Comparison of catheter-directed thrombolysis with and without percutaneous mechanical thrombectomy for subacute iliofemoral deep vein thrombosis

Abstract

Objective

To evaluate and compare the treatment efficacy and safety between catheter-directed thrombolysis monotherapy and catheter-directed thrombolysis combined with percutaneous mechanical thrombectomy for patients with subacute iliofemoral deep vein thrombosis.

Methods

We conducted a retrospective analysis of a total of 74 subacute iliofemoral deep vein thrombosis patients who underwent catheter-directed thrombolysis with and without percutaneous mechanical thrombectomy. Patients treated with catheter-directed thrombolysis combined with percutaneous mechanical thrombectomy (percutaneous mechanical thrombectomy group, n = 30) or catheter-directed thrombolysis monotherapy (catheter-directed thrombolysis group, n = 44) were included. The primary endpoints were the clinical efficacy rate of thrombolysis, primary patency, and the incidence of post-thrombotic syndrome (at 12 months diagnosed according to the original Villalta score criteria. Secondary endpoints were the total urokinase dose, the thrombolysis time, the detumescence rate and complications.

Results

The percentage of successful thrombolysis for percutaneous mechanical thrombectomy group was higher than that for catheter-directed thrombolysis group (P = 0.045). At the 12-month follow-up, there was no difference in the primary patency (P > 0.05) or the incidence of post-thrombotic syndrome (P = 0.36). Percutaneous mechanical thrombectomy group had significant advantages in reducing urokinase doses and thrombolysis times compared with catheter-directed thrombolysis group for patients with thrombus clearance levels II and III (P < 0.05).

Conclusion

Catheter-directed thrombolysis combined with percutaneous mechanical thrombectomy performs better in removing vein thrombi, reducing urokinase doses, and shortening thrombolysis times.

Keywords

Subacute iliofemoral deep vein thrombosis percutaneous mechanical thrombectomy catheter-directed thrombolysis

Introduction

Deep vein thrombosis (DVT) of the lower limbs, especially in the iliofemoral vein, is the major cause of pulmonary embolisms (PEs), and the risk of developing post-thrombotic syndrome (PTS) for patients with DVT ranges from 20% to 50% within two years.^1,2 According to the initial date of DVT symptoms and the standards of the Society of Interventional Radiology (SIR), DVT is categorized as acute phase (less than 14 days), subacute phase (15–28 days), or chronic phase (more than 28 days).³

Standard treatment of deep-vein thrombosis includes immediate anticoagulant therapy and compression therapy.⁴ Although anticoagulation effectively prevents thrombus extension, pulmonary embolism, death, and recurrence, many patients develop venous dysfunction resulting in PTS.^5–7 Besides, evidence is emerging that thrombus removal reduces acute symptoms and recurrent DVT episodes, preserves valvular function, and potentially reduces the risk of PTS. Due to the lack of an adequate understanding of thrombosis or not seeking timely treatment, a large number of patients are already in the clinical subacute phase at initial diagnosis. However, some patients, especially those with iliofemoral DVT, may be refractory to conservative therapy or even develop progressive symptoms due to thrombus extension and, thus, require more aggressive therapy. The CAVENT trial, a randomized study investigating catheter-directed thrombolysis (CDT) in both iliofemoral and femoropopliteal thrombosis, showed CDT reduces PTS in patients with above the knee deep-vein thrombosis.⁶ Besides, a recently published subgroup analysis of the ATTRACT trial investigating iliofemoral DVT revealed that both the severity of PTS and the extent of leg pain and swelling were significantly improved in patients who received pharmacomechanical catheter-directed thrombolysis (PCDT) versus no-PCDT.⁸ These evidences confirmed that early thrombus removal strategies, particularly CDT and percutaneous mechanical thrombectomy (PMT), are effective and safe approaches for acute DVT. Nevertheless, for patients with subacute DVT, the application of CDT or PMT is rarely reported, and there is no study comparing the treatment efficacy and safety between CDT monotherapy and CDT combined with PMT. The aim of this study was to evaluate and compare treatment efficacy and safety between CDT monotherapy and CDT combined with PMT in treating patients with subacute iliofemoral DVT.

