Association Between Systemic ImmuneInflammation Index and Long-Term Mortality in Patients with Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy Below the Knee

Yalçın Avcı1, Mustafa Duran2, Ali Rıza Demir1, Gökhan Demirci1, Ömer Taşbulak1, Arda Güler1, Ahmet Arif Yalçın1, Sezgin Atmaca1, Mehmet Ertürk1

1Clinic of Cardiology, Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Türkiye
2Clinic of Cardiology, Konya City Hospital, Konya, Türkiye

Keywords: Endovascular procedures; inflammation; peripheral arterial disease

Abstract

Introduction: Endovascular interventions have been increasingly used for the treatment of patients suffering from below-the-knee (BTK) ischemic lesions. Yet, there is a paucity of data regarding long-term adverse events in patients with critical limb ischemia (CLI) undergoing endovascular revascularization for BTK lesions. Recently introduced systemic immune-inflammation index (SII) is a reliable indicator of poor outcomes in various cardiovascular conditions. Herein, we aimed to investigate the prognostic role of the SII on mortality in patients with CLI undergoing endovascular revascularization for BTK lesions.

Patients and Methods: The records of 112 patients with symptomatic CLI undergoing endovascular revascularization for BTK lesions between January 2015 and December 2019 were analyzed. Patients were divided into groups with low and high SII values based on an SII cut-off value derived from a ROC analysis. For each group, procedural details and follow-up outcomes were analyzed.

Results: The mean follow-up time was 40.3 ± 19.9 months. According to our data, patients with high SII values had higher rates of mortality compared to patients with low SII values (65.2% vs 30.3%, p< 0.001). To determine the SII cut-off value for predicting mortality, the ROC curve was drawn, and the best cut-off value was determined as 966 by using the Youden index, (AUC= 0.658, 95% CI= 0.556-0.760, p= 0.004). Cox multivariate regression analysis also identified the SII score as an independent predictor of mortality.

Conclusion: SII is an independent predictor of mortality, especially among patients with CLI who underwent endovascular revascularization for BTK lesions.

Introduction

Critical limb ischemia (CLI) is a coronary artery disease risk equivalent and strongly associated with an increased risk of cardiovascular morbidity and mortality(1,2). Although bypass surgery is still the gold standard for below-the-knee (BTK) cases, most patients with significant BTK lesions are deemed ineligible for surgical revascularization due to extensive comorbidities and frailty(3). Therefore, endovascular revascularization has emerged as an alternative treatment option for patients at high or prohibitive surgical risk(4). However, there is a paucity of data regarding long-term adverse events in patients with CLI undergoing endovascular revascularization for BTK lesions(5).

Recently, a novel inflammatory marker has been defined for the evaluation of patients’ inflammatory and immune status: the systemic immune-inflammation index (SII), defined as platelet count x neutrophil/lymphocyte ratio(6). This index was an independent predictor of adverse events in cancer patients and associated with adverse events in several types of cardiovascular conditions(7-10). However, the predictive ability of SII for mortality has not been reported in patients with CLI undergoing endovascular revascularization for BTK lesions. The current study aimed to investigate the prognostic role of the SII on mortality in patients with CLI undergoing endovascular revascularization.

Materials and Methods

Study Population

We screened 142 consecutive patients who underwent below-the-knee endovascular treatment for critical limb ischemia between January 2015 and December 2019. The study population’s demographic and clinical risk factors and the indication for the endovascular procedures were retrospectively analyzed. Exclusion criteria were the presence of active infection, malignancy, chronic inflammatory disease, hepatic failure, and planned major amputation before the endovascular intervention. Patients in whom technical success was not achieved were also excluded from the study. After applying the exclusion criteria, 112 patients were enrolled. Informed consent was obtained from all patients following the ethical guidelines of the 1975 Declaration of Helsinki protocol and the study was approved by a research ethics committee.

Data Collection

The demographics, comorbidities, medications, laboratory parameters, and lesion characteristics were collected from patient records and the hospital database. A comprehensive metabolic panel was conducted to measure complete blood cell counts, liver and kidney functions, and serum lipid levels. Blood samples were collected from the antecubital vein after a 12-h fast before undergoing the endovascular procedure. Complete blood count parameters, including platelets, neutrophils, and lymphocytes were evaluated with an automated analyzer. An automatic hematology analyzer (Sysmex, XT-2000i) was used for whole blood counts. The SII was calculated with the formula, SII= Total peripheral platelets count x neutrophil/lymphocyte ratio(6). Based on the ROC analysis, patients were divided into groups with low (SII< 966) and high (SII> 966) SII values.

