Factors associated with the development of post-thrombotic syndrome in patients with iliofemoral deep venous thrombosis who underwent catheter-directed thrombolysis

Abstract

Objective

To identify predictors of post-thrombotic syndrome in patients with iliofemoral deep venous thrombosis who underwent catheter-directed thrombolysis.

Methods

Fifty-two consecutive patients who underwent catheter-directed thrombolysis were included in this retrospective study. In addition to catheter-directed thrombolysis, aspiration thrombectomy or stent placement was performed if needed. At six months, duplex ultrasound was performed to assess iliofemoral patency and deep venous reflux. Post-thrombotic syndrome was assessed using the clinical, etiologic, anatomic, and pathophysiologic classification (post-thrombotic syndrome present ≥3 on a scale from 0 to 6). Univariate analysis and multivariate logistic regression were used to identify predictors of post-thrombotic syndrome.

Results

Median follow-up was 52 months and post-thrombotic syndrome developed in nine patients (17.3%). In univariate analysis, stent placement (odds ratio 0.16, p = 0.022) was negatively associated with post-thrombotic syndrome, whereas iliofemoral venous obstruction with reflux at six months (OR 6.08, p = 0.037) was positively associated with post-thrombotic syndrome. Multivariate analysis indicated that stent placement was associated with reduced risk of post-thrombotic syndrome (OR 0.17, p = 0.043), and iliofemoral obstruction with reflux was associated with increased risk (OR 6.67, p = 0.046).

Conclusion

Stent placement and iliofemoral venous obstruction with reflux, respectively, were important protective and risk factors for post-thrombotic syndrome in patients who underwent catheter-directed thrombolysis.

Keywords

Venous thrombosis postthrombotic syndrome endovascular procedures thrombolytic therapy risk factors

Introduction

Post-thrombotic syndrome (PTS) is a common chronic complication of deep venous thrombosis (DVT) characterized by swelling, pain, skin change, and venous ulcers, which result in poor quality of life for the patient and present a socioeconomic burden.¹ Despite anticoagulant therapy, 20–50% of patients with DVT may experience PTS, and proximal DVT in particular is associated with a high risk of PTS.^2–4

Catheter-directed thrombolysis (CDT) is a method of delivering a thrombolytic agent into the thrombus through a catheter to accelerate thrombus removal. The aim of CDT is to remove the thrombus by means of low-dose thrombolytic agent and mechanical therapy, especially in the iliofemoral segment.^5,6

Several studies have shown that risk factors for PTS are female sex, advanced age, higher BMI, proximal localization of DVT, residual thrombosis, and presence of valvular reflux.^4,7,8 These studies, however, dealt exclusively with patients treated with anticoagulation therapy, and few studies have identified risk factors for PTS in patients who underwent CDT. The purpose of our study was to identify predictors of PTS development in patients with iliofemoral DVT who underwent CDT.

Methods

Patients

From October 2000 to November 2014, 65 consecutive patients were diagnosed with iliofemoral DVT by duplex ultrasound or computed tomographic venography and treated with CDT in our hospital. Of these 65 patients, two died of malignancy within one year and 11 were lost to follow-up. In total, 52 patients were followed up for more than one year and included in our study. The mean age of all patients was 48.3 ± 13.1 years (range, 15–73 years) and 23 patients (44.2%) were female. We evaluated demographics, underlying risk factors for venous thrombosis, symptom duration, presenting symptoms, technical approach, and follow-up findings via medical records. The Internal Review Board of our institution reviewed and approved the study protocol. The study was a retrospective study and was conducted with a waiver of patient consent.

Procedure

Anticoagulation treatment was initiated on the day of diagnosis using low-molecular-weight heparin (LMWH). CDT was initiated on the first following working day, and LMWH therapy was discontinued at least 8 h prior to the procedure. A bolus dose of 3000–5000 IU unfractionated heparin was given at the start of the procedure, followed by an infusion of unfractionated heparin (15 U/kg/h) that was adjusted to maintain activated partial thromboplastin time at 1.2–1.7 times prolongation, i.e. 40–60 s.