Materials and methods

Patients

This single-center retrospective study was approved by the institutional review board at the participating center, and the need for written informed consent was waived due to its retrospective nature. The study was conducted according to the World Medical Association Declaration of Helsinki. Patients in the subacute phase of iliofemoral DVT and treated with either CDT combined with PMT (PMT group) or CDT monotherapy (PMT group) between December 2015 and May 2018 were screened.

The inclusion criteria were as follows: (1) between 15 and 28 days for the time since the onset of symptoms; (2) severe symptoms with swelling or pain before treatment; (3) lack of imaging evidence of PE; and (4) patients who were clearly diagnosed by color Doppler ultrasonography and/or lower limb ascending venography. The exclusion criteria were as follows: (1) patients in the acute or chronic phase of DVT; (2) contraindications to thrombolysis or anticoagulation drugs; (3) history of cerebral hemorrhage in the last three months; (4) severe renal insufficiency.

Procedures

Dalteparin, a low molecular weight heparin, was administered to all patients on the day of diagnosis at 100 IU/kg every 12 h according to local protocols based on international guidelines.⁴ For safety, a retrievable inferior vena cava (IVC) filter (Aegisy (Lifetech Scientific, Shenzheng, China), OptEase (Cordis, Miami Lakes, Fla)) was implanted via the femoral vein of the nonaffected leg prior to the next step of treatment. All patients received ultrasound-guided puncture to the ipsilateral vein in the prone position. Details of the CDT procedure have been reported previously.⁹ A venography performed at the start of the procedure established the topography of the thrombus. After local anesthesia, an infusion catheter with multiple side holes (Uni×Fuse Infusion Catheter, Angiodynamics, Latham, NY, USA) covering the thrombosed segments was introduced, preferentially into the popliteal vein. For patients treated with PMT, an initial injection of urokinase (300,000 units) using power-pulse mode was performed. The injection site covered the entire thrombus, and the waiting time was 30 min. Following thrombolysis, AngioJet rheolytic thrombectomy (Solent Omni USA Boston Scientific) was used for thrombus aspiration in the direction from the distal end to the proximal end with an aspiration rate of 2 mm/s. The AngioJet rheolytic thrombectomy could be repeated if the residual thrombus caused >30% stenosis of the veins, and the longest effective working time was limited to 480 s. After thrombus aspiration, CDT was used as described above. All patients were continuously pumped with urokinase (600,000 units/24 h) through a thrombolytic catheter upon return to the ward.

During thrombolysis, the fibrinogen level and activated partial thromboplastin time were examined every day. If the fibrinogen level decreased to <1.5 g/L, the amount of urokinase administered was halved; when the fibrinogen level was <1.0 g/L, the thrombolysis was temporarily paused. Lower limb venography was performed using a thrombolytic catheter to evaluate the effects of the thrombolysis every 24 to 48 h. When one of the following indications occurred, the thrombolysis was stopped¹⁰: (1) the symptoms of the affected limb disappeared or had significantly subsided, and the angiography results confirmed that the thrombus had disappeared, (2) there was no significant change in the range of the thrombus in two consecutive reexaminations, or (3) severe complications occurred during the CDT process. If angiography reexamination showed that the residual stenosis was >50% after iliac vein thrombolysis, balloon expansion was performed.¹¹ If the residual stenosis was still >50% after balloon expansion, then stent (14 mm×80 mm, SMART Flex Cordis; 14 mm×140 mm, Zilver USA Cook) implantation was performed in the lesion segment. If a stenotic lesion was found at the junction of the IVC and the common iliac vein, the proximal segment of the stent was extended approximately 0.5 cm into the IVC. After stent implantation, if angiography reexamination showed that the vascular wall was rough and the blood flow was relatively slow, then the thrombolytic catheter was left in, and the thrombolysis was continued for another 24 h.

