Development and validation of a nomogram for ISR within 2 years in patients after iliac or femoral artery stent placement

doi:10.21203/rs.3.rs-3139314/v1

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Development and validation of a nomogram for ISR within 2 years in patients after iliac or femoral artery stent placement

https://doi.org/10.21203/rs.3.rs-3139314/v1

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This study aimed to analyze the risk factors for ISR within 2 years after iliac or femoral artery stent placement.Clinical data of 237 patients diagnosed with LEASO and receiving iliac or femoral artery stent placement for the first time in the Third Hospital of Hebei Medical University from January 2015 to December 2022 were analyzed.Patients were randomized into training and validation set (7:3).Logistic regression was used to perform univariate and multivariate analysis on the possible factors of ISR, screen out independent risk factors, establish a risk nomogram prediction model ,and internally verify the predictability and accuracy of the model.Binary logistic regression analysis showed that diabetes, hyperlipidemia, hyperfibrinogenemia and below-the-knee run-offs were independent risk factors for ISR within 2 years after iliac or femoral artery stent placement in patients with LEASO.Based on these factors, the risk prediction model is established. The c index of the model was 0.856. The results showed that the risk prediction model has good accuracy in predicting ISR within 2 years after iliac or femoral artery stent placement.The risk prediction model based on the 4 risk factors of diabetes, hyperlipidemia, hyperfibrinogenemia and below-the-knee run-offs has good predictive performance.

Lower extremity arteriosclerosis obliterans(LEASO) is a disease caused by the formation of atherosclerotic plaques in arteries of lower extremities, resulting in arterial stenosis or even occlusion, eventually leading to chronic limb ischemia. With the development of society, the improvement of living standards and the trend of aging, the incidence of ASO is increasing year by year.A study has shown that the prevalence of ASO in the population aged 60–90 years in Sweden is 18% [1].In China, the prevalence is 15.91% [ 2,3 ].

The European Society of Cardiology guidelines recommend [3] that stent implantation is an important treatment for iliac or femoral artery lesions [1], but the occurrence of in-stent restenosis (ISR) seriously affects the long-term efficacy of endovascular treatment.Hence, tools for the identification of individual patients at higher risk for ISR with stent implantation are especially needed.Although previous studies have shown that the high incidence of ISR is related to vascular inflammation, neointimal hyperplasia and thrombosis,there are still some limitations in clinical application.At present, we urgently need a solid, well-validated and easy-to-use clinical ISR prediction model to accurately predict the occurrence of ISR, early intervene, and reduce the occurrence of ISR.

Featured by the advantage of visualization, nomogram can assess straightforward the probability of disease for individual patients without complex formula. Because of its convenience and operability, it has become an important tool for clinicians to make clinical decisions.

Based on these premises, this study retrospectively analyzed the clinical data of patients diagnosed with LEASO and receiving iliac or femoral artery stent placement for the first time in the Third Hospital of Hebei Medical University, and explored the risk factors of ISR within 2 years after iliac or femoral artery stent placement. These risk factors were used to develop and validate a nomogram prediction model to help clinicians identify high-risk ISR patients, optimize treatment strategy, and improve patients prognosis.

Patient characteristics

In this study, a total of 237 patients with LEASO who underwent iliac or femoral artery stent placement were included in the study. 166 patients were randomly assigned to the training set and 71 patients were randomly assigned to the validation set.Table 1 lists 15 variables, including the following aspects: clinical characteristics, laboratory test and Imaging characteristics.Of these, 61 patients (44 in the training set and 17 in the validation set) developed ISR. Comparisons between the training and validation set showed no significant differences in all ISR risk-related factors (all P > 0.05).

