE. Elevated postoperative N/LR as a marker of systemic inflammation may help to predict the development of MACCE in these high-risk patients. Ó 2019 Elsevier Inc. All rights reserved. Key Words: surgery; major adverse cardiovascular event; coronary stent; neutrophil; lymphocyte; platelet
PERCUTANEOUS coronary intervention (PCI) with drug-eluting stent (DES) is an important option to treat coronary artery disease, especially in patients with increased surgical risk.1 Perioperative management of patients who underwent previous 1 Address reprint requests to Won Ho Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea. E-mail address: [email protected] (W.H. Kim).
https://doi.org/10.1053/j.jvca.2019.10.009 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
PCI with DES has been a relevant issue because of the high risk of postoperative morbidity.2 A recent 2016 focused update of the 2014 guidelines of the American College of Cardiology/American Heart Association suggested that elective noncardiac surgery (NCS) should be delayed 6 months to 1 year in patients with DES implantation because of the risk of stent thrombosis and other cardiovascular morbidity.3,4 Regarding antiplatelet agents, dualantiplatelet therapy or at least aspirin is recommended to be maintained, especially during the first 4 to 6 weeks after DES
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implantation to prevent stent thrombosis.3,5,6 Despite this recommendation, elective surgeries often are performed within 6 months after PCI with DES because of urgency or non-compliance to the guidelines. However, there is no reliable predictor of postoperative cardiovascular morbidity, including stent thrombosis causing myocardial ischemia or other thrombotic complications. The neutrophil/lymphocyte ratio (N/LR) is a surrogate marker of the systemic inflammatory response and can be calculated easily and inexpensively from a complete blood cell count.7 N/LR is a predictor and prognostic marker of bacteremia in medical emergencies8,9 and is a prognostic marker for various types of cancer.10-12 A high N/LR ratio has been associated with poor baseline renal function13,14 and has served as an independent predictor for acute kidney injury (AKI) after cardiovascular surgery or in patients with sepsis.15-17 N/LR also has been used to predict new-onset atrial fibrillation and poor survival after coronary artery bypass graft (CABG).13,14 Both N/LR and the platelet/lymphocyte ratio (P/LR) have been reported to be prognostic markers in patients with PCI to predict no reflow of the coronary stent or in-hospital adverse events, including reinfarction, stroke, and long-term mortality.18-20 Therefore, it is possible that cell count associated predictors, including N/LR and P/LR, may have a prognostic value to predict postoperative morbidity in patients with previous DES insertion. In this retrospective observational study, the authors sought to evaluate the hypothesis that the N/LR or P/LR could be an independent predictor of major adverse cardiovascular and cerebral events (MACCE) in patients undergoing NCS within 6 months after PCI with DES. Methods The Institutional Review Board approved this retrospective cohort study (H-1608-127-788). Written informed consent was waived by the Institutional Review Board because of the study’s retrospective nature. The electronic medical records of patients who underwent NCS within 6 months after PCI with DES between March 2011 and December 2016 were reviewed. Patients who received a paclitaxel-eluting stent (Taxus; Boston Scientific, Marlborough, MA), a sirolimus-eluting stent (Cypher; Cordis, Hialeah, FL), a zotarolimus-eluting stent (Endeavor/ Resolute; Medtronic, Minneapolis, MN), or an everolimus-eluting stent (Xience Sierra; Abbott, Abbott Park, IL) were included. Study investigators determined whether the patients from the electronic medical record database met the inclusion criteria according to the National Health Insurance prescription codes for DES and general anesthesia. Among the 2,857 patients who met these criteria, the interval between DES implantation and surgery was reviewed and only those who underwent NCS within 6 months after PCI with DES implantation (n = 965) were included in the study cohort. Baseline demographics and medical conditions that were known to be associated with postoperative MACCE were collected (Table 1),21,22 including comorbidity, medication history, laboratory findings, surgical parameters, and anesthesia-related factors including transfusion. The following information was obtained: time interval between PCI and surgery;
type of coronary stent; maintenance of antiplatelet agents after DES (none, aspirin, clopidogrel, or dual-antiplatelet therapy); and discontinuation of antiplatelet therapy before surgery (categorized as maintenance until surgery without stopping, used before surgery but stopped 7 preoperative d). Patients in whom aspirin or clopidogrel was discontinued for 1 to 6 days were not included in the analysis of the association between drug discontinuation and MACCE because of the potential variable residual effect. Study investigators determined the primary outcome as MACCE, which was defined as a composite of nonfatal myocardial infarction, coronary revascularization, pulmonary embolism, and nonhemorrhagic stroke within 1 month after surgery, and this was determined by reviewing medical charts. Detailed definitions of individual diagnosis of MACCE are reported in Supplementary Table S1. Although pulmonary embolism and ischemic stroke are not considered to be coronary stent related morbidity in these patients, pulmonary embolism and ischemic stroke were included in the study’s definition of MACCE to evaluate the prognostic value of N/ LR and P/LR to predict a broad range of cardiovascular and other thrombotic complications. Statistical Analysis SPSS software, Version 25.0 (IBM Corp, Armonk, NY) was used to analyze the data. A p value of <0.05 was regarded as statistically significant. The normality of the distribution of continuous variables was tested using the Shapiro-Wilk test. Incidence variables are reported as numbers with frequencies, and continuous variables are reported as median values with interquartile ranges. Missing data were present in <5% of collected data, which were replaced with their age- and sex-specific median values or mode. There were no missing data pertaining to time from PCI or maintenance of antiplatelet agent. Abnormal outliers were removed and replaced just like missing data. Continuous variables were compared with the unpaired t and Mann-Whitney tests. Categorical variables were compared using the Fisher test or chi-square test according to their expected counts. The sample size was calculated with G*Power 3 (http:// www.gpower.hhu.de/). A sample size of 960 or more patients was required with a power of 0.8 and type I error of 0.05.23 This was calculated under the assumption that the expected odds ratio (OR) for postoperative MACCE in patients who underwent NCS with a postoperative N/LR 4.0 would be 1.5. The incidence of MACCE in patients with postoperative N/LR 4.0 was assumed to be 5%.22 Because there was no previous similar study, the cutoff of 4.0 was obtained from the 4th quartile of the study investigators’ pilot sample. The effect size of 1.5 was chosen for the conservative assumption because it was the smallest one of a previous study that reported the prognostic role of N/LR in cancer patients.24 The following analyses were conducted. First, univariable logistic regression analysis of perioperative cell count associated risk factors for MACCE within 1 month after surgery was performed. These risk factors included neutrophil, lymphocyte, platelet count, N/LR, and P/LR at the following 3 time points:
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Table 1 Baseline Patient Characteristics and Early Postoperative Outcomes According to the Quartiles of Neutrophil/Lymphocyte Ratio on the First Postoperative Day
N/LR on postoperative day 1 Preoperative baseline medical status Age, y (median, interquartile range) Female, n Body-mass index, kg/m2 Hypertension, n Diabetes mellitus, n Chronic obstructive pulmonary disease, n, (%) Cerebrovascular accident, n Chronic kidney disease, n Atrial fibrillation history, n Preoperative LV ejection fraction, % Preoperative heart failure, n Preoperative hemoglobin, g/dL Preoperative albumin, g/dL Preoperative creatinine, mg/dL History of angina pectoris One vessel disease, n Two vessel disease, n Three vessel disease, n Indication for PCI Stable angina, n Acute coronary syndrome, n Time from PCI to surgery, d <1 mo, n 1-6 mo, n Coronary stent data Number of stents inserted, n First-generation DES Sirolimus-eluting stent (Cypher), n Paclitaxel-eluting stent (Taxus), n Second-generation DES Xience, Endeavor/Resoult, Coroflex (B Braun, Melsungen, Germany), n Maintenance of aspirin until surgery without discontinuation, n Maintenance of dual-antiplatelet therapy until surgery without discontinuation, n Intraoperative variables Emergency case, n Surgery type, n Orthopedic surgery, n Vascular surgery, n Neurosurgery, n Nose, mouth, and pharynx, n Urologic surgery, n Gynecologic surgery, n General abdominal surgery, n Miscellaneous, n Duration of surgery, h Anesthesia technique Total intravenous anesthesia, n Inhalational anesthesia, n Estimated blood loss during surgery, mL Intraoperative fluid administration, mL Intraoperative colloid administration, mL Transfusion of packed red blood cells, U Transfusion of fresh frozen plasma, U Transfusion of platelet concentrate, U
