Minimal vessel area predicts in-stent restenosis in nonthrombotic iliac vein compression syndrome after stenting

To the Editor: Iliac vein compression syndrome (IVCS) is a well-documented anatomic abnormality characterized by the compression of iliac veins from the adjacent artery and vertebra. Depending on whether deep vein thrombosis was co-existing, IVCS could be classified into thrombotic and nonthrombotic lesions. Endovascular procedures have become the mainstream treatment for nonthrombotic IVCS.^[1] In most cases, balloon dilation is insufficient to treat nonthrombotic IVCS because the venous wall is easily recoiled. Stenting for iliac vein lesion is therefore necessary for keeping enlargement of the venous lumen. However, stent implantation may bring side effects such as in-stent thrombosis and restenosis. In-stent restenosis (ISR) caused by intimal hyperplasia remains a major drawback of stenting in arterial diseases. However, the evidence about the occurrence and predictors of ISR in nonthrombotic IVCS is limited. We therefore conducted this research to identify the incidence of ISR and explore the potential predictors of ISR in patients with nonthrombotic IVCS.

Patients with nonthrombotic IVCS, who accepted stenting between 2017 and 2020 in our vascular department, were retrospectively analyzed. The study protocol was approved by the Human Research Ethics Committees of Zhongshan hospital, Fudan University (No. B2017-115), and the patient informed consent was waived. Every limb was considered as an independent data in all statistical analysis.

Patients underwent stenting under local anesthesia. To precisely evaluate the venous lesion, intravascular ultrasound was performed for each limb. Diameter or area of venous stenosis was calculated using the formula: (1–minimal vessel diameter [area]/reference vessel diameter [area]) × 100%. Patients received a combination of aspirin and rivaroxaban for at least 6 months after stenting, and follow-up was suggested at 3, 6, 12 months and yearly thereafter.

During the follow-up, all computed tomography (CT) scans were performed with a 64-slice detector (Optima CT 660, General Electric and Aquilion 64, Tokyo, Japan) for all subjects. Coronal, sagittal, and oblique pictures were reformatted, and the degree and location of ISR were evaluated independently by a radiologist and a vascular surgeon. In this study, ISR was defined as any degree of stenosis. Limbs could be classified into the ISR and non-ISR group based on whether stenosis has occurred.

Continuous data were presented as mean ± standard deviation or median (Q₁, Q₃) according to their distribution, while categorical data were presented as counts (percentages). Comparison between the two groups was performed using the χ² test, Mann–Whitney U test, Student's t-test, or Fisher's exact test where appropriate. Multivariable logistic regression analysis was performed by including all potential predictors (P < 0.10 in univariable analyses). A P value (two-sided) <0.05 was recognized as statistically significant; and analyses were conducted using SPSS Statistics (version 23, IBM, Armonk, NY, USA).

A total of 68 patients with 78 limbs were eligible for further analysis. The age was 63.94 ± 8.02 years and more than half of them were female. The body mass index (BMI) was 24.97 ± 2.94 kg/m². The most common comorbidities were hypertension and diabetes. Most of the iliac vein compression (56/78, 71.8%) occurred in the left leg and 10 patients had bilateral lesions. According to the Clinical–Etiology–Anatomy–Pathophysiology classification, there were 6 limbs of C3 (edema), 53 limbs of C4 (skin changes such as pigmentation, eczema, and induration), 7 limbs of C5 (healed venous ulcer), and 12 limbs of C6 (active venous ulcer).

During the follow-up period, 10 patients with 10 limbs presented with ISR (12.8%). ISR mainly occurred at the middle of stent (8/10), a location which was close to the original compression point; the remaining two ISR occurred at the proximal segment of stent. The median time of ISR was 7.5 months (3.0–13.0 months) after stenting. The comparison of demographic and anatomic characteristics between two groups was displayed in Table 1. Specifically, the ISR group tended to be older and had a higher percentage of female patients but a lower BMI than non-ISR group. In contrast, anatomic parameters did not significantly differ between the two groups. But there was a trend toward a lower minimal vessel area (MVA) (43.16 ± 16.68 mm²vs. 55.72 ± 19.70 mm², t = –1.915, P = 0.059) and a higher percent area stenosis (66.35 ± 12.55% vs. 59.93 ± 10.92%, t = 1.703, P = 0.093) in the ISR group compared with non-ISR group, although these differences did not reach statistical significance. In the multivariable logistic regression analysis, area stenosis was not included for avoiding the colinearity.

