Endovascular management of proximal lower limb deep venous thrombosis – A prospective study with six-month follow-up

Abstract

Background

Catheter-directed thrombolysis with assisted mechanical thrombolysis is the standard of medical care for proximal deep vein thrombosis. We studied the immediate and intermediate (six months) safety and effectiveness of catheter-directed thrombolysis in patients with proximal lower limb deep vein thrombosis.

Methodology

Thirty consecutive patients aged between 20 and 70 years with proximal lower limb deep vein thrombosis formed the study group. Catheter-directed thrombolysis was done with streptokinase infuse through a catheter kept in the ipsilateral popliteal vein. Unfractionated heparin was given along with streptokinase. Mechanical thromboaspiration using guiding catheter was performed in addition to thrombolytic therapy. After six months, post-thrombotic syndrome and deep venous patency were assessed by using Villalta scale and duplex ultrasound, respectively.

Results

Thirty patients with proximal lower limb deep vein thrombosis were treated with catheter-directed thrombolysis. Mean age of the study patients was 41.7 ± 15 years. Mean duration of illness was 13.3 ± 12 days. The mean duration of thrombolysis was 4.5 ± 1.3 days. Grade III (complete) lysis was achieved in 10 (33%) and Grade II (50–90%) lysis in 20 (67%) of patients. Patients with significant residual lesion in Grade II lysis following catheter-directed thrombolysis underwent percutaneous transluminal angioplasty alone (12/20) or venous stenting (8/20). All patients improved clinically following catheter-directed thrombolysis or assisted catheter-directed thrombolysis. Four patients (13%) developed pulmonary embolism during course of hospital stay and among them two (6.5%) patients died. Eleven patients (37%) had minor bleeding or hematoma at local site, and seven (23%) developed anemia requiring blood transfusion and four (13%) patients had thrombocytopenia. After six months, iliofemoral patency was found in 20 (72%) and post-thrombotic syndrome was seen in six (21%) patients. Two (6.5%) patients died during follow-up due to nephrotic syndrome and carcinoma breast.

Conclusion

Catheter-directed thrombolysis and conventional manual aspiration thrombectomy are an effective treatment for proximal lower extremity deep vein thrombosis with good short and intermediate outcome.

Keywords

Catheter-directed thrombolysis deep vein thrombosis iliofemoral post-thrombotic syndrome streptokinase

Introduction

Deep vein thrombosis (DVT) along with its clinical sequelae represents a major health care challenge. DVT is a significant cause of morbidity and mortality in the general population.^1,2 It is the third most common cardiovascular pathology after coronary artery disease and stroke, and its incidence is expected to rise over the next decade due to the increasing elderly population and increased exposure of the population to predisposing factors for DVT such as hospital admission, oral contraceptives, pregnancy, obesity, and long distance travel.^3,4 Patients with symptomatic lower extremity venous thromboembolism (VTE), particularly the iliofemoral DVT, are among those who are more likely to develop lifelong adverse clinical consequences as well as being the most frequently hospitalized for treatment.⁵ Proximal (above the knee) DVTs account for 80% of all symptomatic DVTs.⁶ The treatment of VTE has advanced significantly in recent years.⁷ Between 20% and 80% of patients develop post-thrombotic syndrome (PTS) despite adequate anticoagulation therapy.⁸ In venous thromboembolic disease, catheter-directed thrombolysis (CDT) with or without assisted mechanical thrombolysis is becoming the standard of medical care in the treatment of acute and sub-acute proximal DVT.⁹ Anticoagulation therapy is ineffective at removing thrombus of the deep venous system, and when extensive, DVT carries a high risk of developing pulmonary thromboembolism (PTE) and PTS.¹⁰ To avoid the complications, aggressive therapy to remove the venous thrombus/venous obstruction must be undertaken.¹¹ Endovascular management using percutaneous mechanical thrombectomy alone or in combination with pharmacological thrombolytic agents has recently received attention amongst the clinicians as a safe and effective means for the treatment of acute proximal DVT.^12,13 This study was performed to evaluate the safety and efficacy of CDT in the management of proximal lower limb DVT.

Materials and methods

Primary endpoint

Primary endpoint of this study was to evaluate the safety and efficacy of CDT and manual thromboaspiration in proximal lower limb DVT.

Secondary endpoint

Technical success of CDT, defined as complete lysis of the thrombus of the vein,

Thrombolysis-induced hemorrhagic complications,

Duration of hospital admission.

