Is Neutrophil-to-Lymphocyte Ratio useful in Predicting Drug-Eluting Stent Restenosis?

Research Article

Austin J Cardiovasc Dis Atherosclerosis. 2016;3(2): 1026.

Is Neutrophil-to-Lymphocyte Ratio useful in Predicting Drug-Eluting Stent Restenosis?

Sheikh AB¹*, Felzer JR², Daneshvar F³, Munir AB4, Bouchard M5 and Lafferty J3

¹Department of Cardiology, Ochsner Clinical Foundation / John Ochsner Heart and Vascular Institute, New Orleans, LA, USA

²Department of Medicine, Scripps Clinic/Green Hospital, La Jolla, CA, USA

³Department of Cardiology, Northwell Health / Staten Island University Hospital, Staten Island, NY, USA

4Department of Medicine, Northwell Health / Staten Island University Hospital, Staten Island, NY, USA

5Department of Pediatrics, Northwell Health / Staten Island University Hospital, Staten Island, NY, USA

*Corresponding author: Azfar B. Sheikh, M.D, Cardiology Fellow, John Ochsner Heart and Vascular Institute, New Orleans, LA 70130, USA

Received: June 13, 2016; Accepted: September 28, 2016; Published: September 30, 2016


Objectives: This study aims to assess the usefulness of an elevated postprocedural Neutrophil-to-Lymphocyte Ratio (NLR > 4.5) as a prognostic tool in predicting in-stent restenosis (ISR) of coronary drug-eluting stents (DES). We will also assess if ISR can predict 10-year all-cause mortality.

Background: In patients undergoing percutaneous coronary intervention, ISR of DES is life threatening. NLR, a marker of subclinical inflammation, has been used to predict adverse outcomes in cardiovascular disease including ISR and mortality.

Methods: We conducted a case-control study on patients who underwent at least two cardiac catheterizations in Staten Island University Hospital between January 2004 and May 2015. We analyzed hematologic, angiographic and clinical data of 242 patients. A DES must have been implanted during initial cardiac catheterization and later followed by subsequent coronary angiogram which would reveal patency or ISR of DES. NLR was calculated from a blood sample taken within the first 24 hours after the initial procedure. Based on results, patients were divided into two groups, ISR group (≥50%) and non-ISR group (<50%). Propensity score matching (PSM) was used for direct comparison between the groups.

Results: NLR > 4.5 was not predictive of ISR [OR = 2.0, 95% CI (0.6, 6.6)]. Receiver operating curve analysis revealed a NLR value of 3.6 had 33% sensitivity and 76% specificity in predicting ISR. There was no difference 10- year all-cause mortality rate between the two groups. [OR = 1.3, 95% CI (0.5, 3.3)].

Conclusion: This is the first study that shows that an elevated postprocedural NLR has no significant value in predicting ISR of DES.

Keywords: Neutrophil lymphocyte ratio; Drug-eluting stents; In-stent restenosis; Mortality; Coronary artery disease


ACS: Acute Coronary Syndrome; AUC: Area Under Curve; BMS: Bare Metal Stent; CAD: Coronary Artery Disease; CBC: Complete Blood Count; CRP: C-Reactive Protein; DES: Drug-Eluting Stent; DLC: Differential Leukocyte Count; ECP: Eosinophil Cationic Protein; EF: Ejection Fraction; EMR: Electronic Medical Records; GRACE: Global Registry of Acute Coronary Events; IL: Interleukin; IRB: Institutional Review Board; ISR: In-Stent Restenosis; IVUS: Intravascular Ultrasound; MCID: Minimal Clinically Important Difference; MMP: Matrix Metalloproteinase; NLR: Neutrophilto- Lymphocyte Ratio; NSTEMI: Non-ST Elevation Myocardial Infarction; OCT: Optical Coherence Tomography; PAI: Plasminogen Activator Inhibitor; PCI: Percutaneous Coronary Intervention; PSM: Propensity Score Matching; REDCap: Research Electronic Data Capture; ROC: Receiver Operating Characteristics; SD: Standard Deviation; SSDI: Social Security Death Index; ST: Stent Thrombosis; STEMI: ST Elevation Myocardial Infarction; TIMI: Thrombolysis In Myocardial Infarction; WBC: White Blood Cell


With Coronary Artery Disease (CAD) as a leading cause of morbidity and mortality, there are numerous advances being made in the field of interventional cardiology to improve outcomes and minimize complications. Despite the widespread use of Drug- Eluting Stents (DES) during Percutaneous Coronary Interventions (PCI), patients have developed In-Stent Restenosis (ISR), a life threatening complication [1]. The primary mechanisms of ISR are acute inflammation causing neo-intimal proliferation, elastic recoil and negative arterial remodeling. Numerous inflammatory markers have been proposed to predict short and long-term cardiac mortality in patients with Acute Coronary Syndromes (ACS), Bare Metal Stent (BMS) ISR and Stent Thrombosis (ST). These include C-Reactive Protein (CRP), Eosinophil Cationic Protein (ECP), Matrix Metalloproteinase (MMP), and White Blood Cell (WBC) counts. Neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation, has also been used to predict adverse outcomes in cardiovascular disease and cancer [2-10]. The objective of this study is to assess the usefulness of an elevated post-procedural NLR (> 4.5) as a prognostic tool in predicting DES ISR.


