The safety and efficacy of pharmaco-mechanical thrombolysis in lower-extremity deep venous thrombosis

Summary

Objective

The aim of this study was to investigate the impact of accelerated pharmaco-mechanical thrombolysis (PMT) with low-dose second-generation urokinase for the management of cases with lower-extremity deep venous thrombosis (DVT), and to compare its efficacy in subjects with acute and subacute DVT.

Methods

Thirty-five patients with acute (< 15 days) or subacute (15–30 days) DVT who underwent PMT in a tertiary centre were enrolled in this single-arm, prospective study. Following the placement of a temporary vena cava filter, urokinase (200 000 IU) was administered into the occlusion through a multi-hole catheter for 15 to 20 minutes. Control venography was performed to assess venous flow and the rate of acute recanalisation. Percutaneous balloon dilatation and stent placement were carried out in case of a residual iliac vein stenosis of > 50%. Any residual thrombi were suctioned with an aspiration catheter. The primary outcome measures of this study were the percentages of vessel patency and PTS in the third month after PMT.

Results

Complete recanalisation was noted in 23 (66%) patients, while two (6%) had poor recanalisation. The rate of minor complications was 14%. None of the subjects experienced major complications, such as intracranial haemorrhage or pulmonary embolism. No mortality was recorded during the three months of follow up. Control duplex ultrasonography in the third month revealed that the target vein was patent in all subjects. None of the subjects experienced PTS during follow up. In addition, the percentage of acute complete recanalisation was significantly higher in subjects with acute DVT compared to those with subacute DVT (95 vs 27%, p < 0.001).

Conclusion

PMT with an accelerated regimen of low-dose urokinase provided excellent efficacy in the resolution of thrombus and prevented the development of PTS in the midterm when used for the management of lower-extremity DVT.

Pulmonary embolism and deep-vein thrombosis (DVT) are the most common presentations of venous thromboembolism. DVT, which is common in the lower limbs, is characterised by the formation of thrombus in a deep calf vein. The popliteal vein and those proximal to the popliteal vein are affected in more than 80% of subjects with lower-extremity DVT.¹ Further propagation of thrombus is common and leads to several complications through the embolisation of the thrombus or complete occlusion of the relevant vein. The reported incidence of DVT is about 1.6 per 1 000 individuals per year.^2,3

While pulmonary embolism is the most common cause of early mortality associated with venous thromboembolism, chronic thrombotic pulmonary hypertension subsequent to pulmonary embolism may result in long-term morbidity and mortality. On the other hand, post-thrombotic syndrome (PTS), a condition characterised by pain, oedema, swelling and pigmentation has been shown to develop in 25 to 38% of patients with DVT, and results in severe morbidity due to the deterioration in skin integrity.⁴

Inflammatory destruction of the venous valves due to venous incompetence caused by venous obstruction has been proposed as the most probable theory for the development of PTS.⁵ Early removal of the thrombus and restoration of venous flow through systemic use of thrombolytic agents has been shown to prevent venous dysfunction and subsequent PTS.⁶ However, the possibility of major bleeding, especially intracranial haemorrhage, restricts widespread use of systemic thrombolysis in the management of DVT.

It has been shown that three to 6% of subjects treated with intravenous tissue plasminogen activator (TPA) have complications with intracranial haemorrhage.⁷ In contrast to systemic thrombolysis, pharmaco-mechanical thrombolysis (PMT) enables administration of the thrombolytic agent directly into the thrombus with a reduced total dose,⁸ thereby reducing the possibility of systemic complications.⁹ Moreover, systemic thrombolytic agents are delivered to the surface of the thrombus only, whereas PMT enables deep penetration of the thrombolytic agent with relatively low doses.

Our aim was to investigate the impact of accelerated PMT with low-dose, second-generation urokinase for the management of lower-extremity DVT, and to compare its efficacy in subjects with acute and subacute DVT.

Methods

This single-arm, prospective study was conducted on patients with acute (< 15 days) or subacute (15–30 days) DVT who underwent PMT in a tertiary centre between September 2017 and September 2019. Written informed consent was obtained from all participants. The study was approved by the institutional review board and was performed in accordance with the most recent version of the Helsinki Declaration. The study was prospectively registered at clinicaltrials.gov.

Inclusion criteria were as follows: age between 18 and 75 years, having suffered from an iliofemoral or femoropopliteal DVT within the last 30 days, and receiving duplex ultrasonography imaging. Subjects with any absolute contra-indications for thrombolytics, previous contrast allergy, pregnancy, malignancy requiring chemotherapy, those within less than 14 days of surgery, and those with a creatinine clearance rate < 50 ml/min were also excluded.

