Mid-term outcome of endovascular treatment for acute lower extremity deep venous thrombosis

Abstract

Purposes of the study

To evaluate the benefit of stenting the iliac vein in patients with residual iliac vein stenosis treated with catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis.

Procedures

In this randomized prospective study, patients with a first-time acute lower extremity deep venous thrombosis that had persisted <14 days were treated with catheter-directed thrombolysis. After catheter-directed thrombolysis, patients with >50% residual iliac vein stenosis were randomly divided into two groups: catheter-directed thrombolysis + Stent Group and catheter-directed thrombolysis Alone Group. Patients received urokinase thrombolysis and low-molecular-weight heparin/oral warfarin during the hospitalization period and were administrated oral warfarin after discharge. Cumulative deep vein patency, the Clinical Etiology Anatomic Pathophysiologic classification system, the Venous Clinical Severity Score and the Chronic Venous Insufficiency Questionnaire score were evaluated.

Findings

The cumulative deep vein patency rate was 74.07% in the catheter-directed thrombolysis + Stent Group and 46.59% in the catheter-directed thrombolysis Alone Group. The mean postoperative Clinical Etiology Anatomic Pathophysiologic classification and Venous Clinical Severity Score was significantly lower in the catheter-directed thrombolysis + Stent Group than in the catheter-directed thrombolysis Alone Group. The mean postoperative Chronic Venous Insufficiency Questionnaire score was significantly higher in the catheter-directed thrombolysis + Stent Group than the catheter-directed thrombolysis Alone Group.

Conclusions

Placement of an iliac vein stent in patients with residual iliac vein stenosis after catheter-directed thrombolysis for acute lower extremity deep venous thrombosis increases iliac vein patency and improves clinical symptoms and health-related quality of life at mid-term follow-up compared to patients treated with catheter-directed thrombolysis alone.

Keywords

Deep venous thrombosis catheter-directed thrombolysis iliac vein stenosis stent patency

Introduction

Deep venous thrombosis (DVT) is the formation of a clot (thrombus) in a deep vein, predominantly in the legs. Globally, about 1 in 1000 adults has DVT per year, and incidence increases by a factor of 1000 from childhood to old age. Signs of DVT include pain, swelling, redness, warmness, and engorged superficial veins.¹ Complications of DVT manifest as pulmonary embolism (PE), a potentially life-threatening condition, and post-thrombotic syndrome (PTS), which can substantially lower a patient’s health-related quality of life (HRQoL).^2,3

Conventional treatment options for DVT include early and frequent walking, calf muscle exercises, anticoagulants, and graduated compression stockings. However, risks for bleeding complications and thrombosis remain.⁴

In the 1990s, catheter-directed thrombolysis (CDT) was developed as an interventional technique for the treatment of DVT of the lower extremities. CDT has since become a recommended strategy as it delivers high localized concentrations of thrombolytic agent with low systemic doses. CDT shows good clinical safety and efficacy, improves thrombus removal from the lower extremities, prolongs venous patency, prevents venous insufficiency, and reduces DVT recurrence and the incidence and severity of PTS.⁵

Endovascular venous stent placement in conjunction with CDT may improve patency rates in selected cases, particularly if abnormal anatomy is the underlying cause of DVTs, as in patients with May-Thurner syndrome, pelvic tumors, osteophytes, iliac artery aneurysms, endometriosis, pregnancy, and uterine masses.⁶ However, some research suggests that stent occlusion and long-term DVT recurrence may result in patients with combined CDT and stenting.⁷ At present, the American Heart Association (AHA) 2011 and American Venous Forum/Society for Vascular Surgery (AVF/SVS) 2012 guidelines support stent placement in the iliac vein to treat obstructive lesions after a thrombus removal strategy for acute DVT.

Previously, we have reported deep vein patency 11 months after placement of stents in patients with residual iliac vein stenosis following CDT for acute lower extremity DVT.⁸ The current report describes deep vein patency in these patients at mid-term follow-up, as well as clinical symptoms after CDT. The findings will improve our understanding of the treatment of lower extremity DVT.