Quartile 1 <2.2 (n = 254)
Quartile 2 2.2-3.0 (n = 222)
Quartile 3 3.0-4.3 (n = 250)
Quartile 4 >4.3 (n = 239)
p Value
74 (67-80) 73 (28.7) 24.0 (21.5-26.2) 156 (61.4) 90 (35.4) 11 (4.3)
74 (67-81) 66 (29.7) 24.2 (22.0-26.4) 149 (67.1) 83 (37.4) 11 (5.0)
74 (67-80) 81 (32.4) 24.0 (21.8-26.1) 165 (66.0) 90 (36.0) 13 (5.2)
75 (67-81) 89 (28.8) 24.1 (21.9-26.2) 156 (65.3) 91 (38.1) 10 (4.2)
0.173 0.187 0.796 0.577 0.468 0.942
13 (5.1) 23 (9.1) 12 (4.7) 57 (49-61) 9 (3.5) 13.0 (11.2-14.0) 4.2 (3.8-4.4) 0.93 (0.80-1.10)
6 (2.7) 10 (4.5) 7 (3.2) 57 (51-63) 14 (6.3) 13.1 (11.4-13.8) 4.0 (3.9-4.4) 0.90 (0.79-1.02)
7 (2.8) 14 (5.6) 8 (3.2) 58 (53-63) 9 (3.6) 12.9 (11.0-14.1) 4.2 (3.8-4.3) 0.91 (0.78-1.10)
10 (4.2) 12 (5.0) 9 (3.7) 58 (51-64) 5 (2.1) 12.7 (12.0-14.0) 4.1 (3.7-4.3) 0.90 (0.76-1.06)
0.431 0.142 0.777 0.068 0.225 0.906 0.662 0.199
15 (5.9) 13 (5.1) 8 (3.1)
7 (3.2) 6 (2.7) 8 (3.6)
10 (4.0) 6 (2.4) 7 (2.8)
10 (4.2) 15 (6.3) 11 (4.6)
0.507 0.093 0.726
95 (37.4) 159 (62.6) 83 (56-107) 36 (14.2) 218 (26.4)
89 (40.1) 133 (59.9) 80 (55-113) 36 (16.2) 186 (22.5)
100 (40.0) 150 (60.0) 85 (56-113) 29 (11.6) 221 (26.8)
87 (36.4) 152 (63.6) 83 (55-109) 38 (15.9) 201 (24.3)
0.850
1 (1-1)
1 (1-1)
1 (1-1)
1 (1-1)
0.342
53 (20.9) 47 (18.5)
37 (16.7) 56 (26.9)
49 (19.6) 60 (24.0)
41 (17.2) 45 (18.8)
0.594 0.165
158 (62.2)
133 (59.9)
143 (57.2)
156 (65.3)
0.306
59 (23.2)
53 (23.9)
62 (24.8)
64 (26.8)
0.817
30 (11.8)
21 (9.5)
29 (11.6)
25 (10.5)
0.866
6 (2.4)
5 (2.3)
6 (2.4)
3 (1.3)
0.787
0.452 0.452
36 (14.2) 22 (8.7) 6 (2.4) 23 (9.1) 36 (14.2) 3 (1.2) 63 (24.8) 35 (13.8) 1.9 (1.1-2.8)
36 (16.2) 14 (6.3) 10 (4.5) 23 (10.4) 38 (28.8) 3 (1.4) 51 (23.0) 25 (11.3) 2.0 (1.0-2.5)
43 (26.7) 19 (7.6) 11 (4.4) 23 (9.2) 25 (10.0) 7 (2.8) 65 (26.0) 31 (12.4) 2.0 (1.1-2.8)
46 (28.6) 25 (7.1) 14 (5.9) 20 (8.4) 33 (13.8) 7 (2.9) 43 (18.0) 26 (10.9) 2.3 (1.0-3.4)
0.500 0.418 0.285 0.905 0.162 0.380 0.163 0.759 0.911
108 (27.6) 146 (57.5) 150 (50-200) 700 (400-1,450) 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)
88 (22.5) 134 (60.4) 150 (50-250) 650 (400-1,500) 0 (0-50) 0 (0-0) 0 (0-0) 0 (0-0)
107 (27.4) 143 (57.2) 200 (50-300) 720 (400-1,300) 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)
88 (22.5) 151 (63.2) 250 (100-450) 750 (450-1,750) 0 (0-100) 0 (0-1) 0 (0-0) 0 (0-0)
0.496 0.089 0.101 0.250 0.702 0.513 0.689 (continued)
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Table 1 (continued )
N/LR on postoperative day 1 Postoperative outcomes Hospital stay, total, d ICU admission, n Acute kidney injury by KDIGO criteria, n Postoperative hemodialysis, n Postoperative MACCE, n Coronary revascularization Nonfatal myocardial infarction, n Pulmonary embolism, n Nonhemorrhagic stroke, n
Quartile 1 <2.2 (n = 254)
5 (3-7) 2 (0.8) 14 (5.5) 7 (2.8) 10 (3.9) 7 (2.8) 9 (3.5) 1 (0.4)
Quartile 2 2.2-3.0 (n = 222)
5 (3-7) 1 (0.5) 15 (6.8) 8 (3.6) 14 (6.3) 6 (2.7) 12 (5.4) 1 (0.5) 1 (0.5)
Quartile 3 3.0-4.3 (n = 250)
5 (3-7) 3 (1.2) 19 (7.6) 10 (4.0) 18 (7.2) 7 (2.8) 11 (4.4) 3 (1.2) 4 (1.6)
Quartile 4 >4.3 (n = 239)
5 (3-8) 6 (2.5) 20 (8.4) 11 (4.6) 25 (10.5) 9 (3.8) 17 (7.1) 5 (2.1) 3 (1.3)
p Value
0.029 0.067 0.196 0.271 0.035 0.891 0.040 0.162 0.697
NOTE. Quartiles 1, 2, 3, and 4 are the 0 to 25th, 25th to 50th, 50th to 75th, and 75th to 100th percentiles, respectively. The p value is the result of one-way analysis of variance or Kruskal-Wallis test for continuous variables and chi-square or Fisher exact test for categorical variables. Abbreviations: DES, drug-eluting stent; ICU, intensive care unit; KDIGO, Kidney Disease Improving Global Outcomes; LV, left ventricular; LVEF, left ventricular ejection fraction; N/LR, neutrophil-lymphocyte ratio; MACCE, major adverse cardiovascular and cerebral event; PCI, percutaneous coronary intervention.
preoperative, immediately postoperatively, and postoperative day (POD) 1. N/LR and P/LR were analyzed as both continuous and categorized variables. Second, a multivariable logistic regression analysis was performed to identify risk factors of MACCE within 1 month after surgery. POD 1 N/LR and P/LR were entered into the multivariable analysis because these variables were significant both as continuous and categorized variables in the univariable analysis. Predictor variables were selected from a list of candidate variables by performing a backward Wald stepwise variable selection with a significance criterion of p < 0.20. Third, a propensity score analysis was conducted to match the patients with higher POD 1 N/LR (quartile 4: N/LR >4.3) with the remaining patients with lower POD 1 N/LR (4.3) to compare the incidence of MACCE in the matched cohort. Binary multivariable logistic regression analysis was used to determine the probability of assignment for the 2 POD 1 N/LR groups. This probability and a greedy method with 1:1 pair were used for matching. A total of 238 patients with POD 1 N/LR >4.3 were matched with those with POD 1 N/LR 4.3 using the nearest neighbor matching (Supplemental Fig S1). The following variables were used as the contributors to the propensity score: sex, age, body mass index, history of diabetes mellitus, hypertension, heart failure, stroke, chronic kidney disease, generation of DES, maintenance of aspirin, maintenance of dual-antiplatelet therapy, surgery type, duration of surgery, emergency surgery, preoperative hemoglobin, preoperative albumin, and year of surgery. The caliper was defined as 0.20 standard deviations of the logit-transformed propensity score. The balance between the groups was tested using a standardized difference (>0.20 suggests imbalance). The incidence of MACCE in the matched cohort was compared. Fourth, the performance of the multivariable prediction model was compared regarding area under the receiver operating characteristic curves (AUC). The AUCs of a multivariable logistic regression model with N/LR, a model with P/LR, and a model without N/LR or P/LR were compared using DeLong’s methods.25
Fifth, cubic spline function curves of the multivariableadjusted relationship among POD 1 N/LR, P/LR, and the probability of MACCE were drawn to evaluate the continuous relationship among N/LR, P/LR, and the risk of MACCE. Results Among 965 patients analyzed, MACCE developed in 67 patients (6.9% coronary revascularization [n = 29], 3.0% nonfatal myocardial infarction [n = 46], 4.8% pulmonary embolism [n = 10], and 1.0% nonhemorrhagic stroke [n = 11]). Perioperative parameters according to the quartiles of N/LR on POD 1 in all patient cohorts are presented in Table 1. There were no significant differences across the quartiles of N/LR on POD 1. One hundred thirty-nine (14.4%) patients underwent surgery within 1 month after DES implantation. The incidence of MACCE was significantly higher in patients undergoing surgery within 1 month (n = 18/139 [12.9%]) than for patients undergoing surgery 1 to 6 month after DES insertion (n = 49/ 826 [5.9%]; p = 0.003). The cell count associated variables, including platelet count and proportion (%) of neutrophil, lymphocyte, and monocyte, were compared between those with and without MACCE, and the OR was calculated at the following 3 time points: preoperative, immediate postoperative, and POD 1 (Supplemental Table S2). The preoperative, immediately postoperative, and POD 1 N/LR and P/LR were divided into quartiles and were analyzed using univariable logistic regression analysis. POD 1 neutrophil count, immediate postoperative platelet count, and POD 1 platelet count showed significant associations with MACCE. As a continuous variable, immediate postoperative and POD 1 N/LR and immediate postoperative and POD 1 P/LR showed significant associations. As a categorized variable, POD 1 N/LR quartiles showed significant graded associations with MACCE. The distribution of MACCE according to the quartiles of N/LR and P/LR at the 3 time points are shown in Fig 1 and Supplemental Fig S2. The incidence of MACCE was significantly different across
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Fig 1. Incidences (%) of postoperative major adverse cardiovascular and cerebral events in patients undergoing noncardiac surgery after drug-eluting stent implantation according to the neutrophil/lymphocyte ratio quartile. MACCE, adverse cardiovascular and cerebral events; NLR, neutrophil/lymphocyte ratio; POD, postoperative day; Preop_NLR_Q1, 2, 3, 4, preoperative baseline neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; Imm_NLR_Q1, 2, 3, 4, immediate postoperative neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; POD 1_NLR_Q1, 2, 3, 4, = postoperative day 1 neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; Q, quartile.