Percutaneous access was through the popliteal vein (50 accesses) or posterior tibial vein (one access) of the affected leg under ultrasound guidance. In one case, the right internal jugular vein approach was used, because the iliocaval junction could not be traversed with an antegrade approach from popliteal vein. A 7–12 F vascular sheath was inserted, and venography was performed to evaluate the extent of the thrombus. A multi-sideport infusion catheter (Cook, Bloomington, IN) was placed in the thrombotic segments, and urokinase was administered through the catheter as a bolus at a maximum dose of 500,000 U or as a continuous infusion at a maximum rate of 120,000 U/h. Heparin was infused via the vascular sheath during the procedure. The thrombolytic agent was given until complete lysis or no further improvement, with a maximum duration of 72 h. The operator could use additional aspiration thrombectomy with a 6–8 F guiding catheter (Envoy (Cordis) or Shuttle-SL Flexor (Cook)) to eliminate residual thrombus, while negative pressure was applied via the catheter hub to aspirate thrombi. Dilatation with balloon angioplasty was performed on all except one patient. If iliac vein stenosis (>50% narrowed) was seen on completion venography using multiplanar views, adjunctive self-expandable stent placement (SMART stent (Cordis) or Wallstent (Boston Scientific)) was performed (Figure 1). The common iliac vein was typically stented with a 12–16-mm-diameter stent, and the external iliac vein was typically stented with a 10–14-mm-diameter stent. All stents were placed above the inguinal ligament. If there was floating thrombus in the infrarenal inferior vena cava (IVC), a retrievable IVC filter was placed before CDT in 12 patients. Immediate post-treatment venography was performed in all patients, and technical success was defined as successful restoration of antegrade in-line flow in the treated vein with elimination of any underlying obstructive lesion.⁹ All patients continued systemic anticoagulation after CDT.

Figure 1.

A 59-year-old woman with left-sided acute iliofemoral deep venous thrombosis. In the prone position, the venogram shows filling defects secondary to intraluminal DVT from the level of left femoral vein up to the common iliac vein (a, b). Nineteen hours after catheter-directed thrombolysis, follow-up venography demonstrated partial thrombolysis but with significant obstruction of left common iliac veins (c, d). A 14 × 60-mm self-expandable SMART (Cordis) stent was placed to restore venous flow (e). This was an off-label use of a non-dedicated venous stent.

The main safety outcome was bleeding related to thrombolysis during the initial treatment period. Bleeding complication was considered major if it was associated with a hemoglobin decrease of at least 2 g/dL; required transfusion of at least 2 U of packed red blood cells; was retroperitoneal, intracranial, or in a critical organ; or contributed to death. Clinically relevant nonmajor bleeding included epistaxis that required intervention, formation of a large hematoma visible on the skin, or spontaneous macroscopic hematuria. All other hemorrhages were categorized as trivial.¹⁰

Assessment at six-month follow-up

Duplex ultrasound examination was performed at six months after CDT to assess the iliofemoral venous patency and deep venous reflux. Iliofemoral patency was defined as regained when pelvic and femoral venous flow and complete compressibility of the femoral vein were present on ultrasound.¹¹ Venous reflux was defined as present when retrograde flow was longer than 0.5 s after distal compression in the standing position.¹²

Predictors

The influence of the following candidate characteristics as predictors or confounders for PTS was analyzed: (i) demographics characteristics—age, sex, and BMI; (ii) clinical characteristics—underlying risk for DVT and symptom duration before CDT; (iii) procedural characteristics—treatment time with CDT, aspiration thrombectomy, stent placement, and IVC filter insertion; and (iv) ultrasound findings at six-month follow-up—iliofemoral patency and deep venous reflux.