The IVC filter was retrieved after CDT treatment finished within the retrieved time window of the filter for all patients. The patients received rivaroxaban at a dosage of 15 mg bid orally and 20 mg qd after 20 days or warfarin anticoagulant therapy, and the international normalized ratio (INR) was controlled between 2 and 3 until the end of the six-month follow-up. At the end of anticoagulant treatment, patients undergoing iliac-femoral stenting began life-long, daily low-dose (100 mg) consumption of aspirin. Furthermore, all patients wore elastic compression stockings (30–40 mm Hg) for at least one year.

Evaluation and follow-up

The primary endpoints of this study were the clinical efficacy rate of thrombolysis, primary patency, and the incidence of PTS at 12 months. Secondary endpoints were the total urokinase dose, the thrombolysis time, the detumescence rate and complications. The proportion of thrombolysis was judged by venous angiograms and graded as follows: grade I for a free lumen diameter < 50%, grade II for a free lumen diameter between 50% and 99%, and grade III indicated 100% lysis, without residual thrombus. Lysis grades II and III (i.e. at least 50%) were considered clinical efficacies of the thrombolysis.^12,13 Primary patency is defined as the absence of thrombosis recurrence or any repeat intervention during the follow-up period. As the most frequent complication of DVT, PTS was evaluated by the Villalta score of 5 or higher. The Villalta measures and venograms were read by two experienced vascular specialists (CY and BRF) with more than five years of experience in vascular radiology.

Limb circumference was measured at 15 cm above the knee on both sides of the lower extremity daily following admission by the nurses with more than five years working experience. The detumescence rate was determined as follows: (limb circumference difference before lysis minus limb circumference difference after lysis)/limb circumference difference before lysis × 100%. The dose of urokinase used and the period of treatment were recorded. Complications were classified as major bleeding, minor bleeding, catheter-related infection, hemoglobinuria, acute kidney injury (AKI), symptomatic PE, and death. Major bleeding was defined as a decrease in the hemoglobin level by >20 g/L, overt hemorrhage that led to hemodynamic disorder, cerebral hemorrhage, or massive hemorrhage of the digestive tract. Other bleeding events and local ecchymoma were classified as minor bleeding. According to the criteria for detecting postoperative AKI, AKI was defined as an absolute increase in the sCr concentration of ≥26.4 μmol/L (0.3 mg/dL) or a ≥50% increase from baseline within 48 h after operation.^14–16 Hematuria was judged by visual inspection and urine occult blood test results. Patency and thrombosis recurrence were assessed by ultrasound or angiography at 1, 3, 6 and 12 months.

Statistical analysis

SPSS 23.0 software was used for all statistical analyses in this study. Measurement data with normal distributions are represented as the means ± standard deviations (SDs). Comparison of measurement data was performed with Student’s t-test. Comparison of continuous data was performed with Fisher’s exact test or the Chi-square test. The primary patency and cumulative incidence of PTS were estimated with Kaplan–Meier curves; P-values <0.05 were considered statistically significant.

Results

Baseline demographics and clinical characteristics

A total of 74 patients were included in this study, with 30 patients treated with CDT combined with PMT (PMT group) and 44 patients treated with CDT monotherapy (CDT group). The demographics and characteristics of these 74 patients are summarized in Table 1. There were no statistically significant differences between the two groups for any of the demographics and clinical characteristics (all P > 0.05).

Table 1.

Patient demographics and characteristics.^a

Variable	PMT+CDT	CDT	P value*
N	30	44
Age, years	61.40±14.38	63.77±11.56	0.44
Gender, n (%)
Male	18 (60.00)	23 (52.27)	0.51
Female	12 (40.00)	21 (47.73)
Symptom duration, days	17.5±3.72	18.93±3.58	0.10
Thrombus site, n (%)
Left	20 (66.67)	31 (70.45)	0.73
Right	9 (30.00)	11 (25.00)	0.63
Bilateral	1 (3.33)	2 (4.55)	0.80
Predisposing factors, n (%)
Surgery history	10 (33.33)	13 (29.55)	0.73
Cancer	3 (10.00)	5 (11.36)	0.85
Hypercoagulable state	2 (6.67)	3 (6.82)	0.98
Oral administration of contraceptives	1 (3.33)	2 (4.55)	0.80
May–Thurner syndrome	12 (40.00)	17 (38.64)	0.91
Unknown reason	2 (6.67)	4 (9.09)	0.71

Continuous data are presented as the means ± standard deviation; categorical data are given as the counts (percentage).