DVT of the lower limb was confirmed with duplex ultrasonography. Baseline fibrinogen and D-dimer levels were measured in all subjects. All subjects received anticoagulation with unfractionated heparin from admission to discharge.

With ultrasonographic guidance, a 6F sheath was placed into the contralateral femoral vein under local anaesthesia. Temporary inferior vena cava (IVC) filters (Reya Venocat, Biolas, Ankara, Turkey) to the infrarenal IVC were deployed in all patients under fluoroscopic guidance to prevent the risk of clot-fragment embolisation during the procedure. The patient was then placed in the supine position and ultrasonography was used to enter the popliteal vein on the side of the DVT using a 6F sheath. A pre-interventional venogram was obtained to evaluate the location and severity of the thrombus.

A 0.018-inch hydrophilic guidewire (Terumo glidewire, NJ, USA) was used to traverse the thrombotic lesion, followed by the advancement of a catheter with multiple side holes (UniFuse Infusion Catheter; Angiodynamics, Latham, NY, USA) through the guidewire. Doses of 200 000 IU of urokinase were then administered into the occlusion through the multi-hole catheter for 15 to 20 minutes. Control venography was performed to assess venous flow and rate of recanalisation. Percutaneous balloon dilatation and stent placement (Jaguar, Balton Co, Warsaw, Poland) were carried out in cases with residual iliac vein stenosis of over 50%. An aspiration catheter was used to aspirate any remaining residual thrombus.

The IVC filter was retrieved after thrombolysis under fluoroscopic guidance (Fig. 1). Following thrombolysis, subjects were kept on unfractionated heparin, and rivaroxaban (Xeralto) 20 mg/day was initiated and maintained for 12 months. All study subjects underwent a ventilation–perfusion (VQ) scan for detection of the pulmonary embolism during the follow up. All subjects were recommended to use knee-high, elastic compression stockings for 24 months.

Fig. 1.

A: Temporary inferior vena cava (IVC) filters were deployed in all patients to the infrarenal IVC under fluoroscopic guidance to prevent the risk of clot-fragment embolisation during the procedure. B: Entering the popliteal vein on the side with the DVT using a 6F sheath. C: Urokinase was administered into the occlusion through the multi-hole catheter for 15 to 20 minutes. D: Femoropopliteal recanalised venous flow. E: Iliofemoral recanalised venous flow.

Subjects were categorised according to the degree of post-interventional recanalisation as follows: (1) complete recanalisation if the length of the residual thrombus was < 2 cm and venous flow was not limited; (2) partial recanalisation if the length of the residual thrombus was > 2 cm and venous flow was slightly limited by the residual thrombus; (3) poor recanalisation if the venous flow was prominently limited by the residual thrombus. Interventional complications were classified as minor (epistaxis, haematuria, skin ecchymosis) and major complications (pulmonary embolus, intracranial haemorrhage and major bleeding requiring blood transfusion).

All subjects underwent control duplex ultrasonography to evaluate the patency of the relevant vein. Fibrinogen and D-dimer levels were also re-measured. The percentage of vessel patency and PTS development in the third month after PMT were the primary outcome measures of this study.

Statistical analysis

All analyses were performed on SPSS v20 (IBM, Armonk, NY, USA). The Shapiro–Wilk test was used for the normality check. Data are presented as mean ± standard deviation or median (minimum–maximum) for continuous variables, with regard to normality. Comparison of the pre- and post-thrombolysis fibrinogen and D-dimer levels was performed with the paired samples t-test. A two-sided p < 0.05 was accepted as statistically significant.

Results

A total of 35 subjects (mean age 62 ± 14 years, 57% male) with lower-extremity DVT who underwent PMT were enrolled in this study. Baseline characteristics of the study population are presented in Table 1; 57% of the cases were acute DVT (< 15 days) and 77% were in the femoropopliteal region. More than half of the cases were unprovoked DVT.

Table 1. Demographic features and clinical characteristics of the study population (n = 35).

Demographic features	Number (%)
Age, years	62 ± 14
Gender, male	20 (57)
Acute DVT	20 (57)
Location
Iliofemoral	8 (23)
Femoropopliteal	27 (77)
Diabetes	8 (23)
Dyslipidaemia	6 (17)
Smoking	13 (37)
Coronary artery disease	4 (11)
Aetiology
Major surgery	3 (9)
Obstetric conditions	4 (11)
Prolonged immobilisation	8 (23)
Unprovoked	20 (57)

Data are presented as mean ± standard deviation for continuous variables and frequency (%) for categorical variables.

Complete recanalisation was noted in 23 subjects (66%), whereas recanalisation was defined as poor in two (6%). Aspiration thrombectomy was performed as adjunctive technique to remove the residual thrombus in two subjects with poor recanalisation and in seven subjects with partial recanalisation after catheterdirected thrombolysis (CDT). Two patients in the subacute DVT group received stents for residual iliac vein stenosis.