Table 1

Baseline characteristics of the training set and validation set
Factors	Training set(n = 166)	Validation set(n = 71)	P
Age(year)	67.21 ± 9.61	67.68 ± 10.21	0.74
Gender, n(%)			0.16
male	133 (80.1%)	63 (88.7%)
female	33 (19.9%)	8 (11.3%)
smoke, n(%)			0.74
yes	88 (53%)	40 (56.3%)
no	78 (47%)	31 (43.7%)
hypertension, n(%)			0.90
Yes	113 (68.1%)	47 (66.2%)
no	53 (31.9%)	24 (33.8%)
diabetes, n(%)			0.99
Yes	65 (39.2%)	27 (38%)
no	101 (60.8%)	44 (62%)
hyperlipidemia, n(%)			0.78
Yes	68 (41%)	27 (38%)
no	98 (59%)	44 (62%)
Albumin,g/L	38.52 ± 4.55	38.31 ± 4.56	0.89
Globulin,g/L	24.96 ± 5.15	24.83 ± 4.22	0.95
AGR	1.61 ± 0.39	1.61 ± 0.35	1.00
NLR	4.51 ± 2.19	4.51 ± 2.54	0.58
PLR	189.39 ± 101.38	181.84 ± 84.79	0.88
Creatinine			0.27
>81µmol/L	30 (18.1%)	8 (11.3%)
<81µmol/L	136 (81.9%)	63 (88.7%)
Hyperfibrinogenemia			0.32
Yes	64 (38.6%)	33 (46.5%)
no	102 (61.4%)	38 (53.5%)
Below-the-knee run-offs			1.00
3	110 (66.3%)	47 (66.2%)
< 3	56 (33.7%)	24 (33.8%)
Location of stents			0.64
Femoral artery	82 (49.4%)	32 (45.1%)
Iliac artery	84 (50.6%)	39 (54.9%)

Clinical indicator analysis

The results of univariate logistic regression analysis of the training set (Table 2) show that:the related factors (P < 0.1) of ISR within 2 years in patients after iliac or femoral artery stent placement were diabetes、hyperlipidemia、albumin、globulin、AGR、NLR、creatinine > 81µmol/L、hyperfibrinogenemia、below-the-knee run-offs、location of stents.Multivariate logistic regression analysis showed that the independent risk factors (P < 0.05) were diabetes、hyperlipidemia、hyperfibrinogenemia、below-the-knee run-offs, as shown in Table 3.

Table 2

Univariate logistic regression analysis of risk factors of ISR within 2 years in patients after iliac or femoral artery stent placement in training set.
Factors	ISR group(n = 44)	Non-ISR group(n = 122)	Wald value	OR value (95% CI)	P
Age(year)	66.05 ± 10.30	67.63 ± 9.36	0.88	0.98(0.95,1.01)	0.35
Gender			2.02	0.55(0.25,1.25)	0.16
female	12(27.27%)	21(17.12%)
male	32(72.73%)	101(82.88%)
Smoke			0.056	1.09(0.55,2.17)	0.81
yes	24(54.54%)	64(52.46%)
no	20(45.46%)	58(47.54%)
hypertension			0.60	1.35(0.63,2.89)	0.44
yes	32(72.73%)	81(66.39%)
no	12(27.27%)	41(33.61%)
Diabetes			11.76	3.51(1.71,7.20)	0.001
yes	27(61.36%)	38(31.15%)
no	17(38.64%)	84(68.85%)
hyperlipidemia	24/20	44/78	4.48	2.13(1.06.4.28)	0.034
yes	24(54.55%)	44(36.07%)
no	20(45.45%)	78(63.93%)
Albumin	36.97 ± 5.03	39.07 ± 4.25	6.62	0.90(0.84,0.98)	0.01
Globulin	26.64 ± 5.51	24.35 ± 4.90	6.15	1.09(1.02,1.17)	0.013
AGR	1.46 ± 0.40	1.66 ± 0.37	8.40	0.23(0.083,0.62)	0.004
NLR	5.41 ± 2.73	4.19 ± 1.87	8.93	1.27(1.09,1.49)	0.003
PLR	201.03 ± 106.97	185.19 ± 99.41	0.78	1.00(0.99,1.01)	0.38
Creatinine > 81µmol/L			5.10	2.59(1.13,5.91)	0.024
yes	13(29.55%)	17(13.93%)
no	31(70.45%)	105(86.07%)
Hyperfibrinogenemia			12.44	3.65(1.78,7.49)	0.00
yes	27(61.36%)	37(30.33%)
no	17(38.64%)	85(69.67%)
Below-the-knee run-offs			34.25	0.092(0.041,0.20)	0.00
3	12(27.27%)	98(80.33%)
< 3	32(72.73%)	24(19.67%)
Location of stents			14.43	4.47(2.06,9.68)	0.00
Femoral	33(75%)	49(40.16%)
Iliac	11(25%)	73(59.84%)