Endovascular Procedure

Before the endovascular intervention, a multidisciplinary vascular team assessed the patient’s eligibility for endovascular revascularization, considering the patient’s functional status, comorbid conditions, and technical feasibility. All procedures were performed under systemic heparinization to maintain an activated clotting time of approximately 300 s. Antegrade access with the use of 6F sheaths is the preferred access site for the majority of the patients. In case of access failure, a retrograde approach was used. The equipment, intervention approach, and procedural technique were left at the operator’s discretion. Technical success was described as restoring direct flow in the target vessel and residual stenosis of <30%. After the intervention, the vascular access site closure was achieved via ProGlide (Abbott, USA) vascular closure device or, if necessary, via manual compression. All patients were treated with 81 or 100 mg of acetylsalicylic acid and clopidogrel (75 mg). Acetylsalicylic acid therapy was continued indefinitely, and clopidogrel was continued for six months. Other medications, including antihypertensive, cilostazol, and lipid-lowering drugs, were prescribed according to evidence-based guidelines.

After the index procedure, patients were followed in accordance with a prespecified protocol. During the scheduled follow-up visits routine physical examination, ankle-brachial index (ABI) measurement, and serial duplex ultrasound imaging were performed. The need for reintervention, development of adverse clinical events, and health status were also evaluated. Patients had follow-up visits at one, six, and 12 months and every year after that.

The primary endpoint of the study was long-term mortality, which is a composite of cardiovascular and non-cardiovascular deaths occurring after the index procedure. The secondary endpoint of the study was major amputation, which is defined as the amputation above the ankle. Primary and secondary endpoints of the study population were reviewed and confirmed by a multidisciplinary vascular team blinded to patients’ clinical and laboratory data.

Statistical Analysis

The data analysis was performed using SPSS Statistics for Windows, version 16.0 (IBM Corp., Armonk, USA). In this study, data are expressed as mean ± standard deviation (SD) for normal distribution and as median (25th-75th percentiles) for abnormal distribution. The Kolmogorov-Smirnov and Shapiro-Wilk test was utilized to check continuously distributed variables. The Chi-square and Fisher’s exact test were utilized to evaluate qualitative variables. The Student’s t-test was utilized for normally distributed variables and the variables were shown as mean ± SD. The Mann-Whitney U test was utilized to compare continuously non-normally distributed variables. In all analyses, p< 0.05 was considered statistically significant. The receiver-operating characteristic (ROC) curve analysis was utilized to assess the optimal cut-off point of SII to predict mortality following the endovascular intervention. The impact of several variables on mortality was assessed by univariate regression analysis. In these analyses, any variable with unadjusted p< 0.05 was identified as a confounding factor and was included in multivariate regression analyses to identify the independent predictor of mortality. Cumulative survival rates were also illustrated using the Kaplan-Meier method.

Results

Among the 112 patients with CLI who underwent endovascular revascularization for BTK lesions, 76.8% were male with a mean age of 64.4 ± 11.0 years. High SII values were detected in 46 patients, and 66 had low SII values. Baseline demographic characteristics, detailed medical history, and laboratory findings of the study population are summarized in Table 1. Both groups had similar demographic and clinical characteristics (p> 0.05). All patients underwent endovascular revascularization with plain balloon angioplasty. Of the whole cohort, the anterior tibial artery was found to be the most intervened artery (54.5%), followed by the posterior tibial artery (40.2%) and the popliteal artery (27.7%). Twenty-five patients (22.3%) also underwent concomitant above-the-knee interventions during the index procedure.

Patients with high SII values had significantly lower levels of serum hemoglobin (11.0 ± 2.2 g/dL vs 12.9 ± 2.1 g/dL), lymphocyte count (1.60 ± 0.61 109 /L vs 2.46 ± 0.82 109 /L), and estimated glomerular filtration rate (eGFR), [72 (28-92) mL/ min/ 1.73 m2 vs 89 (62-96) mL/min/1.73 m2 )] than patients with low SII values, (p< 0.05 respectively). On the other hand, serum C-reactive protein (CRP) level [37 (10-92) mg/L vs 12 (6-29) mg/L], white blood cell counts (WBC), [10.6 (9.1-12.8) 106 /L vs 9.1 (7.5-10.2) 106 /L], neutrophil counts (8.69 ± 3.24 109 /L vs 5.47 ± 1.58 109 /L), and platelet counts (354 ± 120 103 /mm3 vs 259 ± 78 103 /mm3 ) were significantly higher in patients with high SII values compared to patients with low SII values (p< 0.05 respectively). In terms of medications, both groups had similar properties (p> 0.05).