The rate of minor complications was 14%. None of the subjects experienced major complications such as intracranial haemorrhage or pulmonary embolism. No mortality was recorded during the three months of follow up. Control duplex ultrasonography in the third month revealed that the target veins were patent in all subjects. None of the subjects experienced PTS during the three months of follow up.

Comparison of the subjects with acute and subacute DVT is given in Table 2. Subjects with subacute DVT were older than those with acute DVT (70 ± 11 vs 56 ± 14 years, p = 0.003). There were no significant differences between subjects with acute and subacute DVT in terms of risk factors for DVT, aetiology, baseline and third-month fibrinogen and D-dimer levels. Although the frequency of minor complications was slightly higher in those with subacute DVT, the difference did not reach statistical significance. The percentage of patients with acute complete recanalisation was significantly higher in those with acute DVT compared to those with subacute DVT (95 vs 27%, p < 0.001).

Table 2. Comparison of subjects with acute and subacute DVT.

	Acute DVT (n = 20) n (%)	Subacute DVT (n = 15) n (%)	p-value
Age, years	56 ± 14	70 ± 11	0.003
Gender, male	11 (55)	9 (60)	0.767
Dyslipidaemia	4 (20)	2 (13)	0.605
Diabetes	3 (15)	5 (33)	0.201
Coronary artery disease	2 (10)	2 (13)	0.759
Smoking	8 (40)	5 (33)	0.686
Aetiology
Major surgery	3 (15)	0 (0)
Obstetric conditions	3 (15)	1 (7)	0.254
Prolonged immobilisation	3 (15)	5 (33)
Unprovoked	11 (55)	9 (60)
Baseline fibrinogen (mg/dl)	472 ± 114	425 ± 99	0.214
Fibrinogen at 3rd month (mg/dl)	355 ± 85	304 ± 83	0.088
Baseline D-dimer (ìg/ml)	3.4 ± 1.2	4.2 ± 2.4	0.287
D-dimer at 3rd month (ìg/ml)	1.1 ± 0.6	1.8 ± 1.1	0.232
Complete recanalization	19 (95)	4 (27)
Partial recanalization	1 (5)	9 (60)	< 0.001
Poor recanalization	0	2 (13)
Minor complications	1 (5)	4 (27)	0.070
Patency at 3rd month	20 (100)	15 (100)	> 0.999

Data are presented as mean ± standard deviation for continuous variables and frequency (%) for categorical variables.

Discussion

This study aimed to investigate the role of PMT with low-dose urokinase in patients with acute or subacute lower-extremity DVT. Our findings demonstrate that PMT with low-dose urokinase not only provided excellent vessel patency at three months but also enabled safe thrombolysis due to the delivery of lower-dose agents into the thrombus. Notably, with this method, the acute complete recanalisation rate was significantly higher in subjects with acute DVT than those with subacute DVT.

The main therapeutic goals for treating lower-extremity DVT are the preservation of venous valve function and prevention of pulmonary embolism and recurrent DVT. Systemic anticoagulation with low-molecular weight heparin or unfractionated heparin followed by warfarin or new oral anticoagulant agents has been accepted as the standard of care for the majority of the subjects with lower-extremity DVT.¹⁰ In addition, the use of elastic compression stockings is recommended in order to support venous valve function and to prevent PTS development.¹¹ Nevertheless, a considerable number of patients with lower extremity DVT develop PTS and recurrent DVT, despite anticoagulant therapy and the elastic compression stockings.¹²

Theoretically, anticoagulant agents prevent further thrombus propagation but can neither remove the clot nor prevent the sequelae of post-thrombotic alterations.¹³ Given the insufficiency of anticoagulant agents in preventing PTS, the consideration of initial thrombolytic therapy in lower-extremity DVT has attracted attention.

Rapid resolution of the thrombus with systemic thrombolysis in DVT provided promising results concerning the prevention of PTS through the preservation of venous valve function.^14-16 Thrombolytic agents may also prevent the organisation of an occlusive thrombus, thus preventing the development of occlusive disease and venous hypertension. The short-term complete resolution rate of the thrombus with systemic thrombolytic agents is 26 to 67%, and the long-term risk of developing PTS ranges between zero and 80%.17 However, major bleeding, including intracranial haemorrhage and pulmonary embolism are major drawbacks for systemic thrombolytic therapy in DVT.

