Usefulness of the platelet-to-lymphocyte ratio in predicting bare-metal stent restenosis

Abstract

Objectives. Platelet-to-lymphocyte ratio (PLR) provides a simple method for assessment of inflammatory status. The aim of the present study was to investigate the predictive value of preprocedural PLR on development of in-stent restenosis in patients undergoing bare-metal stent (BMS) implantation. Design. Six hundred and seventy-five consecutive patients (mean age: 60.6 ± 8.3, 66% men) who had undergone successful BMS implantation and additional coronary angiography for stable or unstable angina pectoris were analyzed. Mean period between 2 coronary angiographies was 14.3 ± 3.4 months. Results. Patients were divided into tertiles based on preprocedural PLR. Restenosis occurred in 58 patients (26%) in the lowest tertile, in 82 (36%) in the middle tertile, and in 115 (51%) in the highest tertile (p < 0.001). Serum C-reactive protein levels were also significantly higher in patients in tertile 3 than in those in tertiles 1 and 2 (p < 0.001). Smoking, diabetes mellitus, high-density lipoprotein, stent length, preprocedural PLR, and C-reactive protein levels emerged as independent predictors of in-stent restenosis. In receiver-operating characteristics curve analysis, PLR >122 had 81% sensitivity and 72% specificity in predicting in-stent restenosis. Conclusions. High preprocedural PLR is a powerful and independent predictor of BMS restenosis in patients with stable and unstable angina pectoris.

Key words::

• coronary artery disease
• inflammation
• stent restenosis

Introduction

Inflammatory processes play an important role not only in initiation and progression of atherosclerosis, but also in development of stent restenosis (1,2). Despite major advances in interventional techniques and drug therapies, in-stent restenosis remains a major problem in interventional cardiology (3). Vascular responses after percutaneous coronary intervention (PCI)-induced endothelial injury are characterized by the sequence of inflammation, granulation, extracellular matrix remodeling, and smooth muscle cell (SMC) proliferation and migration, which leads to neointimal hyperplasia and restenosis (4,5). Besides technical and mechanical conditions associated with PCI, inflammatory status before and after stent implantation is a significant risk factor for in-stent restenosis (6).

Platelets secrete proinflammatory substances such as chemokines and cytokines that mediate vascular inflammation after being activated by substances released from cells of the vascular wall. Platelet– lymphocyte ratio (PLR) is a novel biomarker showing inflammation in cardiac and non-cardiac patients (7). Previous studies demonstrated an association between major adverse cardiovascular outcomes with higher platelet and lower lymphocyte counts (8,9). The aim of the present study was to evaluate the usefulness of PLR before successful bare-metal stent (BMS) implantation in predicting in-stent restenosis in patients with stable and unstable angina pectoris.

Methods

We retrospectively analyzed clinical, laboratory, and angiographic data from consecutive patients who underwent successful BMS implantation from January 2010 to December 2012 at Türkiye Yüksek Ihtisas Educational and Research Hospital (Ankara, Turkey). Patients who underwent coronary angiography because of stable or unstable angina pectoris and succesful BMS implantation were included in this study. For patients’ data, we retrospectively gained access to the records at the time of interest, when the patients underwent BMS implantation during coronary angiographybecause of clinical indications, including symptoms of angina and abnormal non-invasive test results (either treadmill exercise tests or myocardial perfusion scintigraphy), thus recalling clinical, angiographic, and laboratory characteristics at that time. As part of our preprocedural protocol, complete hemogram analysis and peripheral differential counts had already been available before coronary angiography for all patients. Patients were excluded from study if they had clinical evidence of cancer, chronic inflammatory diseases, hepatic or hemolytic disorders, rheumatologic diseases, or any active infectious diseases. Finally, 675 patients were enrolled in this study.

Patients’ clinical and demographic characteristics, encompassing age, gender, history of arterial hypertension, diabetes mellitus, tobacco use, and the left ventricular ejection fraction, were noted. In addition, serum levels of fasting blood glucose, hemoglobin, C-reactive protein (CRP), and a lipid panel including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were also recorded. The local ethics committee approved the study protocol.