Table 1. Comparison of demographic and clinical characteristics of patients according to SII level

Table 1. Comparison of demographic and clinical characteristics of patients according to SII level (continued)

Of the whole cohort, the mean follow-up time was 40.3 ± 19.9 months. A total of 50 (44.6%) patients died during long-term follow-up. According to our data, patients with high SII values had higher mortality rates than those with low SII values (65.2% vs. 30.3%, p< 0.001). With respect to the secondary endpoint of the study, both groups had similar rates of major amputation (23.9% vs. 18.2%, p> 0.05) (Figure 1).

Figure 1. Comparison of endpoints according to SII level. SII: Systemic immune-inflammation index.

To identify the prognostic mortality indicators, several variables, including age, history of chronic kidney disease (CKD), smoking history, serum hemoglobin, CRP levels, the use of statins, and SII values were included in the univariate Cox regression analysis. After excluding variables that showed no impact on mortality in the univariate analysis, Cox multivariate regression analysis was performed, which identified CKD, the use of statins, and the SII score as independent predictors of mortality (Table 2). According to our data, SII was the best predictor of mortality among the aforementioned parameters (p< 0.001). The ROC curve was drawn to determine the SII cut-off value for predicting mortality and the best cut-off value was determined as 966 by using the Youden index (AUC= 0.658, 95% CI= 0.556-0.760, p= 0.004), (Figure 2). Above this cut-off value, CSF could be detected with a sensitivity of 60.0% and a specificity of 74.2%. The Kaplan-Meier curve demonstrating the follow-up survival in both groups was also illustrated (Figure 3).

Table 2. Univariable and multivariable Cox regression analysis to detect independent risk factors that may affect the mortality

Figure 2. ROC curve analysis of SII value for predicting total mortality. SII: Systemic immune-inflammation index, PPV: Positive predictive value, NPV: Negative predictive value, AUC: Area under the curve, CI: Confidence interval.

Figure 3. Kaplan-Meier curves for total mortality. SII: Systemic immune-inflammation index.

Discussion

In this study, we evaluated the prognostic role of the SII on mortality in patients with CLI undergoing endovascular revascularization for BTK lesions and we found that the SII score was a strong predictor of mortality. To the best of our knowledge, this is the first study evaluating the relationship between SII and mortality in patients with CLI undergoing endovascular revascularization.

Since the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) updated guidelines, endovascular interventions have been increasingly used to treat patients suffering from BTK ischemic lesions(11). Although multiple trials have demonstrated the safety and effectiveness of these endovascular approaches in treating BTK ischemic lesions, it is challenging to determine the optimal strategy to manage these lesions(12). According to currently available data, plain balloon angioplasty is the gold standard endovascular approach in the treatment of BTK ischemic lesions, accompanied by bare-metal stents as a bailout option(13,14). On the other hand, drug-coated balloons (DCB) and drugeluting stents (DES) have shown improved outcomes in the treatment of BTK ischemic lesions(15-18). However, not only is the evidence on the effectiveness and safety of DCB and DES in long diffuse BTK lesions very scarce, but these novel local drug delivery technologies also have higher procedural costs(17,18). Besides, the data regarding the impact of each endovascular treatment modality on procedural outcomes and long-term mortality are sparse. Previous reports revealed that age, body mass index, heart failure, bedridden state, renal failure, lesion severity, previous peripheral revascularization, and technical success were significant predictors of mortality following endovascular revascularization for BTK ischemic lesions(5,19,20).