the quartiles of POD 1 N/LR (p = 0.035) but not in the other time points (see Fig 1). The incidence of MACCE was not significantly different between the quartiles of P/LR at any time point (see Supplemental Fig S2). The results of both univariate and multivariate analyses of risk factors for MACCE are displayed in Table 2. POD 1 N/LR was the only independent cell count associated predictor of MACCE both as a continuous and categorized variable. The quartiles of the POD 1 N/LR were associated with graded increases in the risk of MACCE development (4th quartile [N/LR 4.3] multivariate OR 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040). Other significant risk factors included preoperative left ventricular ejection fraction, albumin, creatinine, surgery within 1 month after PCI, orthopedic and vascular surgery, surgery time, and red cell transfusion. Maintenance of dual-antiplatelet therapy was significantly associated with a decreased risk of MACCE. Propensity score analysis of POD 1 N/LR yielded 237 pairs with POD 1 N/LR 4.3 and POD 1 N/LR >4.3 (see Supplemental Fig S1). After matching, there were no unbalanced covariates with a standardized difference exceeding 0.20 (overall balance test: p = 0.956). The incidence of MACCE was significantly different between 2 matched groups (n = 25/ 237 [10.5%] in N/LR >4.3 v n = 12/237 [5.1%] in N/LR 4.3 [risk difference 5.5%, 95% CI 0.7%-10.3%; p = 0.026]). This difference was mainly from the incidence of nonfatal
myocardial infarction (n = 17/237 [7.2%] in N/LR >4.3 v n = 7/237 [3.0%] in N/LR 4.3; p = 0.036). The performances of the multivariable prediction models are compared in Fig 2 regarding AUC. The AUC of the model with POD 1 N/LR (AUC 0.76, 95% CI 0.70-0.82) was significantly larger than that of the model with POD 1 P/LR (v AUC 0.66, 95% CI 0.60-0.73; p < 0.001) or the model without N/LR or P/LR (v AUC 0.67, 95% CI 0.60-0.74; p < 0.001). The Nagelkerke R2 of the multivariable logistic regression model was 0.30 for the model with N/LR and 0.27 for the model without N/LR or P/LR. The model with N/LR showed good calibration (Hosmer-Lemeshow goodness-offit test: chi-square 5.34; p = 0.721). The cubic spline function curves of the multivariableadjusted relationship among POD 1 N/LR, POD 1 P/LR, and the probability of MACCE are shown in Fig 3. Although both N/LR and P/LR increase the risk of MACCE, the positive relationship was stronger between POD 1 N/LR and MACCE. As an additional analysis, to evaluate the interaction between antiplatelet drug maintenance and N/LR on the risk of MACCE, the multivariable-adjusted ORs of (1) N/LR >4.3 on POD 1 and stopping both aspirin and clopidogrel and (2) N/LR >4.3 on POD 1 and maintaining aspirin but stopping clopidogrel were calculated (see Table 3). The risk of MACCE increased for the discontinuation of clopidogrel or both drugs.
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Table 2 Multivariable Analysis of Patient Characteristics Associated With Postoperative Major Adverse Cardiovascular and Cerebral Events Univariable Analysis Variable Age, y Female Body mass index, kg/m2 Hypertension Diabetes mellitus Chronic obstructive pulmonary disease Cerebrovascular accident Chronic kidney disease Atrial fibrillation Preoperative left ventricular ejection fraction, % Preoperative hemoglobin, g/dL Preoperative albumin, g/dL Preoperative creatinine, mg/dL Three vessel disease Time from PCI to surgery <1 mo Coronary stent type, second generation v first generation Maintenance of aspirin until surgery without discontinuation Maintenance of dual-antiplatelet therapy until surgery without discontinuation Surgery type Orthopedic surgery Vascular surgery Neurosurgery General abdominal surgery Surgical time, h Emergency case Total intravenous anesthesia Transfusion of red blood cells, per unit POD 1 N/LR, continuous variable POD 1 N/LR, quartile Quartile 1, N/LR <2.2 Quartile 2, 2.2 N/LR <3.0 Quartile 3, 3.0 N/LR <4.3 Quartile 4, N/LR 4.3 POD 1 P/LR, continuous variable Quartile 1, P/LR <6.1 Quartile 2, 6.1 P/LR <8.6 Quartile 3, 8.6 P/LR <11.8 Quartile 4, P/LR 11.8
Multivariable Analysis
Odds Ratio (95% CI)
p Value
1.03 (1.00-1.06) 0.90 (0.52-1.54) 1.03 (0.96-1.10) 1.03 (1.00-1.06) 1.18 (0.71-1.96) 1.33 (0.46-3.82) 1.23 (0.37-4.12) 3.95 (1.98-7.88) 3.50 (1.47-8.31) 0.98 (0.96-0.99) 0.98 (0.87-1.11) 0.62 (0.42-0.91) 1.20 (1.10-1.31) 3.76 (1.57-8.99) 2.36 (1.33-4.18) 1.15 (0.69-1.93) 0.72 (0.39-1.34) 0.37 (0.11-1.19)
0.026 0.693 0.386 0.026 0.525 0.600 0.738 <0.001 0.005 0.020 0.785 0.016 <0.001 0.003 0.003 0.597 0.302 0.094
1.35 (0.73-2.50) 3.95 (2.26-6.91) 0.68 (0.16-2.87) 0.72 (0.25-2.41) 1.41 (1.24-1.61) 4.75 (1.67-13.50) 1.23 (0.88-2.34) 1.52 (1.31-1.75) 1.14 (1.06-1.23)
0.339 <0.001 0.597 0.684 <0.001 0.003 0.089 <0.001 0.001
Baseline 0.90 (0.46-1.35) 1.11 (1.01-1.32) 1.63 (1.22-2.09) 1.03 (1.00-1.06) Baseline 1.42 (0.62-3.22) 1.57 (0.70-3.52) 2.65 (1.25-5.62)
0.211 0.042 0.030 0.051 0.406 0.280 0.011
Odds Ratio (95% CI)
p Value
0.98 (0.96-0.99)
<0.001
0.49 (0.30-0.80) 1.26 (1.14-1.40)
0.004 <0.001
1.92 (0.98-3.73)
0.056
0.66 (0.34-0.89)
0.010
2.16 (1.07-4.34) 4.32 (2.14-8.72)
0.031 <0.001
1.26 (1.07-1.49)
0.006
1.98 (1.17-2.88) 1.17 (1.08-1.27)
0.001 <0.001
Baseline 0.63 (0.31-1.33) 1.24 (1.00-1.60) 2.03 (1.12-2.79) 1.01 (0.98-1.05) Baseline 1.28 (0.59-3.62) 1.60 (0.66-3.70) 2.54 (1.20-4.25)
0.174 0.049 0.040 0.102 0.605 0.457 0.024
Abbreviations: CI, confidence interval; N/LR, neutrophil/lymphocyte ratio; PCI, percutaneous coronary intervention; POD, postoperative day; P/LR, platelet/ lymphocyte ratio.
Discussion In the present study, an elevated N/LR on POD 1 was significantly associated with an increased risk of MACCE during postoperative month 1 both as continuous and ordinal variables in patients undergoing NCS within 6 months after DES insertion as a result of coronary artery disease. The quartiles of N/ LR demonstrated a graded association with a cutoff of >3.0 showing an OR of 1.11 and a cutoff of >4.3 showing an OR of 1.63. The POD 1 P/LR >11.8 also showed a significant association, but P/LR was not significant as a continuous variable and the graded association was not found. POD 1 N/LR, which can be calculated easily and inexpensively from a complete blood cell count,7 could help to predict MACCE after NCS after DES implantation. As shown in Table 1, the majority of MACCE were nonfatal myocardial infarction and coronary
revascularization, which suggests that myocardial ischemic events are the most expected postoperative morbidity. In the matched cohort, the difference in MACCE was mainly from the different incidence of myocardial ischemic events, highlighting the prognostic role of N/LR to predict particularly the myocardial ischemic events among MACCE. It is difficult to predict postoperative cardiovascular events accurately in moderate- to high-risk patients.26 The results of the present study confirm and extend previous reports on the predictive role of N/LR. Postoperative N/LR is associated with the development of AKI after cardiovascular surgery.16 Preoperative N/LR >4 has been associated with perioperative myocardial injury measured using serum high-sensitivity troponin T concentration.27 The association between N/LR and postoperative AKI can be traced to the role of inflammation in the pathogenesis of AKI.16,28,29 An acute ischemic insult activates
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7
Fig 2. Comparison of area under the receiver operating characteristic curve among (1) the multivariable prediction model with neutrophil/lymphocyte ratio on postoperative day 1, (2) the model with platelet/lymphocyte ratio on postoperative day 1, and (3) the model with neither neutrophil/lymphocyte ratio nor platelet/lymphocyte ratio on postoperative day 1. N/LR, neutrophil/ lymphocyte ratio; P/LR, platelet/lymphocyte ratio.