All laboratory data were obtained from venous blood samples up to 6 h before stent implantation. Total platelet, lymphocyte, and monocyte counts were calculated using an automated blood cell counter (ADVIA 2120i Hematology System, Siemens Healthcare Diagnostics, Deerfield, IL). PLR was calculated as the preprocedural ratio of platelets to lymphocytes obtained from the same blood samples. CRP was measured by an immunonephelometric method (Roche Diagnostics GmbH, Marburg, Germany).

Coronary interventions were performed according to current practice guidelines and recorded in digital storage for further analysis (10). The degree of coronary stenosis was visually estimated by experienced interventional cardiologists. Luminal narrowing > 50% in a major subepicardial vessel (left anterior descending, left circumflex, or right coronary artery) was defined as significant stenosis. Each patient received aspirin plus clopidogrel (loading dose 300 or 600 mg) before or during coronary intervention. Unfractionated heparin (100 U/kg) was administered at the beginning of the procedure to keep the activated clotting time > 200 s. The access site for intervention was at the physician's preference (femoral or radial). Use of glycoprotein IIb/IIIa inhibitors and predilatation or postdilatation after stent implantation of the lesion was at the operator's discretion. A successful PCI was previously defined as the achievement of a minimum stenosis diameter reduction to < 50% in the presence of grade-3 Thrombolysis In Myocardial Infarction (TIMI) flow (assessed by angiography) without side branch loss, flow-limiting dissection, or angiographic thrombus (11). We also defined successful PCI as a reduction of stenosis diameter to lower than 50% narrowing at final angiography.

During routine clinical follow-up, coronary angiography was performed on clinical indications in patients with stable or unstable angina pectoris. Control coronary angiograms were recorded using the Judkins technique and interpreted by two independent cardiologists who were blinded to patients’ data. The evaluation of stenosis was carried out using the conventional visual assessment technique. Stent restenosis was accepted as narrowing > 50% in a vessel of otherwise normal diameter, including 5 mm proximal and distal to the stent edge. Intra- and interobserver variability of stent restenosis analysis was minimal in a representative subset of 80 patients. The interpretations of the two investigators on the presence or absence of in-stent restenosis agreed in 95% (76 of 80) and 96% (77 of 80), respectively. Intraobserver variability was assessed by one investigator. The two readings were concordant for the presence or absence of in-stent restenosis in 96% (77 of 80) and 97.5% (78 of 80), respectively.

Analyses were performed using SPSS 20.0 (SPSS, Inc., Chicago, IL). Continuous data were presented as median and interquartile range or mean ± SD. To test the distribution pattern, the Kolmogorov–Smirnov test was used. The study population was assigned into tertiles based on PLRs at admission. Comparisons of multiple mean values were carried out by Kruskal–Wallis tests or analysis of variance, as appropriate. Categorical variables were summarized as percentages and compared with chi-square test. Spearman correlation coefficient was computed to examine the association between two continuous variables. Effects of different variables on in-stent restenosis were calculated in univariate analysis for each. Variables for which the unadjusted p value was < 0.10 in logistic regression analysis were identified as potential risk markers and included in the full model. We reduced the model using stepwise multivariate logistic regression analyses and eliminated potential risk markers using likelihood ratio tests. A p value < 0.05 was considered statistically significant and the confidence interval was 95%. An exploratory evaluation of additional cut points was performed using receiver-operating characteristics curve analysis. A two-sided p value < 0.05 was considered statistically significant.

Results

The baseline clinical and procedural characteristics of the study population are summarized in Table I. A total of 675 patients (mean age: 60.6 ± 8.3 years, 66% men) were divided into tertiles according to preprocedural PLR: 94 ± 41 in tertile 1, 115 ± 54 in tertile 2, and 147 ± 58 in tertile 3. Each group was composed of 225 patients. The mean period between the two coronary angiographic studies for all study population was 14.3 ± 3.4 months.

Table I. Baseline characteristics of patients according to preprocedural PLR tertiles.