Study design

This study included patients with lower extremity DVT that were treated with CDT in our vascular surgery department between December 2008 and December 2012. After CDT, patients with residual iliac vein stenosis were randomly assigned to this prospective study.

Methods

Patient selection

Inclusion criteria were: (a) age, 18–70 years; (b) lower extremity DVT having occurred within the past 15 days, including patients with femoropopital DVT; (c) experiencing initial onset of symptoms; (d) residual iliac vein stricture >50% and deep vein patency maintained after CDT, determined by venography conducted in multiple directions; (e) no contraindications for thrombolytic and anticoagulant therapy; (f) provision of written informed consent to participate in the study.

Exclusion criteria were: (a) patients with severe renal impairment; (b) patients in the terminal stage of cancer with a life expectancy of <3 months; (c) pregnancy; (d) patients with congenital coagulation defects; (e) patients reporting previous or current use of thrombolytic procedures, including surgery and thrombolysis.

In all, 66 (26 males, 40 females; mean age, 50.85 ± 1.95 years,) patients were eligible for inclusion in this study. Of these, an iliac vein stent was implanted in 27 patients (CDT + Stent Group) and no stent was implanted in 39 patients (CDT Alone Group). The characteristics and clinical parameters of the patients are shown in Table 1. The study protocol was approved by the Medical Ethics Committee of the Jiangsu Provincial Health Department.

Table 1.

Patient baseline characteristics.

Characteristic	CDT + Stent Group	CDT Alone Group
Age, (mean ± SD years)	53.48 ± 3.04	49.03 ± 2.53
Female gender, n (%)	n = 15 (55.56)	n = 25 (64.10)
Duration of symptoms (days)	5.75 ± 0.91	6.10 ± 0.73
Clot locations, n (%)
Iliac	7 (25.93)	9 (23.08)
Iliofemoropopliteal	20 (74.07)	30 (76.92)
Affected limb, n (%)
Left	24 (88.89)	25 (64.10)
Right	2 (7.41)	11 (28.21)
Both	1 (3.70)	3 (7.69)

CDT: catheter-directed thrombolysis.

Procedure

Diagnosis of DVT was confirmed with venography. According to the guidelines for diagnosis and treatment of DVT 2012 (Second Edition) of The Chinese Medical Association Surgery Branch of the vascular surgery group,⁹ inferior vena cava filters (IVCFs) were used to prevent PE before CDT treatment. These included permanent IVCFs: (Trapease, Cordis US; VenaTech B. Braun Germany) and retrievable IVCFs (Optease, Cordis US; Aegisy, Shenzhen Technology Company, CN). Filters were inserted percutaneously under fluoroscopic control through a femoral or jugular vein. Retrievable filters were removed when the deep vein maintained patency and complete or near complete [>90%] thrombus clearance had been achieved.

An appropriate CDT treatment technique was selected based on the type of thrombosis. The lesser saphenous vein, great saphenous vein, pretibial vein, or popliteal vein was used for venous access. The guide wire and catheters were advanced toward the proximal part of the thrombus. A 4-F/5-F straight thrombolysis catheter with multiple side holes (Uni*Fuse Infusion Catheter, Cordis US) was inserted into the thrombus. Urokinase was continuously infused at a dose of 4400 units/kg/h for 24 h; dosage was adjusted according to patient age, bleeding tendency, and rate of blood coagulation. Complete blood count, prothrombin time, activated partial thromboplastin time, D-dimer levels, and fibrinogen (FIB) were determined during treatment. If bleeding tendency was significant or FIB was <1.0, thrombolysis was terminated. Venography was carried out at 12 h, 24 h, or 48 h intervals until the thrombus was resolved to evaluate the progress of thrombolysis and to adjust the position of the thrombolysis catheter. After clearance of the occluding thrombus (defined as the deep vein maintained patency and complete or near complete [>90%] thrombus clearance), patients with iliac vein stenosis >50% were identified iliac vein stenosis >50% was determined by venography conducted in multiple directions. Patients were randomly assigned to one of two groups. Patients in the CDT + Stent Group were given balloon angioplasty and stent placement (Luminexx, C.R. Bard, Inc, US or S.M.A.R.T control C.R. Cordis Inc, US). The diameter of the stent was 12–14 mm and the length was 6–12 cm. Patients in the CDT Alone Group were without stent.