endothelial renal cells that express adhesion molecules, thus facilitating adhesion of inflammatory blood cells.30 The neutrophil and lymphocyte count all are potential surrogate markers of inflammation and are associated with the development of cardiovascular events.31,32 The predictive value of these 2 components can be combined by calculating the N/LR, which is known to be a prognostic marker of bacteremia, coronary intervention, CABG, and various types of cancer.8-14,20,33,34 A high preoperative N/LR has been associated with poor baseline renal function in patients undergoing CABG13,14 and also was an independent predictor of AKI in patients with severe sepsis and cardiovascular surgery.15-17 In addition to these findings, the authors of the present study have demonstrated that postoperative N/LR could be a prognostic factor to predict MACCE in patients undergoing NCS after DES insertion. There was significant interaction between high N/LR and discontinuation of antiplatelet drugs, which may contribute to the development of thrombogenic complications. This interaction may suggest that the systemic inflammatory reaction and thrombogenic condition contribute to the occurrence of MACCE synergistically. Cardiovascular and cerebrovascular events after surgery are related to stent thrombosis and cerebral and pulmonary thromboembolism. The surgery itself is thrombogenic and leads to an inflammatory response.35 Also, the discontinuation of antiplatelet agent because of the risk of bleeding could contribute to the development of MACCE,4,36 as shown in the authors’ multivariable analysis. The role of inflammation in thrombosis and thromboembolism is well known.37,38 In addition, vascular inflammation is associated with stent restenosis and stent
Fig 3. Cubic spline function curves of the multivariable-adjusted relationship among postoperative day 1 neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and probability of major adverse cardiovascular and cerebral events in patients undergoing noncardiac surgery after drug-eluting stent implantation. Shaded areas represent 95% confidence interval. CI, confidence interval; MACCE, major adverse cardiovascular and cerebral events; POD, postoperative day.
thrombosis.39 Thromboembolism after surgery also may be associated with surgery-related systemic inflammation. A recent retrospective study of patients undergoing knee arthroplasty reported that high N/LR is associated with postoperative venous thromboembolism, including pulmonary embolism.40 N/LR, as a surrogate marker of systemic inflammation, could act as a prognostic marker to predict MACCE after NCS. POD 1 N/LR was a stronger independent predictor of postoperative MACCE, whereas preoperative N/LR was not. This may be because the POD 1 N/LR could reflect the systemic inflammatory response after surgery better than preoperative N/LR. Although P/LR is reported to be a prognostic marker in patients with primary PCI to predict no reflow and mortality,18,19 its association with postoperative MACCE was relatively weaker compared with N/LR. This may be because the implication of platelet count in the surgical condition is different from that in the medical condition, possibly because of the confounder of surgical bleeding. Surgical bleeding may decrease platelet count, leading to relative thrombocytopenia and the
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Table 3 Adjusted Odds Ratio of the First Postoperative Day Neutrophil/Lymphocyte Ratio (N/LR 4.3) to Predict Postoperative Major Adverse Cardiovascular and Cerebral Events According to Preoperative Antiplatelet Medications Variable
N/LR on POD 1 4.3 (n = 239, 24.8%) N/LR on POD 1 4.3 and stopping both aspirin and clopidogrel (n = 168, 14.4%) N/LR on POD 1 4.3 and maintaining aspirin but stopping clopidogrel (n = 47, 4.9%)
Multivariable-Adjusted Odds Ratio (95% Confidence Interval)
p Value
2.03 (1.12-2.79)
0.040
3.02 (2.14-4.48)
0.006
2.44 (1.24-3.85)
0.045
NOTE. The same covariates in Table 2 were used to calculate the adjusted odds ratios. Stopping means discontinuation of at least 1 day before surgery. Abbreviations: N/LR, neutrophil/lymphocyte ratio; POD, postoperative day.
resulting postoperative platelet count may be less meaningful to reflect the prognosis of these patients. However, the amount of surgical bleeding in the present study was rather small. Activation and release of platelet-related mediators or acute phase reactants such as fibrinogen may confer a stronger association with MACCE rather than the platelet count itself.41 Nonetheless, lymphocyte count alone is associated with the prognosis of patients with cardiovascular disease,32,42 which may contribute to the P/LR being a significant prognostic factor, although its predictive value was less than that of N/LR. The cutoff of the 4th quartile was used as a cutoff of high POD 1 N/LR. However, this was arbitrary, and the normal reference ranges have not been defined for N/LR and P/LR. Previous studies have used cutoffs of tertile or quartile from their distribution of N/LR or P/LR,16,33,43 but it appears that the distribution of N/LR or P/LR varies significantly according to the patient population, type of surgery, and time point of measurements. Predictors for MACCE in the present study are mostly consistent with previous studies. According to American College of Cardiology/American Heart Association 2014 guidelines and a 2016 focused update, elective NCS after DES implantation may be performed after 180 days.3,4 These guidelines are supported by 2 recent studies that reported that the incidence of major adverse cardiovascular events did not differ when surgery is performed 6 months after DES implantation.5,22 The risk of MACCE was significantly high when surgery was conducted within 1 month after DES compared with surgery 1 to 6 months after PCI. The high risk of immediate surgery within 1 month after PCI was consistent in the previous studies.5,22,44 There were other predictors of postoperative MACCE, including baseline left ventricular ejection fraction, hemoglobin concentration, and serum albumin level. These predictors are related to the baseline medical conditions, which often are associated with postoperative morbidity and mortality.45,46 Long surgery time and intraoperative transfusion amount may be associated with surgical procedural difficulty and these variables generally are not modifiable as well as the poor baseline medical conditions.
Although not modifiable, risk factors in the present study, including N/LR, may help physicians to plan postoperative management based on the risk of postoperative MACCE. High-risk patients could be managed in the intensive care unit with advanced hemodynamic monitoring and screening for pulmonary embolism and stroke. Myocardial injury after NCS may be evaluated with high-sensitivity cardiac troponin T.47 Postoperative oral anticoagulant administration such as dabigatran may help to lower the risk of MACCE after surgery.48 Predictors in the present study can be incorporated into the inclusion criteria of clinical trials. The present study has several important limitations. First, because of its retrospective design, the results can only suggest an association between N/LR and postoperative MACCE. External validity is limited. It is not possible to completely control the bias and confounders. Prospective validation of the prognostic value of N/LR is required. Furthermore, the suggested cutoff of POD 1 N/LR to predict MACCE may have limited generalizability for other populations or different types of surgery. POD 1 N/LR after cardiac surgery had a 4th quartile cutoff of 10 in a previous study,16 but the 4th quartile cutoff of the present study was 4.3. Second, a larger sample size would be required to fully address the potential confounders. The present study’s power may be weak compared with previous studies.13,34 Because the present study was powered to discern the association between N/LR and postoperative MACCE, the other analyses are of limited value. Third, the patients included in this study underwent heterogenous types of surgeries with varying risk and different types of anesthesia. The different risk of surgery may affect the association between N/LR and MACCE. Total intravenous anesthesia may decrease N/LR immediately after surgery.49 The type of surgery, type of anesthesia, and year of surgery performed were included as the covariates of multivariable analysis and propensity score matching to address this confounder. Fourth, patients in whom aspirin or clopidogrel was discontinued for 1 to 6 days were excluded from the multivariable analysis, and only the variable regarding whether drugs were maintained or discontinued for 7 days before surgery were included in the analysis because of concerns of variable residual antiplatelet effect between 1 to 6 days. However, a 2017 European Society of Cardiologists focused update recommended that clopidogrel should be discontinued for at least 5 days before NCS.50 Therefore, the effect of stopping the drug for 5 days according to the recent guidelines could not be adjusted in the present analysis. In conclusion, there was a robust and independent association between POD 1 N/LR and postoperative MACCE in the first 1-month after NCS within 6 months after DES implantation. Therefore, N/LR, which is easily calculated and routinely available, could assist in identifying MACCE in high-risk surgical patients. Declaration of Competing Interest All authors declared no financial conflict of interest. Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1053/j.jvca.2019.10.009.
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48 Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): An international, randomised, placebo-controlled trial. Lancet 2018;391: 2325–34. 49 Kim WH, Jin HS, Ko JS, et al. The effect of anesthetic techniques on neutrophil-to-lymphocyte ratio after laparoscopy-assisted vaginal hysterectomy. Acta Anaesthesiol Taiwan 2011;49:83–7. 50 Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60.
