Figure 1. Study flowchart. MI: myocardial infarction. MACE: mayor adverse cardiovascular events. TLR...

Figure 2. Values of the NLR 6 hours after the PCI based on the presence of MACE.

Table 1. Association between clinical and procedural variables and the presence of MACE at the in-h...

Table 2. Association between laboratory variables and the presence of MACE at the follow-up.

Table 3. Predictors of MACE. Multivariate analysis. Logistic regression model.

Introduction

Major adverse cardiovascular events (MACE) associated with percutaneous coronary intervention (PCI) minimize procedural and clinical success alike. Percutaneous coronary intervention triggers myocardial inflammation whose size and magnitude depends on the duration of the ischemia produced and is divided into 3 phases: 1) phase of alarm (release of protein molecules), 2) phase of leukocyte migration (neutrophil recruitment into the blood flow and tissue infiltrating lymphocytes with a corresponding decrease in blood), and 3) resolution phase.1,2

Elevated cardiac biomarkers are the clinical expression of the aforementioned cardiac inflammatory status. Consistent with this, the neutrophil-to-lymphocyte ratio (NLR) marker is easy to establish, easy-to-use, cost-effective, reproducible, and often available. The NLR is associated with a greater atherosclerotic load3, more chances of stent thrombosis,4 and type 4a myocardial infarction.5

The PCI reduces the symptoms of myocardial ischemia, the risk of infarction, and mortality rate when it is successful.6 The risk stratification of complications at the follow-up is essential for secondary prevention purposes and imposes the search for markers associated with the results.7

The objective of this study was to determine the value of the NLR to predict MACE in patients treated with PCI.

Methodological design

This was a descriptive, correlational, and prospective study conducted between November 2018 and October 2019. Patients over 18 treated with PCI were included. The following patients were excluded: those with left ventricular ejection fraction (LVEF) < 30%, those treated with PCI on chronic total coronary occlusions, with myocardial revascularization surgery the previous 3 months, patients with severe pulmonary disease, neoplasm, on chemotherapy, with chronic blood disorders, on corticosteroid therapy over the last year, with chronic inflammatory disease, active infections, and patients who refused to participate in the study. The sample eventually included 101 patients.

The follow-up variable: MACE, as a composite endpoint, was defined based on the presence of some of the following events during the hospital stay or at the follow-up: stent thrombosis, need for new target vessel revascularization, stroke, nonfatal myocardial infarction, need for new target lesion revascularization or cardiovascular death. All these events were studied separately. Cardiovascular death was defined as deaths associated with cardiovascular complications such as myocardial infarction, stent thrombosis, stroke, malignant ventricular arrhythmias, and heart failure.

Ethical considerations

This study was approved by the scientific research and technical review ethics committee. The patients’ informed written consent was obtained prior to their participation in the study.

Techniques and procedures

leukogram conducted using the Pentra-DX NEXUS Hematology analyzer. Parameters analyzed: neutrophils and lymphocytes were expressed as absolute values (#). The differential WBC count was performed based on the packed cell volume, shape of the nucleus, granules, chromatic appearance of the nucleus, and intensity of the stain. It was conducted up to 1 week prior to the PCI and repeated 6 hours after the PCI.

Follow-up

A minimum follow-up of 6 months and a maximum follow-up of 17 months were conducted (median follow-up, 11-5 months).

Techniques of information processing and analysis

Qualitative variables were expressed as absolute numbers and percentages. Quantitative variables were expressed as mean and standard deviation (SD) when data had a normal distribution. For the lack of normal distribution, the median and interquartile range (IQR) [minimum and maximum] were used. In the univariate analysis performed for qualitative variables the chi-square test was used. The Student t test was used when data had a normal distribution; on the contrary, the Mann-Whitney U test was used. A binary logistics regression model was used for the multivariate analysis. Adjusted odds ratios (OR) and 95% confidence intervals were estimated for each variable. In all hypothesis testing, P values = .05 and 95% confidence intervals were considered statistically significant.

RESULTS

Out of the 152 patients initially included, 51 had incomplete data in their medical records or were lost to the follow-up. In 30 (29.7%) of the 101 patients studied, at least, 1 MACE occurred. The most common adverse event was the need for new target lesion revascularization (17 patients/16.8%). Figure 1.