In our study, significant predictors of mortality following endovascular revascularization were CKD, the use of statins, and higher SII scores. Among these parameters, a higher SII score was the strongest independent predictor of death (p< 0.001). Previous reports revealed a strong association between hematological indices, including neutrophils, platelets, lymphocytes, and atherosclerotic burden. They also revealed the negative impacts of these hematological indices on several cardiovascular conditions(21,22). Additionally, they combined these hematological indices, such as the neutrophilto-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), and used them as novel risk scores for predicting adverse events in patients with a history of cardiovascular diseases(23,24). Apart from these biomarkers, a novel SII index has been introduced to clinical practice. This index is a simple and effective biomarker that combines these hematological indices and has a better predictive ability in determining the patient’s inflammatory status. Findings from previous reports proved the prognostic value of SII for major adverse clinical events and mortality in various cardiac conditions such as chronic heart failure, coronary artery disease, and severe aortic stenosis(25,26). In our study, patients with higher SII scores had higher neutrophil and lower lymphocyte values, which reflect more severe inflammation. In the immune-inflammatory response setting, higher neutrophil counts provoke plaque disruption, direct endothelial cell damage, and microvascular plugging, whereas lower lymphocyte counts lead to adverse physiological stress with a hypercoagulable state. Therefore, patients with higher NLR and PLR were more prone to severe atherosclerosis and major adverse events(27-29).

The immune-inflammatory process is also involved in the pathophysiology of peripheral artery disease severity. According to previous reports, there is an increased risk of progression to CLI in patients with peripheral artery disease having higher NLR or PLR values(30,31). In addition, these hematological indices are associated with poor response to medical treatment, amputation requirement, cardiovascular complications, and worse survival(32-35). Likewise, a higher SII score has been shown as an independent risk factor for peripheral artery disease severity and associated complications(36). Considering the complex interaction between peripheral artery disease severity and inflammation, our results confirmed the outcomes of previous reports. In addition, the higher mortality rates in patients with higher SII scores compared with lower SII scores confirmed the proven role of these indices not only in the severity of inflammation but also in predicting future adverse events.

Study Limitations

There are several limitations of our study. First, this study has a limited number of patients and was conducted at a single center. Second, although there have been several studies investigating the prognostic ability of SII in terms of predicting major adverse cardiovascular events (MACE) in various conditions, we did not follow our patients regarding those parameters. Third, in our study, we included only the patients in whom technical success was achieved which might lead to an underestimation of long-term mortality following the procedure. Fourth, due to common practice, in our study, all patients underwent endovascular revascularization by using plain balloon angioplasty, accompanied by bare-metal stents as a bailout option. Therefore, the results of our study cannot be extrapolated to patients undergoing endovascular revascularization by using DCB or DES.

Conclusion

SII is an independent predictor of mortality, especially among patients with CLI who underwent endovascular revascularization for BTK lesions. Considering the strong association between peripheral artery disease severity and systemic inflammation this simple and easily calculable index can be utilized in daily practice.

Cite this article as: Avcı Y, Duran M, Demir AR, Demirci G, Taşbulak Ö, Güler A, et al. Association between systemic immune-inflammation index and long-term mortality in patients with critical limb-threatening ischemia undergoing endovascular therapy below the knee. Koşuyolu Heart J 2022;25(3):262-269.

Ethics Committee Approval

The approval for this study was obtained from İstanbul Mehmet Akif Ersoy Thoraric and Cardiovascular Surgery Training and Research Hospital Clinical Research Ethics Committee (Decision no: 2022.06.40, Date: 02.08.2022).

Peer Review

Externally peer-reviewed.

Author Contributions

Concept/Design - YA, MD; Analysis/Interpretation - YA, ÖT; Data Collection - YA, SA, GD; Writing - YA, AG; Critical Revision - AY, ME; Final Approval - ME; Statistical Analysis - AD; Overall Responsibility - YA.

Conflict of Interest

The authors have no conflicts of interest to declare.

Financial Disclosure

The authors declare that this study has received no financial support.

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Figure and Tables

Figure 1. Comparison of endpoints according to SII level. SII: Systemic immune-inflammation index.
Figure 2. ROC curve analysis of SII value for predicting total mortality. SII: Systemic immune-inflammation index, PPV: Positive predictive value, NPV: Negative predictive value, AUC: Area under the curve, CI: Confidence interval.
Figure 3. Kaplan-Meier curves for total mortality. SII: Systemic immune-inflammation index.
Table 1. Comparison of demographic and clinical characteristics of patients according to SII level
Table 1. Comparison of demographic and clinical characteristics of patients according to SII level (continued)
Table 2. Univariable and multivariable Cox regression analysis to detect independent risk factors that may affect the mortality