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Original Article
Neutrophil/Lymphocyte Ratio in Patients Undergoing Noncardiac Surgery After Coronary Stent Implantation Jaeyeon Chung, MD, Jinyoung Bae, MD, Yongsuk Kwon, MD, Hyun-Kyu Yoon, MD, Seokha Yoo, MD, Ho-Jim Lee, MD, Sun-Kyung Park, MD, PhD, Jin-Tae Kim, MD, PhD, 1 Won Ho Kim, MD, PhD Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Objective: Perioperative cell count associated predictors, including the neutrophil/lymphocyte ratio (N/LR) and platelet/lymphocyte ratio (P/LR), are associated with poor clinical outcomes including myocardial injury. Study investigators aimed to examine the association among the perioperative N/LR, P/LR, and postoperative major adverse cardiovascular and cerebral events (MACCE) after noncardiac surgery in patients with drug-eluting stent (DES) insertion. Design: Retrospective and observational. Setting: Single university hospital. Participants: The study comprised 965 patients who underwent noncardiac surgery within 6 months after DES implantation. Interventions: None. Measurements and Main Results: Baseline perioperative clinical parameters, including N/LR and P/LR measured before surgery, immediately after surgery, and on postoperative day (POD) 1, were obtained. MACCE was defined as a composite of nonfatal myocardial infarction, coronary revascularization, nonhemorrhagic stroke, and pulmonary embolism within 1 month after surgery. Multivariate logistic regression analysis and propensity score matching were used to identify predictors of MACCE after surgery. MACCE occurred in 67 patients (6.9%) and was more common in patients with N/LR on POD 1 >4.3 (multivariable-adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040 and as a continuous N/LR [OR 1.17, 95% CI 1.08-1.27; p < 0.001]). This association was consistent after propensity score matching and was stronger when the antiplatelet agent was stopped before surgery (OR 3.02, 95% CI 2.14-4.48; p = 0.006 for stopping dual antiplatelet therapy). Conclusions: In patients undergoing noncardiac surgery within 6 months after DES implantation, elevated N/LR on POD 1 is independently associated with postoperative MACCE. Elevated postoperative N/LR as a marker of systemic inflammation may help to predict the development of MACCE in these high-risk patients. Ó 2019 Elsevier Inc. All rights reserved. Key Words: surgery; major adverse cardiovascular event; coronary stent; neutrophil; lymphocyte; platelet
PERCUTANEOUS coronary intervention (PCI) with drug-eluting stent (DES) is an important option to treat coronary artery disease, especially in patients with increased surgical risk.1 Perioperative management of patients who underwent previous 1 Address reprint requests to Won Ho Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea. E-mail address: [email protected] (W.H. Kim).
https://doi.org/10.1053/j.jvca.2019.10.009 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
PCI with DES has been a relevant issue because of the high risk of postoperative morbidity.2 A recent 2016 focused update of the 2014 guidelines of the American College of Cardiology/American Heart Association suggested that elective noncardiac surgery (NCS) should be delayed 6 months to 1 year in patients with DES implantation because of the risk of stent thrombosis and other cardiovascular morbidity.3,4 Regarding antiplatelet agents, dualantiplatelet therapy or at least aspirin is recommended to be maintained, especially during the first 4 to 6 weeks after DES
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implantation to prevent stent thrombosis.3,5,6 Despite this recommendation, elective surgeries often are performed within 6 months after PCI with DES because of urgency or non-compliance to the guidelines. However, there is no reliable predictor of postoperative cardiovascular morbidity, including stent thrombosis causing myocardial ischemia or other thrombotic complications. The neutrophil/lymphocyte ratio (N/LR) is a surrogate marker of the systemic inflammatory response and can be calculated easily and inexpensively from a complete blood cell count.7 N/LR is a predictor and prognostic marker of bacteremia in medical emergencies8,9 and is a prognostic marker for various types of cancer.10-12 A high N/LR ratio has been associated with poor baseline renal function13,14 and has served as an independent predictor for acute kidney injury (AKI) after cardiovascular surgery or in patients with sepsis.15-17 N/LR also has been used to predict new-onset atrial fibrillation and poor survival after coronary artery bypass graft (CABG).13,14 Both N/LR and the platelet/lymphocyte ratio (P/LR) have been reported to be prognostic markers in patients with PCI to predict no reflow of the coronary stent or in-hospital adverse events, including reinfarction, stroke, and long-term mortality.18-20 Therefore, it is possible that cell count associated predictors, including N/LR and P/LR, may have a prognostic value to predict postoperative morbidity in patients with previous DES insertion. In this retrospective observational study, the authors sought to evaluate the hypothesis that the N/LR or P/LR could be an independent predictor of major adverse cardiovascular and cerebral events (MACCE) in patients undergoing NCS within 6 months after PCI with DES. Methods The Institutional Review Board approved this retrospective cohort study (H-1608-127-788). Written informed consent was waived by the Institutional Review Board because of the study’s retrospective nature. The electronic medical records of patients who underwent NCS within 6 months after PCI with DES between March 2011 and December 2016 were reviewed. Patients who received a paclitaxel-eluting stent (Taxus; Boston Scientific, Marlborough, MA), a sirolimus-eluting stent (Cypher; Cordis, Hialeah, FL), a zotarolimus-eluting stent (Endeavor/ Resolute; Medtronic, Minneapolis, MN), or an everolimus-eluting stent (Xience Sierra; Abbott, Abbott Park, IL) were included. Study investigators determined whether the patients from the electronic medical record database met the inclusion criteria according to the National Health Insurance prescription codes for DES and general anesthesia. Among the 2,857 patients who met these criteria, the interval between DES implantation and surgery was reviewed and only those who underwent NCS within 6 months after PCI with DES implantation (n = 965) were included in the study cohort. Baseline demographics and medical conditions that were known to be associated with postoperative MACCE were collected (Table 1),21,22 including comorbidity, medication history, laboratory findings, surgical parameters, and anesthesia-related factors including transfusion. The following information was obtained: time interval between PCI and surgery;
type of coronary stent; maintenance of antiplatelet agents after DES (none, aspirin, clopidogrel, or dual-antiplatelet therapy); and discontinuation of antiplatelet therapy before surgery (categorized as maintenance until surgery without stopping, used before surgery but stopped 7 preoperative d). Patients in whom aspirin or clopidogrel was discontinued for 1 to 6 days were not included in the analysis of the association between drug discontinuation and MACCE because of the potential variable residual effect. Study investigators determined the primary outcome as MACCE, which was defined as a composite of nonfatal myocardial infarction, coronary revascularization, pulmonary embolism, and nonhemorrhagic stroke within 1 month after surgery, and this was determined by reviewing medical charts. Detailed definitions of individual diagnosis of MACCE are reported in Supplementary Table S1. Although pulmonary embolism and ischemic stroke are not considered to be coronary stent related morbidity in these patients, pulmonary embolism and ischemic stroke were included in the study’s definition of MACCE to evaluate the prognostic value of N/ LR and P/LR to predict a broad range of cardiovascular and other thrombotic complications. Statistical Analysis SPSS software, Version 25.0 (IBM Corp, Armonk, NY) was used to analyze the data. A p value of <0.05 was regarded as statistically significant. The normality of the distribution of continuous variables was tested using the Shapiro-Wilk test. Incidence variables are reported as numbers with frequencies, and continuous variables are reported as median values with interquartile ranges. Missing data were present in <5% of collected data, which were replaced with their age- and sex-specific median values or mode. There were no missing data pertaining to time from PCI or maintenance of antiplatelet agent. Abnormal outliers were removed and replaced just like missing data. Continuous variables were compared with the unpaired t and Mann-Whitney tests. Categorical variables were compared using the Fisher test or chi-square test according to their expected counts. The sample size was calculated with G*Power 3 (http:// www.gpower.hhu.de/). A sample size of 960 or more patients was required with a power of 0.8 and type I error of 0.05.23 This was calculated under the assumption that the expected odds ratio (OR) for postoperative MACCE in patients who underwent NCS with a postoperative N/LR 4.0 would be 1.5. The incidence of MACCE in patients with postoperative N/LR 4.0 was assumed to be 5%.22 Because there was no previous similar study, the cutoff of 4.0 was obtained from the 4th quartile of the study investigators’ pilot sample. The effect size of 1.5 was chosen for the conservative assumption because it was the smallest one of a previous study that reported the prognostic role of N/LR in cancer patients.24 The following analyses were conducted. First, univariable logistic regression analysis of perioperative cell count associated risk factors for MACCE within 1 month after surgery was performed. These risk factors included neutrophil, lymphocyte, platelet count, N/LR, and P/LR at the following 3 time points:
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3
Table 1 Baseline Patient Characteristics and Early Postoperative Outcomes According to the Quartiles of Neutrophil/Lymphocyte Ratio on the First Postoperative Day