Table 3

Multivariate logistic regression analysis of risk factors of ISR within 2 years in patients after iliac or femoral artery stent placement in training set.
Factor	B	SE	Wald-χ	P	OR (95% CI)
Diabetes	0.947	0.447	4.499	0.034	2.579(1.075,6.189)
Hyperlipidemia	1.153	.461	6.266	0.012	3.168(1.284,7.812)
Hyperfibrinogenemia	1.235	.455	7.381	0.007	3.440(1.411,8.388)
Below-the-knee run-offs	−2.499	.463	29.190	0.00	0.082(0.033,0.203)

Drawing and validation of a nomogram

Based on univariate and multivariate logistic regression analysis, we obtained four independent risk factors and established a nomogram prediction risk model for ISR after iliac or femoral artery stent placement ( Fig. 1 ).The model was internally validated by the parallel Bootstrap method (after repeated sampling of the included data 1,000 times), and the calibration curve was close to the ideal curve (Fig. 2),indicating that the predicted ISR of the nomogram is highly consistent with the actual ISR.The ROC curves of the training set and the validation set drawn by the nomogram ( Fig. 3) showed that the AUC of the training set was 0.856 ( 95% CI : 0.787–0.926 ), and the AUC of the validation set was 0.837 ( 95% CI : 0.729–0.945 ), indicating that the prediction risk model of the nomogram has a reasonable degree of discrimination and accuracy for the high-risk population of thrombus detachment.The clinical decision curve ( Fig. 4 )shows that using the nomogram to predict ISR can achieve greater benefits if threshold probability is < 87%.Therefore, the nomogram could be used to predict the risk of ISR within 2 years after femoral artery or iliac artery stent implantation which has a high accuracy and a wider range of threshold probabilities, and it might have potentially great significance in clinical application.

Stent implantation is an effective therapy for LEASO. However, ISR seriously affects the long-term efficacy of endovascular treatment. According to the current research, the causes of ISR can be summarized as follows : 1 ) stent underexpansion [ 4 ]; 2 ) stent fracture; 3)vascular intimal hyperplasia;4)in-stent neoatherosclerosis;5) in-stent thrombosis [ 5 ].Under the condition of successful stent implantation, this study mainly discusses the last three factors.

In this study, diabetes, hyperfibrinogenemia, hyperlipidemia, and below-the-knee run-offs were found to independently predict ISR within 2 years in patients with LEASO who receiving iliac or femoral artery stent placement.Based on these independent risk factors, we established a risk nomogram prediction model that provides a solid, well-validated and easy-to-use tool for clinicians to conduct individualized assessment of patients at high risk of ISR.In addition, prospectively informing patients after stent implantation to control risk factors is of great significance for reducing the rate of ISR.