Chi-square test and Fisher exact test were used.

PMT: percutaneous mechanical thrombectomy; CDT: catheter-directed thrombolysis.

Clinical efficacy outcomes at the end of the procedure

In all patients, the technical success rate was 100%. All patients underwent IVC filter placement before treatment, and all filters were successfully removed without complications. The clinical efficacies of the lysis for the PMT group were 86.67% (26/30) and for the CDT group was 65.91% (29/44); the difference was statistically significant (P = 0.045, Table 2). The primary patency was 93.3% (28/30) and 88.6% (39/44), respectively, in the two groups at the 12-month follow-up, and the results were not statistically significant (P = 0.694, Figure 1). Patients with DVT recurrence were treated with CDT. The reason for thrombus recurrence was inadequate anticoagulation time in two cases, cancer in three cases, and protein C and protein S deficiency in two cases. The incidences of PTS were 20% (6/30) and 29.55% (13/44), respectively, in the two groups at the 12-month follow-up, but the results were not statistically significant (P = 0.852, Figure 2).

Table 2.

Comparison of the clinical efficacy and complications in the two groups.

Variable	PMT+CDT (N = 30)	CDT (N = 44)	P value*
Limb circumference above knee, cm
Before lysis	3.97 ± 1.63	3.80 ± 1.69	0.67
After lysis	1.33 ± 1.03	1.31 ± 1.14	0.95
Detumescence rate (%)	66 ± 26.10	62.95 ± 28.72	0.06
Thrombolysis grade, n (%)
I	4(13.33)	15(34.09)	0.045
II	15(50.00)	22(50.00)	0.99
III	11(36.67)	7(15.91)	0.04
Clinical efficacy lysis rate	26(86.67)	29(65.91)	0.045
Complications, n (%)
Major bleeding	0	0	–
Minor bleeding	2(6.67)	3(6.82)	0.98
Puncture site bleeding	2(6.67)	2(4.55)	0.66
Gingival bleeding	0	1(2.27)
Hemoglobinuria	5(16.67)	0	–
AKI	3(10.00)	1(2.27)	0.15
Infections	1(3.34)	2(4.55)	0.8
Symptomatic PE	0	0	–
Death	0	0	–

Chi-square test and Student’s t-test were used.

PMT: percutaneous mechanical thrombectomy; CDT: catheter-directed thrombolysis; AKI: acute kidney injury; PE: pulmonary embolism.

Figure 1.

A Kaplan–Meier curve showing the primary patency rates during follow-up.

Figure 2.

A Kaplan–Meier curve showing the cumulative incidence of post thrombotic syndrome (PTS) during follow-up.

The differences in preoperative and postoperative limb circumference for the two groups are presented in Table 2. The detumescence rate of the PMT group was higher than that of the CDT group, but the difference was not statistically significant (P = 0.06). The mean total CDT times and the doses of thrombolytic drugs for patients who underwent PMT+CDT were lower compared with patients who underwent CDT, and the difference was statistically significant for the grade II and grade III groups (Table 3). After successful lysis, there were 12 and 17 cases of iliac vein stenosis in the two groups, respectively, and all patients with iliac vein stenosis were treated with angioplasty and stenting.

Table 3.

Comparison of the thrombolysis time and drugs between the two groups.