Pooled analysis of systemic thrombolytic therapy in DVT shows that nine to 13% of subjects receiving streptokinase or TPA for DVT develop major bleeding.^17,18 Moreover, the success of systemic thrombolysis in patients with organised and old thrombus burden is unsatisfactory, most probably due to the limited penetration of the thrombolytic agent into the thrombus.¹⁹

Although pulmonary embolism resulting from systemic thrombolytic therapy is a theoretical concern, Schweitzer et al. reported that 4.5% of their study group, which included patients with leg or pelvic deep venous thrombosis, suffered a pulmonary embolus during systemic thrombolytic therapy.²⁰ The underlying mechanism associating systemic thrombolytic agents and pulmonary embolism is not clear; however, complete removal of a huge thrombus from the vessel wall with systemic application of a thrombolytic agent may be the cause of such a scenario.

Regional thrombolytic therapy, which allows the delivery of the thrombolytic agent directly into the venous thrombus, has emerged in the last few decades as a potentially superior approach in the management of DVT. With this technique, physicians aspire to overcome the main limitations of systemic thrombolysis, such as the unpredictability of thrombolytic effects and the high risk for major bleeding. PMT relies on the administration of low-dose thrombolytic agents directly into the clot while optimising exposure of the lytic agent to the clot by catheters with multiple side holes. The improved penetration of the thrombolytic agent and additional mechanical fragmentation of the thrombus by the administration of the lytic agent through specialised catheters facilitates the complete resolution of the thrombus. The efficacy of PMT in restoring venous patency and reducing symptoms in the setting of acute DVT has been shown in several studies.^9,21

Risk for the development of PTE is negatively correlated with the amount of thrombus remaining at the end of CDT. It has been shown that removal of ≥ 90% of the thrombus significantly reduces the risk for PTS.²² A recent meta-analysis including six trials has reported that compared to CDT, PMT reduced thrombolysis time, length of hospital stay and thrombus score. The meta-analysis also showed that PMT had similar complication rates to CDT.²³ Findings of the recent ATTRACT trial showed that 48% of the patients with lower-extremity DVT who received CDT developed PTS within two years.²⁴

Although long-term follow-up data are lacking, our findings demonstrate a higher efficacy of CDT compared to that of the Venous Thrombolysis Registry. Restoration of forward venous flow was achieved in 94% of our study population, despite the enrollment of a considerable number of subjects with subacute DVT. Supporting the findings of the Venous Thrombolysis Registry, which reported complete lysis of the thrombus in 65% of patients with acute (< 10 days) DVT, the complete resolution rate of the thrombus in acute DVT subjects of our study was significantly higher than those with subacute DVT.

The increased success rate noted in complete resolution of the thrombus in this study compared to previous studies might be associated with technical advances and the use of secondgeneration urokinase, as well as the exclusion of subjects with recurrent DVT. In addition, the vein affected by DVT was patent in all our subjects at mid-term follow up. Moreover, none of the subjects in our study developed PTS, which is closely associated with the forward flow at midterm follow up.

Although head-to-head comparisons of the risk of intracranial bleeding in systemic thrombolysis, PMT and CDT are lacking, it seems to be quite rare with CDT. A pooled analysis of 19 studies revealed a zero to 1% rate of intracranial bleeding following CDT, which is lower than the intracranial bleeding rate reported with systemic thrombolysis.²⁵ The data regarding intracranial bleeding in PMT are limited. None of the subjects enrolled in our study suffered intracranial haemorrhage during the three months of follow up. We consider that the low-dose administration of urokinase with an accelerated regimen (15 to 20 minutes) in our study was the main cause of the lower frequency of intracranial bleeding, compared to previous studies.

With data from our study and previous studies on this topic, we suggest that accelerated PMT with low-dose urokinase can be used in both acute and subacute lower-extremity DVT with high efficacy and safety. Accelerated PMT with low-dose urokinase may completely prevent the development of PTS, at least until midterm follow up.

This study has some limitations. First, it was a prospective but single-arm study. Therefore, we could not provide data comparing the safety and efficacy of other treatments with either anticoagulant alone or with systemic thrombolysis. However, there is sufficient evidence demonstrating the superiority of PMT in terms of safety and efficacy compared to CDT, systemic thrombolysis or anticoagulants. Second, the follow-up period of the study for the outcomes was three months, which is relatively short to reach a clear conclusion regarding the role of PMT on the development of PTS. Further studies with longer follow up are required to address the role of accelerated PMT with low-dose urokinase in patients with lower-extremity DVT.

Conclusions

This study shows that PMT with an accelerated regimen of low-dose urokinase provides excellent efficacy in the resolution of thrombus and prevents the development of PTS within three months when used for the management of lower-extremity DVT. Moreover, the safety of PMT with low-dose urokinase was highly satisfactory as none of the subjects enrolled in this study experienced either intracranial bleeding or pulmonary embolism. Nevertheless, further studies with longer follow up are needed to address the role of accelerated PMT with low-dose urokinase in patients with lower-extremity DVT.