All patients adopted anticoagulant therapy with subcutaneous low-molecular-weight heparin (4000–5000 u/q12 h) for a minimum of 7 days during CDT to avoid spread of the thrombus. Subsequently, patients received drugs such as aescine sodium or diosmin, and oral warfarin was administered for at least 6 months; the dose of oral warfarin was adjusted to achieve an international normalized ratio (INR) of 2.0–3.0. After discharge from the hospital, patients were advised to wear compression stockings and use oral drugs to promote blood flow.

Outcomes

Patient risk factors for DVT, the average duration of thrombolysis therapy, and complications associated with treatment of DVT were analyzed to assess the safety and efficacy of the DVT management strategy. Duplex ultrasound or venography was used to evaluate primary patency rates. The Clinical Etiology Anatomic Pathophysiologic (CEAP) classification system and Venous Clinical Severity Score (VCSS) were used to assess postoperative clinical efficacy. The Chronic Venous Insufficiency Questionnaire (CIVIQ) was used to examine postoperative patient HRQoL.

Statistical analysis

Cumulative patency rates were analyzed using Kaplan-Meier curves and the log rank test. Continuous variables are reported as means ± standard deviation. Postoperative CEAP classification and VCSS and postoperative CIVIQ score in the CDT + Stent Group and CDT Alone Group were compared using independent and paired sample t-tests. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software (version 17).

Results

Baseline characteristics of patients

Baseline characteristics of patients in the CDT + Stent Group and CDT Alone Group are shown in Table 1.

The mean ages of patients in the CDT + Stent Group and CDT Alone Group were 53.48 ± 3.04 years and 49.03 ± 2.53 years, respectively. There were 15 females in the CDT + Stent Group and 25 in the CDT Alone Group. Duration of symptoms in the CDT + Stent Group and CDT Alone Group were 5.75 ± 0.91 days and 6.10 ± 0.73 days, respectively. Clots were located in the iliac vein (CDT + Stent Group, 7 vs. CDT Alone Group, 9) or the iliofemoropopliteal vein (CDT + Stent Group, 20 vs. CDT Alone Group, 30). The left limb was affected in 24 patients in the CDT + Stent Group and 25 patients in the CDT Alone Group. The right limb was affected in two patients in the CDT + Stent Group and 11 patients in the CDT Alone Group. Both limbs were affected in one patient in the CDT + Stent Group and three patients in the CDT Alone Group. There were no significant differences between Groups.

In all, 42.4% of patients with acute lower extremity DVT had no risk factors, and 57.6% of patients had at least one risk factor, including immobilization (7.58%), post-partum (15.2%), family history (3.0%), or a postoperative state (31.8%) due to general surgery (3.0%), orthopedic surgery (15.2%), urological surgery (3.0%), gynecological surgery (7.6%), or neurosurgery (3.0%) (Figure 1).

Figure 1.

Patient risk factors for deep venous thrombosis.

In-hospital outcomes

CDT was administered to 66 patients. The deep venous system was accessed via the lesser saphenous vein (n = 46; 69.70%), the great saphenous vein (n = 10; 15.15%), the pretibial vein (n = 5; 7.58%), or the popliteal vein (n = 5; 7.58%). A Uni * Fuse Infusion Catheter was placed in the location of the thrombus. Mean duration of thrombolysis was 4.24 ± 0.30 days (range, 2–15 days) in all patients, 3.64 ± 0.23 days in the CDT + Stent Group, and 4.63 ± 0.46 days in the CDT Alone Group (p > 0.05).

During CDT, three haemorrhages occurred, two at the access site and one was retroperitoneal. In each case, the hemorrhage was alleviated after hemostasis and puncture point compression bandaging.

A total of 65 patients received IVCF before CDT; 6 IVCFs were found to have a small amount of thrombus within the filter. After successful CDT, 27 patients received self-expanding iliac vein stents.