	Platelet-to-lymyphocte ratio
Variables	94 ± 41 (n = 225)	115 ± 54 (n = 225)	147 ± 58 (n = 225)	p value
Age (years)	59.9 ± 10.1	61.2 ± 9.8	61.1 ± 10.4	0.427
Men	145 (64%)	151 (67%)	154 (68%)	0.354
Diabetes mellitus	60 (26%)	75 (33%)	89 (39%)	< 0.001
Current smoker	85 (37%)	98 (44%)	121 (53%)	< 0.001
Hypertension	115 (51%)	109 (48%)	121 (54%)	0.495
Reason for stent implantation
Stable angina pectoris	163 (72%)	151 (67%)	144 (64%)	0.126
Unstable angina pectoris	62 (28%)	74 (33%)	81 (36%)	0.126
Number of coronary arteries narrowed
1	40 (17%)	41 (18%)	49 (21%)	0.521
> 1	185 (83%)	184 (82%)	176 (79%)	0.521
Target coronary artery
Left anterior descending artery	110 (49%)	99 (44%)	117 (52%)	0.083
Right coronary artery	55 (24%)	49 (21%)	59 (26%)	0.414
Circumflex artery	60 (27%)	77 (35%)	49 (22%)	0.024
Stent diameter (mm)	3 (2.75–3)	3 (2.5–3)	3 (2.75–3)	0.485
Stent length (mm)	15 (12.5–18)	16 (13–17.5)	16 (13–18.5)	0.222
Left ventricular ejection fraction (%)	60.2 ± 3.5	61.5 ± 3.8	60.9 ± 4.5	0.541
Fasting glucose (mmol/l)	5.6 (4.9–6.7)	6.1 (5.2–7.1)	6.4 (5.2–8.1)	0.024
High-density lipoprotein cholesterol (mmol/l)	1.06 (0.90–1.29)	1.03 (0.85–1.19)	0.95 (0.80–1.16)	0.015
Low-density lipoprotein cholesterol (mmol/l)	3.49 (2.71–4.63)	3.68 (3.67–4.89)	3.93 (2.71–4.97)	0.004
Triglycerides (mmol/l)	1.50 (1.10–2.31)	1.53 (1.18–2.23)	1.63 (1.13–2.31)	0.208
Hemoglobin (g/l)	145 ± 31	140 ± 36	138 ± 34	0.185
Platelet count (x10^9/l)	225 (195–284)	236 (204–290)	251 (215–318)	< 0.001
Lymphocyte count (x10^9/l)	2.36 (1.1–3.7)	2.04 (0.8–3.2)	1.71 (0.51–2.92)	< 0.001
C-reactive protein (nmol/l)	16.1 (8.0–30.0)	29.5 (15.4–70.9)	55.7 (37.6–118.1)	< 0.001
Period between the two coronary angiographies (months)	14.5 ± 2.7	13.8 ± 3.1	14.5 ± 2.9	0.345
In-stent restenosis	58 (26%)	82 (36%)	115 (51%)	< 0.001

Data are expressed as mean ± SD, number (percentage), or median (interquartile range).

Patients in tertile 3 had significantly higher rates of in-stent restenosis compared with those in tertiles 1 and 2 (p < 0.001, Figure 1). A positive correlation was observed between PLR and CRP levels (r = 0.35, p < 0.001). Higher PLRs before stent deployment were associated with an increased in-stent restenosis by logistic regression analysis. Diabetes mellitus, smoking, high-density lipoprotein cholesterol, stent length, and preprocedural PLR and CRP levels were found to be independent predictors of in-stent restenosis (Table II). Receiver-operating characteristic curve analysis was used to explore the relation between preprocedural PLR and in-stent restenosis. The area under the curve was 0.82 (95% confidence interval: 0.77–0.91, p < 0.001). Preprocedural PLR with a cut-off level of > 122 predicted in-stent restenosis with sensitivity of 81% and specificity of 72% (Figure 2).

Figure 1. Percentage of patients developing in-stent restenosis stratified by tertile of preprocedural PLR (p for trend < 0.001).

Figure 2. Receiver-operating characteristic curve for preprocedural PLR for predicting in-stent restenosis.

Table II. Odds ratio (OR) for in-stent restenosis in univariate and multivariate logistic regression analysis.