Table 1.

Baseline and anatomic characteristics of the ISR and non-ISR group after stenting in iliac vein compression syndrome patients.

Items	ISR (n = 10)	Non-ISR (n = 68)	U/t/χ 2	P values
Age (years)	68.00 ± 7.48	63.24 ± 7.95	−1.972∗	0.058
Female	8 (80.0)	34 (50.0)	3.157†	0.076
BMI (kg/m2)	23.50 ± 2.71	25.18 ± 2.93	−1.764∗	0.078
Left side	9 (90.0)	47 (69.12)	0.988†	0.320
CEAP classification||			−0.263∗	0.813
C3	1 (10.0)	5 (7.4)
C4	6 (60.0)	47 (69.1)
C5	1 (10.0)	6 (8.8)
C6	2 (20.0)	10 (14.7)
MVD (mm)	3.19 ± 1.55	3.66 ± 1.45	1.054∗	0.292
RVD (mm)	10.67 ± 2.62	10.22 ± 2.17	0.596‡	0.553
Percent diameter stenosis (%)	67.88 ± 18.42	63.26 ± 13.39	1.196∗	0.232
MVA(mm2)	43.16 ± 16.68	55.72 ± 19.70	1.915‡	0.059
RVA (mm2)	139.29 ± 60.01	142.86 ± 44.18	0.228‡	0.820
Percent area stenosis (%)	66.35 ± 12.55	59.93 ± 10.92	1.703‡	0.093
Stent type			–	0.682§
Luminexx	2 (20.0)	18 (26.5)
Wallstent	7 (70.0)	47 (69.1)
Other	1 (10.0)	3 (4.4)
Stent number			–	0.506§
1	9 (90.0)	64 (94.1)
2	1 (10.0)	4 (5.9)
Stent size			0.632∗	0.527
12 mm	2 (20.0)	10 (14.7)
14 mm	3 (20.0)	33 (48.5)
16 mm	3 (30.0)	20 (29.4)
18 mm	2 (20.0)	5 (7.4)
Stent length			0.688∗	0.491
4 cm	0 (0)	1 (1.5)
6 cm	2 (20.0)	11 (16.2)
7 cm	0 (0)	1 (1.5)
8 cm	0 (0)	9 (13.2)
9 cm	5 (50.0)	31 (45.6)
10 cm	1 (10.0)	6 (8.8)
12 cm	2 (20.0)	9 (13.2)
Stent entering into IVC	4 (40.0)	29 (42.6)	0.025†	0.854
Post-stenting MVD (mm)	10.27 ± 1.74	10.09 ± 2.28	0.235‡	0.815
Post-stenting RVD (mm)	11.36 ± 1.57	12.32 ± 1.63	−0.982‡	0.235
Residual diameter stenosis (%)	9.50 ± 9.26	17.74 ± 16.97	−1.498‡	0.138
Post-stenting MVA (mm2)	131.84 ± 48.52	131.05 ± 43.63	0.053‡	0.958
Post-stenting RVA (mm2)	149.28 ± 53.41	159.77 ± 51.81	−0.596‡	0.553
Luminal diameter increased (mm)	7.08 ± 2.57	6.43 ± 2.20	0.851‡	0.397
Luminal area increased (mm2)	88.68 ± 43.07	75.33 ± 36.50	1.056‡	0.294
Residual area stenosis (%)	11.29 ± 10.91	16.55 ± 16.61	−0.968‡	0.336
Red blood cells (×1012/L)	4.29 ± 0.66	4.38 ± 0.51	−0.830∗	0.407
Hemoglobin (g/L)	125.40 ± 15.05	133.34 ± 14.12	−1.647‡	0.104
Platelets (×109/L)	221.80 ± 61.47	196.35 ± 47.82	1.514‡	0.134
White blood cells (×109/L)	5.33 ± 1.23	5.90 ± 1.60	−1.082‡	0.283
Fibrinogen (mg/dL)	276.60 ± 48.48	268.19 ± 63.77	−0.710‡	0.478

Data are presented as n (%) or mean ± standard deviation.