Assessment of PTS

A follow-up visit was performed at 1, 3, 6, and 12 months and then annually. At each visit after discharge, the patients were evaluated for signs and symptoms of PTS. During the clinical examination, all signs of chronic venous hypertension in the affected leg were recorded, that is, swelling, edema, varicose veins, skin changes, and ulcers. The reported outcomes were evaluated at their last visit. The severity of PTS was scored according to the clinical score (range 0–6) of the CEAP classification (Clinical, Etiologic, Anatomic, and Pathophysiologic).¹³ In this classification, patients with class 0 represent no visible or palpable signs of venous disease; class 1 telangiectases or reticular veins; class 2 varicose veins; class 3 edema without skin changes; class 4 skin changes ascribed to venous disease (pigmentation, lipodermatosclerosis); class 5 skin changes with a healed ulcer and class 6 skin changes with active ulceration. PTS was defined present if the classification was three or more.

Statistical analyses

The study sample was divided into two groups: with and without PTS. Differences in categorical variables were compared by Fisher’s exact tests, and differences in continuous variables were compared by Student’s t test between the two groups. It was hypothesized that the primary predictors for PTS would be age, female gender, and BMI.¹⁴ In addition to age, sex, and BMI, variables achieving a p-value < 0.05 in univariate analyses were included in a multivariate logistic regression analysis. Results are presented as odds ratio (OR), 95% confidence interval (CI), and p-value. All computations were performed using SPSS software, version 18.0 (SPSS, Chicago, IL, USA), and p-values less than 0.05 were considered statistically significant.

Results

Descriptives

Among 52 patients, thrombosis was unilateral on the left side in 43 patients (83.7%), and none of the patients had bilateral DVT. Median duration of symptoms before the CDT procedure was seven days (interquartile range, 3–11.25 d). Mean treatment time with CDT was 23.0 h ± 15.9. An aspiration thrombectomy was performed in 44 patients (84.6%), and stents were inserted in the iliac veins of 40 patients (76.9%). Stents were placed on the left side in 33 cases and on the right side in seven cases. Successful lysis was achieved in all patients, and there were no bleeding complications related to thrombolysis during or shortly after the CDT procedure.

Predictors of PTS

Median follow-up was 52 months (range, 12–159 months), and the 52 patients were classified according to whether they developed PTS. PTS developed in nine patients (17.3%). Among the patients with PTS, seven had a CEAP score of 3 and two had a CEAP of 4. None of the patients was diagnosed with CEAP score of 5 or 6.

Tables 1 and 2 detail the distribution of characteristics from patients stratified by PTS development. In univariate analysis, stent placement (OR 0.16, 95% CI: 0.03–0.73, p = 0.022) was negatively associated with PTS, whereas iliofemoral venous obstruction with reflux at six months (OR 6.08, 95% CI: 1.21–30.47, p = 0.037) was positively associated with PTS. Multivariate logistic regression analyses showed that stent placement was associated with a reduced risk of PTS (adjusted OR 0.17, 95% CI: 0.03–0.95, p = 0.043), and iliofemoral obstruction with reflux was associated with an increased risk (adjusted OR 6.67, 95% CI: 1.04–42.88, p = 0.046) (Table 3).

Table 1.

Demographic and clinical characteristics of patients.

Characteristics	No PTS (n = 43)	PTS (n = 9)	OR (95% CI)	p
Age	49.0 ± 13.9	45.3 ± 7.8	–	0.452
Female gender	20 (46.5)	3 (33.3)	0.58 (0.13–2.60)	0.714
BMI	24.74 ± 3.87	25.70 ± 2.18	–	0.474
Left-sided DVT	37 (86.0)	6 (66.7)	0.32 (0.06–1.66)	0.177
Symptom duration before CDT (>2 weeks)	7 (16.3)	3 (33.3)	2.60 (0.52–12.80)	0.349
Predisposing factor
Surgery within three months	5 (11.6)	3 (33.3)	3.80 (0.72–20.19)	0.130
Immobilization	2 (4.7)	0 (0.0)	–	1.000
Oral contraconceptive	4 (9.3)	0 (0.0)	–	1.000
Thrombophilia	6 (14.0)	0 (0.0)	–	0.574
Cardiopulmonary disease	2 (4.7)	0 (0.0)	–	1.000
Malignancy	2 (4.7)	0 (0.0)	–	1.000
No risk factors for venous thrombosis	20 (46.5)	6 (66.7)	2.30 (0.51–10.41)	0.465

Data are presented as numbers with percentages in parentheses or mean ± SD.