N/LR on postoperative day 1 Preoperative baseline medical status Age, y (median, interquartile range) Female, n Body-mass index, kg/m2 Hypertension, n Diabetes mellitus, n Chronic obstructive pulmonary disease, n, (%) Cerebrovascular accident, n Chronic kidney disease, n Atrial fibrillation history, n Preoperative LV ejection fraction, % Preoperative heart failure, n Preoperative hemoglobin, g/dL Preoperative albumin, g/dL Preoperative creatinine, mg/dL History of angina pectoris One vessel disease, n Two vessel disease, n Three vessel disease, n Indication for PCI Stable angina, n Acute coronary syndrome, n Time from PCI to surgery, d <1 mo, n 1-6 mo, n Coronary stent data Number of stents inserted, n First-generation DES Sirolimus-eluting stent (Cypher), n Paclitaxel-eluting stent (Taxus), n Second-generation DES Xience, Endeavor/Resoult, Coroflex (B Braun, Melsungen, Germany), n Maintenance of aspirin until surgery without discontinuation, n Maintenance of dual-antiplatelet therapy until surgery without discontinuation, n Intraoperative variables Emergency case, n Surgery type, n Orthopedic surgery, n Vascular surgery, n Neurosurgery, n Nose, mouth, and pharynx, n Urologic surgery, n Gynecologic surgery, n General abdominal surgery, n Miscellaneous, n Duration of surgery, h Anesthesia technique Total intravenous anesthesia, n Inhalational anesthesia, n Estimated blood loss during surgery, mL Intraoperative fluid administration, mL Intraoperative colloid administration, mL Transfusion of packed red blood cells, U Transfusion of fresh frozen plasma, U Transfusion of platelet concentrate, U
Quartile 1 <2.2 (n = 254)
Quartile 2 2.2-3.0 (n = 222)
Quartile 3 3.0-4.3 (n = 250)
Quartile 4 >4.3 (n = 239)
p Value
74 (67-80) 73 (28.7) 24.0 (21.5-26.2) 156 (61.4) 90 (35.4) 11 (4.3)
74 (67-81) 66 (29.7) 24.2 (22.0-26.4) 149 (67.1) 83 (37.4) 11 (5.0)
74 (67-80) 81 (32.4) 24.0 (21.8-26.1) 165 (66.0) 90 (36.0) 13 (5.2)
75 (67-81) 89 (28.8) 24.1 (21.9-26.2) 156 (65.3) 91 (38.1) 10 (4.2)
0.173 0.187 0.796 0.577 0.468 0.942
13 (5.1) 23 (9.1) 12 (4.7) 57 (49-61) 9 (3.5) 13.0 (11.2-14.0) 4.2 (3.8-4.4) 0.93 (0.80-1.10)
6 (2.7) 10 (4.5) 7 (3.2) 57 (51-63) 14 (6.3) 13.1 (11.4-13.8) 4.0 (3.9-4.4) 0.90 (0.79-1.02)
7 (2.8) 14 (5.6) 8 (3.2) 58 (53-63) 9 (3.6) 12.9 (11.0-14.1) 4.2 (3.8-4.3) 0.91 (0.78-1.10)
10 (4.2) 12 (5.0) 9 (3.7) 58 (51-64) 5 (2.1) 12.7 (12.0-14.0) 4.1 (3.7-4.3) 0.90 (0.76-1.06)
0.431 0.142 0.777 0.068 0.225 0.906 0.662 0.199
15 (5.9) 13 (5.1) 8 (3.1)
7 (3.2) 6 (2.7) 8 (3.6)
10 (4.0) 6 (2.4) 7 (2.8)
10 (4.2) 15 (6.3) 11 (4.6)
0.507 0.093 0.726
95 (37.4) 159 (62.6) 83 (56-107) 36 (14.2) 218 (26.4)
89 (40.1) 133 (59.9) 80 (55-113) 36 (16.2) 186 (22.5)
100 (40.0) 150 (60.0) 85 (56-113) 29 (11.6) 221 (26.8)
87 (36.4) 152 (63.6) 83 (55-109) 38 (15.9) 201 (24.3)
0.850
1 (1-1)
1 (1-1)
1 (1-1)
1 (1-1)
0.342
53 (20.9) 47 (18.5)
37 (16.7) 56 (26.9)
49 (19.6) 60 (24.0)
41 (17.2) 45 (18.8)
0.594 0.165
158 (62.2)
133 (59.9)
143 (57.2)
156 (65.3)
0.306
59 (23.2)
53 (23.9)
62 (24.8)
64 (26.8)
0.817
30 (11.8)
21 (9.5)
29 (11.6)
25 (10.5)
0.866
6 (2.4)
5 (2.3)
6 (2.4)
3 (1.3)
0.787
0.452 0.452
36 (14.2) 22 (8.7) 6 (2.4) 23 (9.1) 36 (14.2) 3 (1.2) 63 (24.8) 35 (13.8) 1.9 (1.1-2.8)
36 (16.2) 14 (6.3) 10 (4.5) 23 (10.4) 38 (28.8) 3 (1.4) 51 (23.0) 25 (11.3) 2.0 (1.0-2.5)
43 (26.7) 19 (7.6) 11 (4.4) 23 (9.2) 25 (10.0) 7 (2.8) 65 (26.0) 31 (12.4) 2.0 (1.1-2.8)
46 (28.6) 25 (7.1) 14 (5.9) 20 (8.4) 33 (13.8) 7 (2.9) 43 (18.0) 26 (10.9) 2.3 (1.0-3.4)
0.500 0.418 0.285 0.905 0.162 0.380 0.163 0.759 0.911
108 (27.6) 146 (57.5) 150 (50-200) 700 (400-1,450) 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)
88 (22.5) 134 (60.4) 150 (50-250) 650 (400-1,500) 0 (0-50) 0 (0-0) 0 (0-0) 0 (0-0)
107 (27.4) 143 (57.2) 200 (50-300) 720 (400-1,300) 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)
88 (22.5) 151 (63.2) 250 (100-450) 750 (450-1,750) 0 (0-100) 0 (0-1) 0 (0-0) 0 (0-0)
0.496 0.089 0.101 0.250 0.702 0.513 0.689 (continued)
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Table 1 (continued )
N/LR on postoperative day 1 Postoperative outcomes Hospital stay, total, d ICU admission, n Acute kidney injury by KDIGO criteria, n Postoperative hemodialysis, n Postoperative MACCE, n Coronary revascularization Nonfatal myocardial infarction, n Pulmonary embolism, n Nonhemorrhagic stroke, n
Quartile 1 <2.2 (n = 254)
5 (3-7) 2 (0.8) 14 (5.5) 7 (2.8) 10 (3.9) 7 (2.8) 9 (3.5) 1 (0.4)
Quartile 2 2.2-3.0 (n = 222)
5 (3-7) 1 (0.5) 15 (6.8) 8 (3.6) 14 (6.3) 6 (2.7) 12 (5.4) 1 (0.5) 1 (0.5)
Quartile 3 3.0-4.3 (n = 250)
5 (3-7) 3 (1.2) 19 (7.6) 10 (4.0) 18 (7.2) 7 (2.8) 11 (4.4) 3 (1.2) 4 (1.6)
Quartile 4 >4.3 (n = 239)
5 (3-8) 6 (2.5) 20 (8.4) 11 (4.6) 25 (10.5) 9 (3.8) 17 (7.1) 5 (2.1) 3 (1.3)
p Value
0.029 0.067 0.196 0.271 0.035 0.891 0.040 0.162 0.697
NOTE. Quartiles 1, 2, 3, and 4 are the 0 to 25th, 25th to 50th, 50th to 75th, and 75th to 100th percentiles, respectively. The p value is the result of one-way analysis of variance or Kruskal-Wallis test for continuous variables and chi-square or Fisher exact test for categorical variables. Abbreviations: DES, drug-eluting stent; ICU, intensive care unit; KDIGO, Kidney Disease Improving Global Outcomes; LV, left ventricular; LVEF, left ventricular ejection fraction; N/LR, neutrophil-lymphocyte ratio; MACCE, major adverse cardiovascular and cerebral event; PCI, percutaneous coronary intervention.
preoperative, immediately postoperatively, and postoperative day (POD) 1. N/LR and P/LR were analyzed as both continuous and categorized variables. Second, a multivariable logistic regression analysis was performed to identify risk factors of MACCE within 1 month after surgery. POD 1 N/LR and P/LR were entered into the multivariable analysis because these variables were significant both as continuous and categorized variables in the univariable analysis. Predictor variables were selected from a list of candidate variables by performing a backward Wald stepwise variable selection with a significance criterion of p < 0.20. Third, a propensity score analysis was conducted to match the patients with higher POD 1 N/LR (quartile 4: N/LR >4.3) with the remaining patients with lower POD 1 N/LR (4.3) to compare the incidence of MACCE in the matched cohort. Binary multivariable logistic regression analysis was used to determine the probability of assignment for the 2 POD 1 N/LR groups. This probability and a greedy method with 1:1 pair were used for matching. A total of 238 patients with POD 1 N/LR >4.3 were matched with those with POD 1 N/LR 4.3 using the nearest neighbor matching (Supplemental Fig S1). The following variables were used as the contributors to the propensity score: sex, age, body mass index, history of diabetes mellitus, hypertension, heart failure, stroke, chronic kidney disease, generation of DES, maintenance of aspirin, maintenance of dual-antiplatelet therapy, surgery type, duration of surgery, emergency surgery, preoperative hemoglobin, preoperative albumin, and year of surgery. The caliper was defined as 0.20 standard deviations of the logit-transformed propensity score. The balance between the groups was tested using a standardized difference (>0.20 suggests imbalance). The incidence of MACCE in the matched cohort was compared. Fourth, the performance of the multivariable prediction model was compared regarding area under the receiver operating characteristic curves (AUC). The AUCs of a multivariable logistic regression model with N/LR, a model with P/LR, and a model without N/LR or P/LR were compared using DeLong’s methods.25
Fifth, cubic spline function curves of the multivariableadjusted relationship among POD 1 N/LR, P/LR, and the probability of MACCE were drawn to evaluate the continuous relationship among N/LR, P/LR, and the risk of MACCE. Results Among 965 patients analyzed, MACCE developed in 67 patients (6.9% coronary revascularization [n = 29], 3.0% nonfatal myocardial infarction [n = 46], 4.8% pulmonary embolism [n = 10], and 1.0% nonhemorrhagic stroke [n = 11]). Perioperative parameters according to the quartiles of N/LR on POD 1 in all patient cohorts are presented in Table 1. There were no significant differences across the quartiles of N/LR on POD 1. One hundred thirty-nine (14.4%) patients underwent surgery within 1 month after DES implantation. The incidence of MACCE was significantly higher in patients undergoing surgery within 1 month (n = 18/139 [12.9%]) than for patients undergoing surgery 1 to 6 month after DES insertion (n = 49/ 826 [5.9%]; p = 0.003). The cell count associated variables, including platelet count and proportion (%) of neutrophil, lymphocyte, and monocyte, were compared between those with and without MACCE, and the OR was calculated at the following 3 time points: preoperative, immediate postoperative, and POD 1 (Supplemental Table S2). The preoperative, immediately postoperative, and POD 1 N/LR and P/LR were divided into quartiles and were analyzed using univariable logistic regression analysis. POD 1 neutrophil count, immediate postoperative platelet count, and POD 1 platelet count showed significant associations with MACCE. As a continuous variable, immediate postoperative and POD 1 N/LR and immediate postoperative and POD 1 P/LR showed significant associations. As a categorized variable, POD 1 N/LR quartiles showed significant graded associations with MACCE. The distribution of MACCE according to the quartiles of N/LR and P/LR at the 3 time points are shown in Fig 1 and Supplemental Fig S2. The incidence of MACCE was significantly different across
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Fig 1. Incidences (%) of postoperative major adverse cardiovascular and cerebral events in patients undergoing noncardiac surgery after drug-eluting stent implantation according to the neutrophil/lymphocyte ratio quartile. MACCE, adverse cardiovascular and cerebral events; NLR, neutrophil/lymphocyte ratio; POD, postoperative day; Preop_NLR_Q1, 2, 3, 4, preoperative baseline neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; Imm_NLR_Q1, 2, 3, 4, immediate postoperative neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; POD 1_NLR_Q1, 2, 3, 4, = postoperative day 1 neutrophil/lymphocyte ratio quartile 1, 2, 3, 4; Q, quartile.