	Univariate		Multivariate
Variables	OR (95% CI)	P value	OR (95% CI)	P value
Age	1.04 (0.92–1.12)	0.414
Diabetes mellitus	1.24 (1.11–1.38)	< 0.001	1.21 (1.07–1.32)	0.002
Hypertension	1.12 (0.98–1.22)	0.092	1.07 (0.95–1.16)	0.345
Smoker	1.32 (1.15–1.43)	< 0.001	1.36 (1.19–1.49)	< 0.001
High-density lipoprotein	0.91 (0.84–0.95)	0.001	0.93 (0.97–0.85)	0.024
Low-density lipoprotein	1.10 (0.97–1.19)	0.215
Triglycerides	1.05 (0.94–1.15)	0.429
Platelet-to-lymphocyte ratio	1.23 (1.10–1.34)	< 0.001	1.19 (1.06–1.29)	0.018
C-reactive protein	1.26 (1.14–1.39)	< 0.001	1.29 (1.17–1.41)	< 0.001
Stent length	1.19 (1.07–1.32)	0.001	1.17 (1.05–1.28)	0.032
Stent diameter	1.07 (0.98–1.13)	0.298

Discussion

In the present study, we investigated the relationship between preprocedural PLR and development of in-stent restenosis. We demonstrated that PLR is a powerful and independent predictor of in-stent restenosis in patients undergoing successful BMS implantation. Patients in the highest tertile of PLR were at greater risk, and PLR > 122 measured before stent placement had an 81% sensitivity and a 72% specificity in predicting in-stent restenosis.

Adverse reactions to BMS implantation include stent thrombosis and restenosis. Although thrombosis in BMSs mainly seems to be affected by procedural factors, restenosis is a more complex procedure involving mechanisms of tissue repair after vessel injury occurring during implantation (12). The cellular response to mechanical vascular damage initiated immediately after PCI includes an early phase consisting of platelet activation and inflammation, followed by an intermediate phase of granulation tissue corresponding to SMC migration and proliferation, a late phase of tissue remodeling (neointima), and finally progression to in-stent restenosis (2). Although the exact causative mechanisms remain to be completely elucidated, pre- and postprocedural inflammatory status seem to be the most important risk factors for in-stent restenosis (13). Several inflammatory biomarkers have been investigated in the setting of coronary stenting to stratify the risk of both angiographic and clinical outcomes. CRP is the most widely studied biomarker in patients undergoing PCI, and represents a sensitive marker of systemic inflammation. A meta-analysis of nine studies showed that preprocedural CRP levels were a significantly predictor of in-stent restenosis after BMS placement (14). Many other proinflammatory biomarkers, including fibrinogen (15), interleukin-1 (15), neutrophil–lymphocyte ratio (16), lipoprotein a (17), interleukin-6 (17), and soluble CD40 ligand (18) have also been found to be related to preprocedural inflammatory status and prediction of in-stent restenosis.

Previous studies have demonstrated that higher platelet and lower lymphocyte counts are associated with poor clinical outcomes in various cardiovascular diseases (8,19–21). The PLR, as an independent predictor, merges the predictive risk of platelet and lymphocyte counts into a single risk factor. It has been found that a higher PLR is associated with severity and complexity of coronary artery disease (22), poor coronary collateral devolepment (23), no re-flow after primary PCI (24), non-dipper hypertension (25), and occlusive peripheral arterial disease (26). A recent study by Temiz et al. showed that in patients with ST-elevated myocardial infarction, in-hospital mortality was increased in the high PLR group when compared with that in the low PLR group (12.7% vs. 5.9%, p = 0.004) (27). In addition, Azab et al. showed that higher PLR is a significant independent marker of long-term mortality in patients with non-ST elavated myocardial infarction (28). To the best of our knowledge, we have for the first time demonstrated an association of PLR with in-stent restenosis in patients presenting with stable or unstable angina pectoris. According to our findings, higher PLR values on admission were significantly associated with in-stent restenosis during follow-up.

The results of our study should be interpreted in light of several limitations. First, the study was designed in a retrospective manner and represents a single-center experience with only BMS restenosis. Second, the definition of in-stent restenosis was based on visual assessment rather than more quantitative and informative intravascular ultrasound or optical computed tomographic results. Third, a single blood sample obtained in the preprocedural period may not be representative for the long-term PLR.

Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.