Table 2.

Procedural characteristics and venous abnormalities at six-month follow-up.

Characteristics	No PTS (n = 43)	PTS (n = 9)	OR (95% CI)	p
Procedural characteristics
Treatment time with CDT (hours)	23.3±17.0	21.4±9.5		0.747
Aspiration thrombectomy	36 (83.7)	8 (88.9)	1.56 (0.17–14.48)	1
Stent placement	36 (83.7)	4 (44.4)	0.16 (0.03–0.73)	0.022^a
IVC filter insertion	10 (23.3)	2 (22.2)	0.94 (0.17–5.28)	1
US findings at six-month follow-up
Iliofemoral obstruction only	4 (9.3)	0 (0.0)	–	1
Deep venous reflux only	9 (20.9)	4 (44.4)	3.02 (0.67–13.63)	0.203
Obstruction combined with reflux	5 (11.6)	4 (44.4)	6.08 (1.21–30.47)	0.037^a

Data are presented as numbers with percentages in parentheses or mean ± SD.

^aStatistically significant.

Table 3.

Predictors of post-thrombotic syndrome at multivariate logistic regression.

Characteristics	aOR (95% CI)	p
Age	0.98 (0.92–1.05)	0.586
Female gender	0.65 (0.11–3.88)	0.684
BMI	1.10 (0.86–1.41)	0.445
Stent placement	0.17 (0.03–0.95)	0.043^a
Obstruction combined with reflux	6.67 (1.04–42.88)	0.046^a

aOR, adjusted odds ratio.

^aStatistically significant.

Discussion

In our study, 17.3% of patients with iliofemoral DVT who underwent a CDT procedure developed PTS after a median follow-up of 52 months. Multivariate regression analyses identified stent placement as a protective factor and iliofemoral venous obstruction with reflux at six months as a risk factor of PTS development.

Recently, the Norwegian Catheter-directed Venous Thrombolysis (CaVenT) study, a prospective multi-center randomized controlled trial comparing standard anticoagulation with additional CDT, demonstrated that CDT reduced the risk of PTS over periods of two and five years. Additionally, iliofemoral patency after six months was improved, and deep venous reflux after two years was reduced in the CDT group.^15,16 These findings can be explained by the open vein hypothesis, which postulates that early thrombus removal and restoration of venous flow can prevent PTS. In contrast, the recent Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial demonstrated that the addition of CDT to anticoagulation did not reduce the incidence of PTS.¹⁷ However, the severity scores for the PTS were significantly lower in pharmacomechanical–thrombolysis group than in the control group at all time points between 6 and 24 months (p < 0.01 for the all Villalta score comparisons). This indicates that patients were significantly more likely to be symptomatically better if they received CDT than if treated medically. The most recent study, CAVA trial, showed that additional ultrasound-accelerated CDT did not change the risk of PTS one year after acute iliofemoral DVT compared with standard anticoagulation therapy.¹⁸ However, the CAVA trial has some similarities to the ATTRACT trial in the following ways: PTS severity (Villalta score) was apparently lower in the CDT group, and moderate or severe PTS occurred less in the CDT group with International Society of Thrombosis and Haemostasis Villalta scoring method (12 (16%) of 77 vs. 19 (25%) of 75).