the quartiles of POD 1 N/LR (p = 0.035) but not in the other time points (see Fig 1). The incidence of MACCE was not significantly different between the quartiles of P/LR at any time point (see Supplemental Fig S2). The results of both univariate and multivariate analyses of risk factors for MACCE are displayed in Table 2. POD 1 N/LR was the only independent cell count associated predictor of MACCE both as a continuous and categorized variable. The quartiles of the POD 1 N/LR were associated with graded increases in the risk of MACCE development (4th quartile [N/LR 4.3] multivariate OR 2.03, 95% confidence interval [CI] 1.12-2.79; p = 0.040). Other significant risk factors included preoperative left ventricular ejection fraction, albumin, creatinine, surgery within 1 month after PCI, orthopedic and vascular surgery, surgery time, and red cell transfusion. Maintenance of dual-antiplatelet therapy was significantly associated with a decreased risk of MACCE. Propensity score analysis of POD 1 N/LR yielded 237 pairs with POD 1 N/LR 4.3 and POD 1 N/LR >4.3 (see Supplemental Fig S1). After matching, there were no unbalanced covariates with a standardized difference exceeding 0.20 (overall balance test: p = 0.956). The incidence of MACCE was significantly different between 2 matched groups (n = 25/ 237 [10.5%] in N/LR >4.3 v n = 12/237 [5.1%] in N/LR 4.3 [risk difference 5.5%, 95% CI 0.7%-10.3%; p = 0.026]). This difference was mainly from the incidence of nonfatal
myocardial infarction (n = 17/237 [7.2%] in N/LR >4.3 v n = 7/237 [3.0%] in N/LR 4.3; p = 0.036). The performances of the multivariable prediction models are compared in Fig 2 regarding AUC. The AUC of the model with POD 1 N/LR (AUC 0.76, 95% CI 0.70-0.82) was significantly larger than that of the model with POD 1 P/LR (v AUC 0.66, 95% CI 0.60-0.73; p < 0.001) or the model without N/LR or P/LR (v AUC 0.67, 95% CI 0.60-0.74; p < 0.001). The Nagelkerke R2 of the multivariable logistic regression model was 0.30 for the model with N/LR and 0.27 for the model without N/LR or P/LR. The model with N/LR showed good calibration (Hosmer-Lemeshow goodness-offit test: chi-square 5.34; p = 0.721). The cubic spline function curves of the multivariableadjusted relationship among POD 1 N/LR, POD 1 P/LR, and the probability of MACCE are shown in Fig 3. Although both N/LR and P/LR increase the risk of MACCE, the positive relationship was stronger between POD 1 N/LR and MACCE. As an additional analysis, to evaluate the interaction between antiplatelet drug maintenance and N/LR on the risk of MACCE, the multivariable-adjusted ORs of (1) N/LR >4.3 on POD 1 and stopping both aspirin and clopidogrel and (2) N/LR >4.3 on POD 1 and maintaining aspirin but stopping clopidogrel were calculated (see Table 3). The risk of MACCE increased for the discontinuation of clopidogrel or both drugs.
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Table 2 Multivariable Analysis of Patient Characteristics Associated With Postoperative Major Adverse Cardiovascular and Cerebral Events Univariable Analysis Variable Age, y Female Body mass index, kg/m2 Hypertension Diabetes mellitus Chronic obstructive pulmonary disease Cerebrovascular accident Chronic kidney disease Atrial fibrillation Preoperative left ventricular ejection fraction, % Preoperative hemoglobin, g/dL Preoperative albumin, g/dL Preoperative creatinine, mg/dL Three vessel disease Time from PCI to surgery <1 mo Coronary stent type, second generation v first generation Maintenance of aspirin until surgery without discontinuation Maintenance of dual-antiplatelet therapy until surgery without discontinuation Surgery type Orthopedic surgery Vascular surgery Neurosurgery General abdominal surgery Surgical time, h Emergency case Total intravenous anesthesia Transfusion of red blood cells, per unit POD 1 N/LR, continuous variable POD 1 N/LR, quartile Quartile 1, N/LR <2.2 Quartile 2, 2.2 N/LR <3.0 Quartile 3, 3.0 N/LR <4.3 Quartile 4, N/LR 4.3 POD 1 P/LR, continuous variable Quartile 1, P/LR <6.1 Quartile 2, 6.1 P/LR <8.6 Quartile 3, 8.6 P/LR <11.8 Quartile 4, P/LR 11.8
Multivariable Analysis
Odds Ratio (95% CI)
p Value
1.03 (1.00-1.06) 0.90 (0.52-1.54) 1.03 (0.96-1.10) 1.03 (1.00-1.06) 1.18 (0.71-1.96) 1.33 (0.46-3.82) 1.23 (0.37-4.12) 3.95 (1.98-7.88) 3.50 (1.47-8.31) 0.98 (0.96-0.99) 0.98 (0.87-1.11) 0.62 (0.42-0.91) 1.20 (1.10-1.31) 3.76 (1.57-8.99) 2.36 (1.33-4.18) 1.15 (0.69-1.93) 0.72 (0.39-1.34) 0.37 (0.11-1.19)
0.026 0.693 0.386 0.026 0.525 0.600 0.738 <0.001 0.005 0.020 0.785 0.016 <0.001 0.003 0.003 0.597 0.302 0.094
1.35 (0.73-2.50) 3.95 (2.26-6.91) 0.68 (0.16-2.87) 0.72 (0.25-2.41) 1.41 (1.24-1.61) 4.75 (1.67-13.50) 1.23 (0.88-2.34) 1.52 (1.31-1.75) 1.14 (1.06-1.23)
0.339 <0.001 0.597 0.684 <0.001 0.003 0.089 <0.001 0.001
Baseline 0.90 (0.46-1.35) 1.11 (1.01-1.32) 1.63 (1.22-2.09) 1.03 (1.00-1.06) Baseline 1.42 (0.62-3.22) 1.57 (0.70-3.52) 2.65 (1.25-5.62)
0.211 0.042 0.030 0.051 0.406 0.280 0.011
Odds Ratio (95% CI)
p Value
0.98 (0.96-0.99)
<0.001
0.49 (0.30-0.80) 1.26 (1.14-1.40)
0.004 <0.001
1.92 (0.98-3.73)
0.056
0.66 (0.34-0.89)
0.010
2.16 (1.07-4.34) 4.32 (2.14-8.72)
0.031 <0.001
1.26 (1.07-1.49)
0.006
1.98 (1.17-2.88) 1.17 (1.08-1.27)
0.001 <0.001
Baseline 0.63 (0.31-1.33) 1.24 (1.00-1.60) 2.03 (1.12-2.79) 1.01 (0.98-1.05) Baseline 1.28 (0.59-3.62) 1.60 (0.66-3.70) 2.54 (1.20-4.25)
0.174 0.049 0.040 0.102 0.605 0.457 0.024
Abbreviations: CI, confidence interval; N/LR, neutrophil/lymphocyte ratio; PCI, percutaneous coronary intervention; POD, postoperative day; P/LR, platelet/ lymphocyte ratio.