Diabetes is an important risk factor for coronary artery disease, stroke and LEASO [6].The risk for LEASO is as much as three to four times higher in diabetic patients, and this risk increases by 26% with every 1% increase in the HbA1c level[7].Similarly, diabetes is a factors for ISR.Endothelial dysfunction is one of the causes of LEASO and ISR.Stent implantation can cause vascular endothelial injury, and in the environment of hyperglycemia, monocyte chemoattractant protein-1 ( MCP1 ) and vascular cell adhesion molecule-1 ( VCAM1 ) expression increased, enhance the interaction between monocytes and endothelial cells, and further promote endothelial dysfunction [8].Endothelial dysfunction leads to reduced secretion of cytokines that inhibit the proliferation and migration of smooth muscle cells.Excessive proliferation and migration of smooth muscle cells is another important reason for ISR.In addition, endothelial dysfunction further promotes thrombosis, leading to the occurrence of ISR [9].Diabetes also promotes platelet activation.As one of the markers of platelet activation, platelet-derived microparticle ( PDMP ) plays an important role in coagulation.

Diabetes patients typically display hypercoagulability and platelet hyperaggregability with increased levels of PDMP which suggests that patients with diabetes are more likely to develop ISR[10].In an expert consensus about the prevention of cardiovascular diseases in people with diabetes, it is pointed out that exercise, including aerobic exercise, resistance exercise, and their combination, can not only control blood glucose, but also control the occurrence of cardiovascular disease [6].In other words, controlling blood glucose can reduce the risk of ISR.

Fibrinogen is a new biomarker of oxidative stress and inflammation in recent years[11].Hyperfibrinogenemia is an independent risk factor for cardiovascular and cerebrovascular diseases and ISR after coronary stent implantation [12, 13].Fibrinogen is mainly expressed in hepatocytes, and its synthesis is regulated by inflammatory factors, such as IL-6 derived by monocytes, macrophages and vascular endothelial cells [14, 15].In our study, fibrinogen > 4g / L is defined as hyperfibrinogenemia.Hyperfibrinogenemia suggests that the patient is in a hypercoagulable state and the risk of thrombosis is increased, which is one of the causes of in-stent restenosis.In addition, fibrinogen is an important inflammatory marker that plays an important role in platelet aggregation[16].After stent implantation, mechanical vascular injury occurred,which causing the aggregation of inflammatory cells and the production of cytokines.Fibrinogen also promotes endothelin-1(ET-1) secretion by endothelial cells and ET-1 can effectively constricts blood vessels [17].In addition, fibrinogen and its degradation products can stimulate the proliferation and migration of smooth muscle cells [18].These evidences indicate that hyperfibrinogenemia is one of the risk factors for ISR.

A meta-analysis showed that the risk of LEASO was higher in patients with familial hypercholesterolemia[19].Excessive cholesterol in the vascular promotes endothelial dysfunction and activates inflammatory cells,which leads to increased production of inflammatory cytokines and reactive oxygen species, increased expression of adhesion molecules,which is an important step in the development of LEASO[20].Hyperlipidemia plays an equally important role in ISR [ 21].In our study, hyperlipidemia was defined as TG > 1.70mmol / L or TC > 5.72mmol / L or both.Anatomical and intravascular imaging studies have recognized that neoatherosclerosis plays an important role in the occurrence of ISR.Neoatherosclerosis is defined as foamy macrophage infiltration into the peri-strut or neointimal area after stent implantation, potentially leading to ISR,and hyperlipidemia accelerates this process[22, 23].In addition to hyperlipidemia, the below-the-knee run-offs is an independent risk factor affecting the patency of stents[24], which was also verified in our study .Initiative management of below-the-knee run-offs may reduce the incidence of ISR.

To summarize,diabetes, hyperlipidemia, hyperfibrinogenemia and below-the-knee run-offs are independent risk factors for ISR within 2 years after iliac or femoral artery stent placement in patients with LEASO, and the nomogram risk prediction model established has good prediction performance and high clinical value.