Our data showed that adjunctive venous stent placement with the CDT procedure was associated with a decreased risk of PTS. There is no consensus on the indications for stenting, but the current guideline recommends stenting for short-segment iliocaval stenosis.^19,20 Stent placement was reported to improve patency rates in the National Multicenter Registry including 303 limbs treated with CDT.²¹ In a recent studies by Engelberger et al.,^22,23 stent placement was performed in 80% of patients, and the incidence of PTS after 12 months was less than 12%. Compared with these studies, the CaVenT study showed a relatively high PTS rate (41%), which may be partly due to the relatively low rate of stent placement (17%).¹⁵ In the ATTRACT trial, PTS occurred in 92 (48%) of 190 patients with iliofemoral DVT who underwent pharmacomechanical CDT.¹⁷ However, a total of 82 patients underwent stenting, which means that at most 43.2% of patients with iliofemoral DVT had a stent placed. This rate is higher than that seen in CaVenT, but still is lower than the 80% stenting rate of the previously mentioned studies.^22,23 These results suggest that more aggressive stenting can reduce PTS. According to a retrospective study by Chung et al.,²⁴ the majority of patients (80%) with acute iliofemoral DVT had underlying anatomic abnormalities on CT venography, and this might be overcome by stents. However, the difference in incidence of PTS among different studies may be due to variations in the measurement and reporting methods of outcome rather than the technical approach. Therefore, further comparative study is needed to define the criteria for stent placement in iliofemoral DVT.

Haig et al.²⁵ reported that iliofemoral patency and deep venous reflux assessed by duplex ultrasound at six months were the strongest predictors of PTS development in the CDT arm. These findings support the notion that the main pathophysiological causes of development of PTS are damage to venous valves and incomplete thrombus resolution. Valve destruction leads to chronic venous insufficiency, and residual thrombus leads to partial or complete venous obstruction. These may cause chronic venous hypertension and development of PTS.^26,27 Our results showed that the combination of venous obstruction and reflux significantly increased the risk of PTS. However, the presence of obstruction alone or reflux alone was not predictive of PTS.

Our study showed similar or better results in evaluation of venous patency and PTS compared to other CDT studies;²⁸ in particular, there were no cases with bleeding complications in our study. Our study differs from other CDT studies in that the proportion of combined aspiration thrombectomy with CDT was higher (84.6%). Aspiration thrombectomy can remove thrombus more rapidly and reduce the dose of thrombolytic agent, thereby decreasing treatment time and bleeding complications. Although aspiration thrombectomy is not frequently used in clinical practice, some studies have reported the safety and effectiveness of this procedure.^29,30

Our study has some limitations. First, our studies have shown that stent insertion reduces PTS, but our treatment protocols did not have strict criteria for stent insertion. Typically, a 50% diameter stenosis by complete venography was considered significant stenosis. However, it can be challenging to decide when to stent based on venography after successful thrombolysis. Because stenotic iliac vein lesion can be elliptical, flattened, or diffuse, venography, even with multiplanar techniques, has limited views that may miss highly eccentric lesions. The Venogram versus IVUS for Diagnosing Iliac vein Obstruction (VIDIO) trial have suggested that intravascular ultrasound (IVUS) identified significant iliofemoral vein stenosis not detected with multiplanar venography in 26.3% of patients and frequently led to revised treatment plans such as stent placement.³¹ However, IVUS could not be used in our hospital, because it was not covered by medical insurance. Second, this was a retrospective study that may have been affected by bias with respect to patient selection and information. Third, the present study was performed at a single center with a relatively small sample size. Moreover, the subjects have been recruited over a 14-year period, but only 4–5 CDT procedures have been performed per year. Fourth, there was no objective, gold standard method to diagnose PTS. The disadvantage of the CEAP classification is that subjective symptoms are not included. There is no established cut-off for what defines a PTS using CEAP, and different studies have used ≥C2, C3, or C4. Although the Villalta scale is the most widely applied clinical scale used to diagnose and define PTS,³² this scoring system was difficult to apply to our study because of the retrospective nature of the data. The Villalta scale uses a point system, whereby 11 factors (including pain and edema) are rated from 0 (none) to 3 (severe), and this level of detail was not available in our study.

In conclusion, stent placement and iliofemoral venous obstruction with reflux, respectively, were important protective and risk factors for PTS in patients who underwent CDT.

Footnotes

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) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Institutional Review Board approval was obtained.

Guarantor

Hong Suk Park

Contributorship

Conception and design: HSP and YSD; Data collection: DH, SKC, and KBP; Analysis and interpretation: MSK and HSP; Writing: MSK; Critical revision: HSP; Statistics: MSK; all authors reviewed and approved the final manuscript.

ORCID iD

Hong S Park

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