Follow-up outcomes

The average follow-up time for the remaining patients was 23.56 ± 1.57 months in the CDT + Stent Group and 18 ± 1.19 months in the CDT Alone Group (p > 0.05) (range for all patients, 12–42 months). No cases of clinically evident PE were recorded during CDT or follow-up examinations. Three patients experienced recurrence of lower extremity DVT after hospital discharge in the iliac vein, femoral vein, or popliteal vein. CDT was used to restore deep vein blood flow. Two patients experienced thrombosis in the IVCF, which resulted in contralateral lower limb DVT. CDT or thrombus suction was used to dissolve the thrombosis and restore blood flow.

The cumulative patency rate was significantly higher in the CDT + Stent Group compared to the CDT Alone Group (74.07% vs. 46.59%; p < 0.05; Figure 2). The mean postoperative CEAP classification was significantly lower in the CDT + Stent Group compared to the CDT Alone Group (n = 66; 1.26 ± 0.36 vs. 2.63 ± 0.33; p = 0.002). The mean postoperative VCSS was significantly lower in the CDT + Stent Group compared to the CDT Alone Group (n = 66; 1.07 ± 0.31 vs. 1.96 ± 0.32; p = 0.05; Table 2). The mean postoperative CIVIQ score was significantly higher in the CDT + Stent Group compared to the CDT Alone Group (n = 66; 93.11 ± 1.28 vs.88.56 ± 1.40, p = 0.009; Table 2)

Figure 2.

Cumulative patency rate following treatment for acute lower extremity deep venous thrombosis. The cumulative patency rate was 74.07% in the CDT + Stent Group and 46.59% in the CDT Alone Group.

Overall comparisons
Log Rank (Mantel-Cox)	Chi square	df	Sig.
Log Rank (Mantel-Cox)	5.496	1	0.019

Table 2.

Preoperative and postoperative outcomes.

Outcomes	CDT + Stent Group	CDT Alone Group	p
CEAP
Preoperative	3.19 ± 0.08	3.15 ± 0.06	0.73
Postoperative	1.26 ± 0.36	2.63 ± 0.33	0.002
VCSS
Preoperative	8.04 ± 0.20	8.07 ± 0.18	0.89
Postoperative	1.07 ± 0.31	1.96 ± 0.32	0.05
CIVIQ
Postoperative	93.11 ± 1.28	88.56 ± 1.40	0.009

CDT: catheter-directed thrombolysis; CIVIQ: Chronic Venous Insufficiency Questionnaire; CEAP: Clinical Etiology Anatomic Pathophysiologic; VCSS: Venous Clinical Severity Score.

Discussion

The treatment of DVT has evolved from anticoagulation and systemic thrombolysis to surgical incision to extract the thrombus, in order to prevent acute or chronic complications and improve patient quality of life. Many previous studies have indicated that anticoagulation did not effectively prevent PTS,¹⁰ and systemic thrombolysis was associated with unacceptably high rates of serious bleeding complications.¹¹

Since the 1990s, surgical and endovascular interventions have become the preferred treatment options for femoroiliac DVT, as they may reduce the severity and duration of lower extremity symptoms, prevent PE and PTS, and diminish the risk for recurrence of iliofemoral thrombosis; in particular, CDT is increasingly used in clinical applications.^5,12,13 CDT involves the localized delivery of thrombolytic agents directly into a thrombus. CDT has similar efficacy for treatment of acute lower extremity DVT compared to surgical thrombectomy, but patients treated with CDT report less trauma and quicker recovery.⁶ CDT treatment of acute lower extremity DVT may be more effective in restoring venous patency while reducing the risk for bleeding complications and the incidence of lower extremity PTS compared to conventional anticoagulant therapy and systemic thrombolysis.^6,14,15

The CDT treatment technique depends on the site and extent of thrombosis.¹⁶ Venous access via the popliteal vein is suitable for cases of iliac vein thrombosis and central types of DVT. Small saphenous vein access is appropriate for central, mixed, and peripheral types of DVT. Great saphenous vein access is only used in patients with no obviously developing varicose veins. In our study, in 77% of patients, venous access via the small saphenous vein was chosen as its confluence with the popliteal vein is relatively straight, and it has a high success rate. As technology advances, it is likely that the popliteal, tibial, or posterior tibial veins will be used more frequently to access the deep venous system.