The mean age was 60.6 ± 12.8 years, and the main clinical characteristics were diabetes mellitus (38.6%), previous myocardial infarction (49.5%), and PCIs performed in the acute coronary syndrome setting (56.4%). A total of 53.5% of the patients had multivessel coronary artery disease with a median/IQR in the SYNTAX score of 11.0/15 points. A total of 31 patients (30.7%) were treated with multivessel PCI, 46.5% with the simple bifurcation technique. The use of drug-eluting stents (DES) was predominant (76.2%). The angiographic success rate was 92.1%. Table 1.

The absolute number of neutrophils prior to the PCI, according to the median/IQR was 5.0/1 (a minimum of 2, and a maximum of 8), and 6.0/1 (4-10) after 6 hours; the NLR prior to the procedure was 3.0/1 (2-5), and 2.0/2 (6 hours later), although with a wider range (1-7). Table 2.

The variables associated with the presence of MACE were: LVEF (P = .021); 18 patients with left ventricular systolic dysfunction, multivessel coronary artery disease (21 cases, 20.8% vs 33 cases, 32.7%; P = .030), SYNTAX score (P < .001), multivessel PCI (14/13.9% vs 17/16.8%; P = .024), bifurcation lesions (21/20.8% vs 30%/29.7%; P = .011), true bifurcation lesions (17/16.8% vs 16/15.8%; P = .001), complex bifurcation techniques, and number of stents implanted, among others.

Table 2 and figure 2 show that the absolute number of neutrophils 6 hours after the PCI was 7.0/2 vs 6.0/1; P < .001) and the NLR 6 hours after the PCI was 4.0/3 vs 2.0/1; P < .001) were associated with the presence of MACE. The absolute number of lymphocytes 6 hour after the PCI showed a trend towards statistical significance (2.0/0 vs 2.0/1; P = .006).

In the multivariate analysis, the SYNTAX score (P = .002; OR, 1.201; 95%CI, 1.067- 1.352), and the NLR after the procedure (P = .010, OR, 2.254; 95%CI, 1.217-4.178) are independent variable predictors of events. A high NLR increases the chances of MACE by 2.254 times. Table 3.

DISCUSSION

This study assessed the value of the NLR in 101 patients treated with PCI to predict MACE with a median follow-up of 11.5 months.

The patients’ baseline characteristics are consistent with those of other studies where having a medical history of male sex, age > 60, diabetes mellitus, and previous myocardial infarction is associated with higher chances of being treated with PCI.7

Over half of the study patients showed multivessel disease associated with a median SYNTAX score of 11.0; this estimate was made only in lesions with > 70% stenosis in vessels ≥ 2 mm in diameter. This strategy has been recommended by the ERACI IV trial to facilitate a more reasonable assessment of the coronary anatomy and more conservative percutaneous coronary interventions.8

The incidence rate of bifurcation lesions is between 15% and 20%.9 The definition of a true bifurcation is the presence of a significant plaque in the secondary branch ostium. The stepped approach has yielded the best results proving superior to the complex or scheduled technique with 2 stents;10 consistent with this, the present series (46.5%) used the stepped approach. The use of the PCI is not that common in complex bifurcations (secondary branch with lesions ≥ 10 mm, stenosis diameter ≥ 70% in the left main coronary artery or ≥ 90% in the remaining bifurcations, < 45 or > 70-degree angles, among other) whereas the 2-stent technique systematically yields the best clinical results of all.11

Drug-eluting stents have been more widely used with more complex anatomies, multivessel PCI, for the management of bifurcation lesions, and in the clinical context of unstable patients. In all these clinical settings, the use of drug-eluting stents has proven undoubtedly favorable.12

During the PCI the blood flow towards the myocardium is reduced and microembolizations can occur causing specific metabolic changes and acute inflammatory activity in the myocardium and the damaged coronary artery. The most severe condition is myocardial necrosis that induces the production and activation of free radicals, the start of a cytokine storm, and the release of the tumor necrosis factor alpha.13 This postoperative inflammation is obvious in the elevated levels of neutrophils reported and, consequently, in the NLR.

This study shows increased median absolute neutrophil counts, wider neutrophil absolute values (baseline levels: 5.0/1 between 2 and 8; after 6 hours: 6.0/1 between 4 and 10), and an elevated NLR (baseline levels: 3.0/1 between 2 and 5; after 6 hours: 2.0/2 between 1 and 7). Similar results were published by Rodríguez S et al.14 who showed a significantly higher postoperative NLR (baseline levels: 3.316 [2.999 – 4.001] and 3.878 [3.214 – 4.491 after 6 hours] P = .003) in patients with acute coronary syndrome.