Study design

We conducted an observational case-control study on patients who underwent cardiac catheterizations at Staten Island University Hospital (Staten Island, New York) between January 2004 and May 2015. After the local Institutional Review Board (IRB) approved the study protocol, access was granted to the patient data using Electronic Medical Records (EMR).

The inclusion criteria included patients between the ages of 18 and 90, availability of a Complete Blood Count (CBC) drawn within the first 24 hours after the initial cardiac catheterization procedure in which a DES was implanted into native coronary vessels due to an abnormal stress test, stable angina refractory to medical management, or ACS. The procedure must have been considered a successful PCI, defined as luminal stenosis diameter < 20% with final Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow without any major complications [11]. This must be followed by a later coronary angiography allowing for assessment of previously stented vessels and determination of patency or ISR. After DES placement, the patient had to be compliant with their dual antiplatelet therapy for a minimum of 1 year, followed by one antiplatelet medication thereafter. Exclusion criteria included evidence of prior BMS placement in a native coronary vessel amenable for DES implantation, DES placement in graft vessel(s), End-Stage Renal Disease (ESRD) on dialysis, chronic inflammatory or autoimmune disease, active cancers, and conditions altering differential leukocyte counts such as HIV/AIDS, leukemia, lymphoma, chronic corticosteroid therapy (> 3 weeks), chemotherapy or other immunosuppressive medications. Patients that developed major or life-threatening bleeds in between the two cardiac catheterization procedures contraindicating the use of dual antiplatelet agents were also excluded.

Each patient had their demographic, hematologic and angiographic data collected and stored in Research Electronic Data Capture (REDCap) which included age, gender, medication use, history of hypertension, diabetes, hyperlipidemia, Chronic Kidney Disease (CKD), tobacco use, family history of CAD, left ventricular ejection fraction (EF), cell counts, post-procedural NLR, DES characteristics, time interval between cardiac catheterizations, and ISR percentage. The neutrophil, lymphocyte, monocyte, total WBC counts were collected from the first CBC obtained during the first 24 hours after the first cardiac catheterization procedure. Differential leukocyte counts (DLC) were obtained by the Coulter Counter apparatus (Coulter® Gen. S Hematology Analyzer, Beckman Coulter Corp., Hialeah, Florida). The NLR was calculated as the ratio of postprocedural neutrophil to lymphocyte counts from the same blood sample. Based on the collected data, patients were divided into two groups. Patients who developed significant ISR (≥50%) were labeled as part of the ISR group and patients who did not have significant ISR were labeled as part of the non-ISR group.

Assuming that the prevalence of an elevated pre-procedural NLR in patients with DES ISR was 19.5% compared to 6.6% in patients without ISR, as mentioned in a recent study [12], our sample size was estimated to detect a minimal clinically important difference (MCID) of 15% between the two groups. To detect this association with 5% type 1 error and 80% power required a minimum of 118 patients in each group.

The primary end points were prevalence of an elevated postprocedural NLR (> 4.5) in each group, and whether an elevated post-procedural NLR could predict DES ISR. Secondary endpoint included 10-year all-cause mortality assessed using EMR and/or Social Security Death Index (SSDI).

Statistical analysis

The Kolmogorov-Smirnov test was used to test the distribution pattern. Categorical variables were summarized as frequencies and percentages. They were compared using chi square or Fisher’s exact test depending on sample size. Continuous variables are summarized as mean ± standard deviation (SD) and compared using two-sample t-test (or Wilcoxon Rank Sum Test). Analysis of the primary endpoint was carried out initially using univariate logistic regression analysis. Variables for which the unadjusted p value was < 0.1 in univariate logistic regression analysis were included in propensity score matching (PSM) analysis to account for confounders. The odds ratio (OR) for primary and secondary endpoints was calculated along with the associated 95% confidence intervals (CI) using propensity score matched data. Additionally, we explored cut-points using receiver operating characteristics (ROC) curves to assess how well postprocedural NLR can predict ISR. (Figure 1). All statistical analyses were conducted using SAS 9.3 (SAS Institute Inc., Cary, North Carolina). A p-value ≤ 0.05 was considered statistically significant.