Study population

This study is a retrospective case-control study.According to the inclusion criteria, we collected 237 clinical data of ASO patients who have received iliac or femoral artery stent placement for the first time in the Third Hospital of Hebei Medical University from January 2015 to December 2022.According to local regulations, the protocol was approved by the Ethics Committee of the Third Hospital of Hebei Medical University.We confirmed that all methods were performed in accordance with the relevant guidelines and regulations.Since this is a retrospective study using existing research data, we gave up written informed consent and obtained the approval of the Ethics Committee of the Third Hospital of Hebei Medical University.Inclusion criteria:(1)Patients met the diagnostic criteria of LEASO;(2)CTA or DSA confirmed the presence of iliac artery or femoral artery lesions ;(3)Patient received iliac or femoral artery stent placement for the first time;(4)Postoperative DSA confirmed that the stenosis of iliac or femoral artery was less than 30%.Excluded criteria:(1)Patients did not meet the diagnostic criteria of LEASO;(2)Patients who have received iliac or femoral artery stent placement in the past.(3)Patients were treated with drug-coated balloon and drug-eluting stent;(4)Patients who underwent arterial thrombectomy or catheter thrombolysis or endarterectomy;(5) Patient's clinical data were incomplete.The sample size was estimated using the event per variable (EVP) method, and since the recommended empirical guideline in logistic regression is a sample size of 10–15 times the number of covariates, this study used EPV = 10, involving 15 covariates, so ≥ 150 patients were required [25].Finally, 237 patients were included. The standard of ISR within 2 years was defined as the stenosis of iliac or femoral artery confirmed by DSA examination was greater than 50%[26]. Of the 237 patients, 61 patients developed ISR, and the restenosis rate was 25.74%.

Risk factors

Based on clinical plausibility and previous studies,A total of 15 candidate factors were identified for further processing,including clinical characteristics (age, sex, hypertension, diabetes, hyperlipidemia, smoking,hyperfibrinogenemia),laboratory test(albumin, globulin, AGR, NLR, PLR, creatinine)and imaging characteristics(ocation of stents, below-the-knee run-offs).AGR is defined as the ratio of albumin and globulin,NLR is defined as the ratio of absolute counts of neutrophils and lymphocytes within 3 days after surgery,PLR is defined as the ratio of absolute counts of platelet and lymphocytes within 3 days after surgery.

Statistical analysis

All the data in this study were analyzed by R software (4.2.0).The data were randomly divided into a training set and validation set at a sample size of 7:3.The binary variables were compared by chi-square test or fisher exact test, and the continuous variables were compared by t test or ranked sum test.Univariate and multivariate logistic regression analysis was used to analyze the risk factors of ISR within 2 years after iliac or femoral artery stent placement in the training set.The independent variable P < 0.1 in univariate analysis was included in multivariate regression analysis. The logistic regression model with the least amount of information in the Akaike information criterion ( AIC ) was selected as the final prediction model, and the R software is used to visualize the output through the nomogram.The receiver operating character (ROC) curve was plotted to assess discrimination and calibration of the model by the area under curve (AUC).The calibration curve was plotted to compare actual risk with predicted risk; the decision curve analysis (DCA) was plotted to evaluate the clinical application value of the nomogram by calculating the net benefit under different threshold probabilities.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Author Contributions

J.L. and R.A.wrote the main manuscript. X.L. Y.L. P.C. andQ.H. prepared all figures and tables. F.W. Y.W. Y.D. andZ.J. performed the statistical analysis. L.L.andY.Z. revised the manuscript. All authors read and approved the final manuscript.

J.L. and R.A. have contributed equally to this work and share first authorship

Competing interests

The authors declare no competing interests

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No competing interests reported.

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Development and validation of a nomogram for ISR within 2 years in patients after iliac or femoral artery stent placement

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Abstract

Figures

Introduction

Results

Patient characteristics

Clinical indicator analysis

Drawing and validation of a nomogram

Discussion

Methods

Study population

Risk factors

Statistical analysis

Declarations

References

Additional Declarations

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