We used urokinase as it has greater clinical efficacy, is associated with fewer side effects, and is more cost-effective than other options.^17–20 We chose a low-dose continuous intravenous infusion of 4400 units/kg/h for 24 h, and thrombosis dissolution was achieved within 4.24 ± 0.30 days.

Stenosis of the left iliac vein is common because it receives anterior compression from the right iliac artery and posterior compression from the spine. Multiple studies have confirmed that DVT is highly correlated with left iliac vein stenosis.^21–23 Chinese guidelines indicate that iliac vein lesions are an important secondary risk factor for DVT, and treatment of iliac vein stenosis plays an important role in the prognosis of the thrombus.⁹ We used endovascular venous stent placement in conjunction with CDT in patients with residual iliac vein stenosis in an attempt to improve patency rates. Mid-term follow-up showed that iliac vein patency rate was 74.07% in the CDT + Stent Group compared to 46.59% in the CDT Alone Group. In our previous study, short-term follow-up showed that iliac vein patency rate was 87.5% in the CDT + Stent Group and 29.6% in the CDT Alone Group at 11 months of follow-up.⁸ Other scholars also found that successful stent implantation in the iliac vein can substantially improve deep vein blood flow in patients treated with CDT for acute DVT of the lower extremities, reduce the recurrence of thrombosis rates, and improve long-term outcomes.^24–26

During follow-up, long-term oral anticoagulant therapy for at least six months post operation and the use of compression stockings are also important for management of DVT. As such, we conclude that the active and on-going treatment of iliac vein disease is essential to maintain deep vein patency in the lower extremities after CDT treatment.

The CEAP classification, VCSS, and CIVIQ were used to evaluate the clinical symptoms and HRQoL of our patients during recovery.^27–32 The postoperative CEAP classification and VCSS in the CDT + Stent Group were significantly lower than in the CDT Alone Group. The postoperative CIVIQ score in the CDT + Stent Group was significantly higher than in the CDT Alone Group, and the difference in CIVIQ score between the two groups was increased with duration of follow-up. These data suggest that stent placement in the iliac vein alleviated clinical symptoms of acute lower extremity DVT and had a positive impact on patient HRQoL.

Clinical case reports suggest that CDT reduces the occurrence of bleeding complications compared to conventional thrombolytic therapy.^18,24,33 In this study, two patients experienced bleeding complications related to the puncture site and one was retroperitoneal, but they recovered after conservative treatment.

The use of IVCFs as an adjunct to CDT remains controversial. In our study, 9.1% patients suffered from filter-related thrombosis and 6% of IVCFs that were removed had a small amount of thrombus within the filter, suggesting that IVCFs may cause contralateral lower extremity DVT, or recurrence of ipsilateral thrombosis. Thrombosis in the IVCF was treated with thrombus suction and CDT. Recurrence of DVT of the lower extremities was treated with CDT. During follow-up, two patients exhibited severe lower extremity edema, skin pigmentation, and an unhealed ulcer secondary to PTS. Other patients experienced mild lower limb edema but reported a CIVIQ score of 80 points or more.

In conclusion, CDT with stenting can improve the efficacy of acute lower extremity DVT treatment, alleviate clinical symptoms, and reduce the incidence of chronic PTS at mid-term follow up. Endovascular treatment with stent implantation to relieve residual iliac vein stenosis should be used after CDT, especially in patients with iliac vein stricture. These postoperative strategies to maintain deep vein patency will decrease the incidence of PTS and reduce recurrence of thrombosis. Further information in this patient population will be reported following studies of long-term follow-up and data collection relating to primary/assisted and secondary patency.

Footnotes

Authors’ contributions

Xiao-Qiang Li: Study design. Kun Jiang: Data collection and Writing. Hong-Fei Sang, Ai-Min Qian, Jian-Jie Rong, Cheng-Long. Li: Data analysis.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from National Natural Science Foundation of China (No.81400345), Clinical Medical Science and Technology Project of Jiangsu Provincial Science and Technology Department (BL2014043), Suzhou City’s Young Scientific Talent Program (KJXW2013014).

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