Variable	PMT+CDT	CDT	P value*
Thrombolysis grade I
CDT times days（±SD）	3.63±0.35	4.61±1.03	0.08
Dose of thrombolytic（±SD）	212.5±51.23	228±65.16	0.67
Thrombolysis grade II
CDT times days（±SD）	3.01±0.81	4.14±0.79	<0.001
Dose of thrombolytic（±SD）	172.67±36.93	204.45±48.62	0.04
Thrombolysis grade III
CDT times days（±SD）	2.20±5.77	3.11±0.80	0.01
Dose of thrombolytic（±SD）	135±29.79	172.86±44.61	0.048

Student’s t-test was used.

PMT: percutaneous mechanical thrombectomy; CDT: catheter-directed thrombolysis; SD: standard deviation.

Complications after procedure

Five minor bleeding complications were reported: puncture site bleeding in four patients and gingival bleeding in one patient. The incidences of minor bleeding complications were 6.67% and 6.82%, respectively, and the difference was not statistically significant. Five patients developed gross hemoglobinuria the day after AngioJet rheolytic thrombectomy and recovered within 24 h following hydration and urine alkalization. Acute kidney injury (AKI) developed in 3 of the 30 patients in the PMT group and in 1 of the 44 patients in the CDT group. The incidence of AKI in the PMT group was higher than that in the CDT group (10.00% vs. 2.27%), but the difference was not statistically significant. There were two cases of puncture-related infections and one case of catheter-related infections. All infections were cured by antibiotic therapy and removal of the catheters. There were no serious complications related to the treatments between the two groups, such as major bleeding, symptomatic PE and death (Table 2).

Discussion

The study demonstrated that both CDT monotherapy and CDT combined with PMT were effective and safe treatment modalities for treating subacute iliofemoral DVT. Compared with CDT monotherapy, PMT combined with CDT has no advantage in reducing the incidence of thrombosis recurrence and PTS at the 12-month follow-up. PMT combined with CDT performed better in removing vein thrombi, reducing urokinase doses, and shortening thrombolysis times.

Currently, the clinical staging of DVT differs across various research institutions and guidelines.^3,13,17–19 The staging is mainly determined based on the onset time of the patient’s clinical symptoms and the examination results of ultrasonography and/or digital subtraction angiography (DSA),³ which may cause inaccuracy of staging and prognostic evaluation. At present, the determination of the age of the thrombus is still in the exploratory stage. In this study, we adopted the SIR reporting standard to determine staging.

There are large randomized studies investigating catheter-based therapies for acute DVT. In the CAVENT trial demonstrated, the PTS rate at 24 months was lower in the CDT group than in the group treated with anticoagulation alone (41.1% vs. 55.6%; P = 0.047).⁶ Although the ATTRACT trial failed to prove that the incidence of PTS at 24 months can be reduced by PCDT, the subgroup analysis of the ATTRACT trial demonstrated that PCDT lead to improvement in the quality of life.^8,20 Besides, The CAVA trial showed that CDT does not change the risk of PTS at 12 months compared with the standard therapy alone. Nevertheless, the incidence of PTS in CDT group and standard therapy group was 29% and 35% respectively; the outcome suggests the possibility of a moderate beneficial effect with CDT.²¹ To date, few studies have reported treatment comparisons between CDT and PMT monotherapy for subacute DVT.¹⁹ Furthermore, whether PMT combined with CDT may improve thrombosis efficiency and decrease the incidence of PTS is uncertain, since there have been no studies comparing the treatment efficacy and safety of CDT monotherapy and CDT combined with PMT for subacute iliofemoral DVT. In this study, we aimed to compare the treatment efficacy and safety of CDT monotherapy and CDT combined with PMT for treating subacute iliofemoral DVT. In our study, the mean total CDT time and the dose of thrombolytic drugs for those who underwent CDT+PMT were lower compared with those who underwent CDT monotherapy, and the difference was statistically significant in the grade II and grade III groups. Our results are comparable with previous publications, although the patients in these studies all had acute DVT.²²

In addition, the clinical efficacies of lysis for the PMT group were 86.67% (26/30) and for the CDT group was 65.91% (29/44) in our study. Our results are not quite comparable to those reported by Lin et al.²³ Compared with the PEARL data, the clinical efficacy of lysis of PCDT is higher than the efficacies reported in our study.²⁴ The reason for this is that the PEARL data were obtained primarily from acute DVT patients, where the thrombus was relatively immature. In addition, t-PA and rt-PA are not on-label for DVT thrombolytic therapy in China; instead, urokinase-based thrombolytic drugs are mainly used. This might still lead to inadequate treatment effects since the thrombolytic effect of urokinase is affected by the thrombosis duration.