Major adverse cardiovascular events (MACE) are a group of complications associated with procedural failure, an impaired quality of life, and the patient’s death. A total of 9 cases were reported during the hospital stay and 26 at the clinical follow-up for an incidence rate of 29.7% that is consistent with that reported by other authors.15 The most common MACE was the need for new target lesion revascularization. Although the technological advances made with coronary stent grafts facilitate PCIs, they have proven insufficient to reduce significantly the incidence rate of restenosis reported in the United States (around 10%).16 Of multifactorial causes, local inflammation is at the basis of the pathophysiology of restenosis of biological causes that eventually results in early aggressive neointimal proliferation or late neoatherosclerosis.17

Consistent with other studies that reported high incidence rates of new target lesion revascularization: 24.8%,18 19.1%,19 and 10%,16 this study incidence rate with first-generation conventional and drug-eluting stents is 16.8% in a sample with a high rate of diabetes mellitus, bifurcation lesions, and patients with acute coronary syndrome.

In this study, the rate of cardiovascular mortality is 8.9% (9 patients dead: 3 myocardial infarctions, 2 strokes, 2 stent thrombosis, and 1 malignant ventricular arrhythmia.1) The author believes that this is a high rate for a median follow-up of 11.5 months that could be associated with the clinical and anatomical complexity of the cases involved (acute coronary syndrome, 56.4%; multivessel disease, 53.5%; bifurcation lesions, 50,5%) compared to 30.7% of multivessel PCIs performed. A total of 70% of the patients with MACE (30 cases) had multivessel disease, 56,7% had true bifurcation lesions, and median SYNTAX scores of 25 compared to 46.6% of multivessel PCIs performed, an association that produces a high residual SYNXTAX score, which is an independent predictor of mortality.20

The number of neutrophils, lymphocytes, and NLR before the procedure showed no correlation with adverse events, a result that is not consistent with the study published by Verdoia M. et al.21 where a NLR > 3 is a predictor of a common in-hospital complication after the PCI: type 4a myocardial infarction.

The NLR keeps a positive and significant correlation with ultrasensitive cardiac troponin, the creatine kinase-MB fraction, and the C-reactive protein, which is indicative of how suitable this NLR is to assess the intensity of myocardial damage. 22

This study confirms the significant correlation that exists between the absolute value of neutrophils and the NLR measured 6 hours of the PCI and the presence of MACE, which is consistent with what other studies have already reported on this regard. After the primary PCI, a NLR > 3.31 increases the risk of adverse events and deaths during the in-hospital stay (12.7% vs 2.8%, P = .010), and (12.7% vs 1.9%, P = .003), respectively.13 A higher postoperative NLR is associated with the presence of type a4 myocardial infarction, more immediate complications,23,14 with all the causes of in-hospital deaths (OR, 2.04, P = .013) and at the 6-month follow-up (OR, 3.88, P < .001),24 with the presence of clinical restenosis (OR, 1.85, P < .001),25 and with the prediction of early stent thrombosis (0.712; 95%CI, 0.610-0.988; P = .012).4

The multivariate analysis found that the NLR measured 6 hours after the PCI became an independent predictor of the risk of major adverse events at the follow-up, which increases the chances of MACE by 2.254 times, which by the way is consistent with a previous report of an OR = 2.45 of a NLR > 3 for the prediction of fatal coronary events.26

Conclusions:

In patients treated with percutaneous coronary intervention, the neutrophil-to-lymphocyte ratio measured 6 hours after the PCI is an independent predictor of major adverse cardiovascular events at the follow-up with a potential value in risk stratification.

Key points:

What is known about the topic?

• Inflammation plays a significant role in acute ischemia by rising the levels of neutrophils and reducing the number of lymphocytes in the bloodstream.

• The NLR is an inflammatory marker. When high it is associated with a greater load, severity, and spread of the coronary artery disease, and with worse prognoses for the patients.

• The NLR is a predictor of myocardial damage in patients with acute coronary events treated with percutaneous coronary intervention.

What does this study add?

• A cost-effective and fully available new marker for risk stratification in these patients.

• A higher NLR after a PCI has become an independent predictor of adverse events at the follow-up.

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