Discussion In the present study, an elevated N/LR on POD 1 was significantly associated with an increased risk of MACCE during postoperative month 1 both as continuous and ordinal variables in patients undergoing NCS within 6 months after DES insertion as a result of coronary artery disease. The quartiles of N/ LR demonstrated a graded association with a cutoff of >3.0 showing an OR of 1.11 and a cutoff of >4.3 showing an OR of 1.63. The POD 1 P/LR >11.8 also showed a significant association, but P/LR was not significant as a continuous variable and the graded association was not found. POD 1 N/LR, which can be calculated easily and inexpensively from a complete blood cell count,7 could help to predict MACCE after NCS after DES implantation. As shown in Table 1, the majority of MACCE were nonfatal myocardial infarction and coronary
revascularization, which suggests that myocardial ischemic events are the most expected postoperative morbidity. In the matched cohort, the difference in MACCE was mainly from the different incidence of myocardial ischemic events, highlighting the prognostic role of N/LR to predict particularly the myocardial ischemic events among MACCE. It is difficult to predict postoperative cardiovascular events accurately in moderate- to high-risk patients.26 The results of the present study confirm and extend previous reports on the predictive role of N/LR. Postoperative N/LR is associated with the development of AKI after cardiovascular surgery.16 Preoperative N/LR >4 has been associated with perioperative myocardial injury measured using serum high-sensitivity troponin T concentration.27 The association between N/LR and postoperative AKI can be traced to the role of inflammation in the pathogenesis of AKI.16,28,29 An acute ischemic insult activates
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Fig 2. Comparison of area under the receiver operating characteristic curve among (1) the multivariable prediction model with neutrophil/lymphocyte ratio on postoperative day 1, (2) the model with platelet/lymphocyte ratio on postoperative day 1, and (3) the model with neither neutrophil/lymphocyte ratio nor platelet/lymphocyte ratio on postoperative day 1. N/LR, neutrophil/ lymphocyte ratio; P/LR, platelet/lymphocyte ratio.
endothelial renal cells that express adhesion molecules, thus facilitating adhesion of inflammatory blood cells.30 The neutrophil and lymphocyte count all are potential surrogate markers of inflammation and are associated with the development of cardiovascular events.31,32 The predictive value of these 2 components can be combined by calculating the N/LR, which is known to be a prognostic marker of bacteremia, coronary intervention, CABG, and various types of cancer.8-14,20,33,34 A high preoperative N/LR has been associated with poor baseline renal function in patients undergoing CABG13,14 and also was an independent predictor of AKI in patients with severe sepsis and cardiovascular surgery.15-17 In addition to these findings, the authors of the present study have demonstrated that postoperative N/LR could be a prognostic factor to predict MACCE in patients undergoing NCS after DES insertion. There was significant interaction between high N/LR and discontinuation of antiplatelet drugs, which may contribute to the development of thrombogenic complications. This interaction may suggest that the systemic inflammatory reaction and thrombogenic condition contribute to the occurrence of MACCE synergistically. Cardiovascular and cerebrovascular events after surgery are related to stent thrombosis and cerebral and pulmonary thromboembolism. The surgery itself is thrombogenic and leads to an inflammatory response.35 Also, the discontinuation of antiplatelet agent because of the risk of bleeding could contribute to the development of MACCE,4,36 as shown in the authors’ multivariable analysis. The role of inflammation in thrombosis and thromboembolism is well known.37,38 In addition, vascular inflammation is associated with stent restenosis and stent
Fig 3. Cubic spline function curves of the multivariable-adjusted relationship among postoperative day 1 neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and probability of major adverse cardiovascular and cerebral events in patients undergoing noncardiac surgery after drug-eluting stent implantation. Shaded areas represent 95% confidence interval. CI, confidence interval; MACCE, major adverse cardiovascular and cerebral events; POD, postoperative day.
thrombosis.39 Thromboembolism after surgery also may be associated with surgery-related systemic inflammation. A recent retrospective study of patients undergoing knee arthroplasty reported that high N/LR is associated with postoperative venous thromboembolism, including pulmonary embolism.40 N/LR, as a surrogate marker of systemic inflammation, could act as a prognostic marker to predict MACCE after NCS. POD 1 N/LR was a stronger independent predictor of postoperative MACCE, whereas preoperative N/LR was not. This may be because the POD 1 N/LR could reflect the systemic inflammatory response after surgery better than preoperative N/LR. Although P/LR is reported to be a prognostic marker in patients with primary PCI to predict no reflow and mortality,18,19 its association with postoperative MACCE was relatively weaker compared with N/LR. This may be because the implication of platelet count in the surgical condition is different from that in the medical condition, possibly because of the confounder of surgical bleeding. Surgical bleeding may decrease platelet count, leading to relative thrombocytopenia and the
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Table 3 Adjusted Odds Ratio of the First Postoperative Day Neutrophil/Lymphocyte Ratio (N/LR 4.3) to Predict Postoperative Major Adverse Cardiovascular and Cerebral Events According to Preoperative Antiplatelet Medications Variable
N/LR on POD 1 4.3 (n = 239, 24.8%) N/LR on POD 1 4.3 and stopping both aspirin and clopidogrel (n = 168, 14.4%) N/LR on POD 1 4.3 and maintaining aspirin but stopping clopidogrel (n = 47, 4.9%)
Multivariable-Adjusted Odds Ratio (95% Confidence Interval)
p Value
2.03 (1.12-2.79)
0.040
3.02 (2.14-4.48)
0.006
2.44 (1.24-3.85)
0.045
NOTE. The same covariates in Table 2 were used to calculate the adjusted odds ratios. Stopping means discontinuation of at least 1 day before surgery. Abbreviations: N/LR, neutrophil/lymphocyte ratio; POD, postoperative day.
resulting postoperative platelet count may be less meaningful to reflect the prognosis of these patients. However, the amount of surgical bleeding in the present study was rather small. Activation and release of platelet-related mediators or acute phase reactants such as fibrinogen may confer a stronger association with MACCE rather than the platelet count itself.41 Nonetheless, lymphocyte count alone is associated with the prognosis of patients with cardiovascular disease,32,42 which may contribute to the P/LR being a significant prognostic factor, although its predictive value was less than that of N/LR. The cutoff of the 4th quartile was used as a cutoff of high POD 1 N/LR. However, this was arbitrary, and the normal reference ranges have not been defined for N/LR and P/LR. Previous studies have used cutoffs of tertile or quartile from their distribution of N/LR or P/LR,16,33,43 but it appears that the distribution of N/LR or P/LR varies significantly according to the patient population, type of surgery, and time point of measurements. Predictors for MACCE in the present study are mostly consistent with previous studies. According to American College of Cardiology/American Heart Association 2014 guidelines and a 2016 focused update, elective NCS after DES implantation may be performed after 180 days.3,4 These guidelines are supported by 2 recent studies that reported that the incidence of major adverse cardiovascular events did not differ when surgery is performed 6 months after DES implantation.5,22 The risk of MACCE was significantly high when surgery was conducted within 1 month after DES compared with surgery 1 to 6 months after PCI. The high risk of immediate surgery within 1 month after PCI was consistent in the previous studies.5,22,44 There were other predictors of postoperative MACCE, including baseline left ventricular ejection fraction, hemoglobin concentration, and serum albumin level. These predictors are related to the baseline medical conditions, which often are associated with postoperative morbidity and mortality.45,46 Long surgery time and intraoperative transfusion amount may be associated with surgical procedural difficulty and these variables generally are not modifiable as well as the poor baseline medical conditions.
Although not modifiable, risk factors in the present study, including N/LR, may help physicians to plan postoperative management based on the risk of postoperative MACCE. High-risk patients could be managed in the intensive care unit with advanced hemodynamic monitoring and screening for pulmonary embolism and stroke. Myocardial injury after NCS may be evaluated with high-sensitivity cardiac troponin T.47 Postoperative oral anticoagulant administration such as dabigatran may help to lower the risk of MACCE after surgery.48 Predictors in the present study can be incorporated into the inclusion criteria of clinical trials. The present study has several important limitations. First, because of its retrospective design, the results can only suggest an association between N/LR and postoperative MACCE. External validity is limited. It is not possible to completely control the bias and confounders. Prospective validation of the prognostic value of N/LR is required. Furthermore, the suggested cutoff of POD 1 N/LR to predict MACCE may have limited generalizability for other populations or different types of surgery. POD 1 N/LR after cardiac surgery had a 4th quartile cutoff of 10 in a previous study,16 but the 4th quartile cutoff of the present study was 4.3. Second, a larger sample size would be required to fully address the potential confounders. The present study’s power may be weak compared with previous studies.13,34 Because the present study was powered to discern the association between N/LR and postoperative MACCE, the other analyses are of limited value. Third, the patients included in this study underwent heterogenous types of surgeries with varying risk and different types of anesthesia. The different risk of surgery may affect the association between N/LR and MACCE. Total intravenous anesthesia may decrease N/LR immediately after surgery.49 The type of surgery, type of anesthesia, and year of surgery performed were included as the covariates of multivariable analysis and propensity score matching to address this confounder. Fourth, patients in whom aspirin or clopidogrel was discontinued for 1 to 6 days were excluded from the multivariable analysis, and only the variable regarding whether drugs were maintained or discontinued for 7 days before surgery were included in the analysis because of concerns of variable residual antiplatelet effect between 1 to 6 days. However, a 2017 European Society of Cardiologists focused update recommended that clopidogrel should be discontinued for at least 5 days before NCS.50 Therefore, the effect of stopping the drug for 5 days according to the recent guidelines could not be adjusted in the present analysis. In conclusion, there was a robust and independent association between POD 1 N/LR and postoperative MACCE in the first 1-month after NCS within 6 months after DES implantation. Therefore, N/LR, which is easily calculated and routinely available, could assist in identifying MACCE in high-risk surgical patients. Declaration of Competing Interest All authors declared no financial conflict of interest. Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1053/j.jvca.2019.10.009.
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