According to several previous studies, the major drawback of CDT therapy is hemorrhagic complications, which have been related to prolonged treatment duration.^13,25 In our study, we did not observe any major bleeding complications, probably due to the small sample size, a shorter thrombolysis time compared with previous studies, and the daily measurement of the fibrinogen level. In addition, Yang et al.¹⁶ reported that patients with acute iliofemoral deep venous thrombosis who underwent PMT using AngioJet had an increased risk of postoperative acute kidney injury (AKI) compared with those who underwent CDT. Fortunately, the incidences of AKI between the two groups were 10% and 2.27%, respectively, in our study and were not statistically significant. The reason may be that the sample size was small and that the AngioJet aspiration time and volume were lower than those reported in other studies. Nevertheless, there have been some retrospective studies reporting postoperative AKI in patients who had received PMT^16,26,27; therefore, our medical staff should be aware of potential postoperative AKI to detect and manage it in time.

At the 12-month follow-up, the incidences of PTS were 20% (6/30) and 29.55% (13/44) in the PMT group and the CDT group, respectively, and the results were not statistically significant. The results were different from those reported in the Huang study, who thought that PMT provides similar treatment success compared with CDT for acute DVT but with a lower risk of PTS at the 12-month follow-up.²⁸ The reason for this difference may be that the follow-up time was short and that our patients had subacute DVT. Besides, Rolf et al.²⁹ have been reported that venous stenting seems to reduce the incidence of the PTS by improving long-term patency rates. In our study, the ration of stent placement in the two groups was not statistically significant (P = 0.91). Further research is warranted to determine whether stent placement influences the outcomes of the two methods. Furthermore, as we previously reported, the clinical efficacy of the lysis of the PMT group was 86.67%, which is significantly better than the 65.91% for the CDT group. Therefore, we predict that the PMT group may have a lower incidence of PTS and a better prognosis of long-term efficacy than the CDT group, but this requires further follow-up and observation. Although the initial results of this study did not indicate complete thrombus clearance, the mid-term results were satisfactory. The primary patency were 93.3% in PMT group and 88.6% in CDT group at the 12-month follow-up, which is in accordance with that reported by Song et al.¹⁹

This study has several limitations. (1) The DVT staging was mainly based on the onset time of clinical symptoms and the imaging data from ultrasonography and (or) DSA, and so our sample may have included chronic patients whose clinical symptoms were delayed. (2) The grouping was not random but was mainly based on patient willingness and economic ability in our department, which may have had an impact on the evaluation of the efficacy of DVT. (3) Some venograms were obtained after stent placement, this may influence the assessment of the efficacy of thrombosis in the two methods. (4) The 12-month follow-up was short. (5) This was a single-center, retrospective, non-randomized controlled study; the conclusions of the present study are limited as a result of the small, retrospective nature of the analysis. In the future, a prospective, randomized controlled study will be needed to further confirm the conclusions.

In conclusion, both CDT monotherapy and CDT combined with PMT are effective and safe treatment modalities for subacute iliofemoral DVT. Compared with CDT monotherapy, CDT combined with PMT performs better in removing vein thrombi, reducing urokinase doses, and shortening thrombolysis times.

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

Approved by First Affiliated Hospital of Soochow University ethics committee.

Guarantor

DP.

Contributorship

XY, HB and CX were involved in data collection; XY, HB, WX and FB took part in data analysis; ZB, YC, JY, NC and DP took part in the study design; and XY, ZB, and YC were involved in the writing of the manuscript.

ORCID iD

Yi-Ding Xu

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