^∗U values.

^†χ² values.

^‡t values.

^§Fisher's exact test was applied.

^||The Clinical–Etiology–Anatomy–Pathophysiology (CEAP) classification; C3 means edema, C4 means skin changes, such as pigmentation, eczema, and induration, C5 means healed venous ulcer, and C6 means active venous ulcer. BMI: Body mass index; CEAP: Clinical–Etiology–Anatomy–Pathophysiology; ISR: In-stent restenosis; IVC: Inferior vena cava; MVA: Minimal vessel area; MVD: Minimal vessel diameter; RVA: Reference vessel area; RVD: Reference vessel diameter; –: Not avaliable.

The receiver operating characteristic (ROC) curve was then conducted for MVA in ISR and identified an optimal cutoff value of 48 mm². The multivariable logistic regression model confirmed that after adjusting for age, sex, and BMI, MVA ≤48 mm² remained an independent predictor of ISR (adjusted OR = 7.464, 95% CI: 1.282–43.476, P = 0.025).

This study provided the data associated with the incidence and risk factor of ISR after stenting in nonthrombotic IVCS patients. According to our results, 12.8% of diseased limbs presented ISR at a median time of 7.5 months after stenting. Multiple regression analyses suggested that MVA was an independent predictor of ISR after stenting in nonthrombotic IVCS. Diseased limbs with an MVA≤48 mm² might need a more rigorous follow-up after stenting.

With consideration of that ISR was more widely used in published reports and intimal hyperplasia might be inappropriate for research when no histopathological report was available for these patients, hence, ISR rather than intimal hyperplasia was adopted in this study.^[2–4] In other researches,^[2,4] the incidence of ISR varied from 27% to 77%, owing to different patients, detection methods, and time to report. Neglén et al^[2] showed that transfemoral venogram identified a cumulative incidence of 77%, 61%, and 15% at 42 months for ISR with any degree, ISR with diameter reduction >20%, and ISR with diameter reduction >50%, respectively. A recent study demonstrated that the incidence of ISR was 27% on post-surgery day 1 and increased to 74% at 3 months.^[4] The incidence and severity of ISR reported by these studies were higher than our research. This might be related to that the patients, who were included in those study, were different. This research only enrolled nonthrombotic IVCS, while both thrombotic and nonthrombotic IVCS were included in previous studies. Based on CT scan, the incidence of ISR in nonthrombotic IVCS was 12.8% at a median time of 7.5 months after stenting in this research. Obviously, this incidence is much higher than the Neglén et al's^[5] report. This discrepancy could be mostly attributed to the different definitions of ISR. Neglén et al^[5] reported a relatively low incidence of ISR based on severe stenosis (>50%), while we recorded ISR based on any degree stenosis in this research. Besides, the CT scan that was used in our study to identify ISR might be more sensitive than ultrasonic examination.

Univariable analysis demonstrated five potential predictors (age, sex, BMI, MVA, and percent area stenosis) for ISR after stenting, but multivariable regression model recognized MVA as the only independent predictor of ISR. Taken together, all these data indicated a role of MVA in predicting the occurrence of ISR. This might be explained by that a smaller MVA indicated a more advanced stage of disease, thus leading to a higher risk of ISR after stenting. Besides, considering the post-stenting MVA was similar between the two groups, the vessel enlargement was much greater in the ISR group, leading to a stronger outward force by the stent, which would result in overreactive intimal hyperplasia. But further research was still needed to confirm the two assumptions mentioned above.

Several limitations needed to be noticed about our study. Firstly, the retrospective nature of this research and the small sample size limited its generalizability, although the majority of included patients were from a prospectively registered cohort. Secondly, since only nonthrombotic IVCS was enrolled in this research, the findings of our study are limited to this subgroup of IVCS. Lastly, the follow-up period was relatively short, the long-term follow up research is needed to observe the association between ISR and the late outcomes of patients.

In conclusion, ISR is not a rare condition after stenting in nonthrombotic IVCS patients. MVA is an independent predictor of ISR after stenting, and diseased limbs with an MVA ≤48 mm² should be recommended with a restrictive follow-up.

Conflicts of interest

None.