Study design

It was a prospective, non-randomized study conducted between 2011 and 2013 at Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, India, which is a 600 bed single speciality tertiary care hospital dedicated to cardiology and cardiovascular surgery. The study design was approved by the institute’s ethics committee and all patients provided written informed consent.

Patients

All patients with proximal lower limb iliofemoral DVT who met the inclusion criteria were included in this study.

Eligibility criteria

Inclusion criteria

Men and women between 20 and 70 years of age

Patients with recent (between 1 and 8 weeks) lower limb proximal DVT

Patients understand the nature of the procedure and provide written informed consent before enrollment in the study.

Exclusion criteria

Patients with DVT of more than eight weeks

Patients for whom antiplatelet therapy, anticoagulants, or thrombolytic drugs are contraindicated

Recent (<6 weeks) ischemic stroke or cerebral bleeding

Patients with recent (<6 weeks) major surgery

Severe uncontrolled hypertension (diastolic blood pressure greater than 110 mm Hg, systolic blood pressure greater than 200 mm Hg)

Patients with a history of prior life-threatening reaction to contrast medium

Patients with uncorrected bleeding disorders (gastrointestinal ulcer, menorrhagia, liver failure)

Patients considered hemodynamically unstable at the onset of the procedure

Patients who refuse treatment

Patients younger than 20 years or older than 70 years

Hemoglobin <9 mg/dl, INR >1.6 before warfarin is initiated, and platelet count <100,000/ml.

Adverse and serious adverse events

Adverse events (AE) were defined as any undesirable experience occurring to a participant during the study, whether or not considered related to the investigational drug or intervention. This definition includes events occurring during the hospital stay or until 30 days of follow-up.

Underlying disease that was present at the time of enrollment was not reported as an AE, but any increase in the severity of the underlying disease was reported as an AE.

All AEs were monitored from the time of enrollment through the 30-day follow-up visit.

Clinical events which were considered and reported as serious AEs include:

Death

Myocardial infarction

Acute pulmonary embolism

Stroke

Bleeding complication requiring interruption or ending of thrombolysis

Bleeding complication requiring surgical intervention

Bleeding complication or blood loss during CDT with mechanical thromboaspiration requiring transfusion.

Clinical events to be considered and reported as minimal AEs include:

Groin hematoma,

Bleeding complication not requiring interruption or ending of thrombolysis, surgical intervention.

Written proformas were filled up during inclusion of patients which contained epidemiological information (age, sex, occupation, and place), questionnaires for risk factor evaluation (smoking, drug history, malignancy, co-morbid condition, and hyper-coagulable state), and information of the clinical examinations (limb involvement).

Investigations

All patients were investigated with the following tests:

Complete blood count

Bleeding time (BT), clotting time (CT), prothrombin time (PT), and activated plasma thromboplastin time (aPTT)

Renal function test, liver function test

Work up for hyper-coagulation state

Duplex venography/ultrasound abdomen.

Intervention

In our study, popliteal vein and/or femoral vein cannulation under ultrasound guidance was done to access the lesion in the same limb which was affected by DVT. Peripheral angiogram was done in this group through popliteal vein approach. At the start of CDT, an intravenous bolus dose of unfractionated heparin (UFH), 5000 U, followed by a continuous intravenous UFH infusion at the rate of 1000 U/h was given through the side port of the sheath.¹⁴ At first, thrombus was manually aspirated by using Judkin’s right guiding catheter (JR 3.0 8F, Cordis) and then CDT was done through multipurpose catheter into the region of the thrombus with streptokinase (STK) infusion. The STK was continued till satisfactory lysis of the clot was achieved. Two-third of the total doses of STK (1 lakh units/h) was given upfront through the catheter and other one-third of STK was given through the side port of popliteal venous sheath to bath the clot along the catheter. UFH was also infused through the side port of the sheath. Check angiogram was done every 24-h to assess the clot burden and efficacy of treatment. The difference between the pre- and post-lysis thrombus scores divided by the pre-lysis score gave the grade of thrombolysis; Grade I ≤ 50%; Grade II = 50–90%, and Grade III = complete thrombolysis.¹⁵ In those who had partial response to CDT and residual venous obstruction, additional percutaneous transluminal angioplasty (PTA) and or stenting of iliac vein was performed. Patients were managed in critical care unit till the end of thrombolytic therapy.

Oral anticoagulant

Patients received oral warfarin or Nicoumalone for six months (where predisposing factors were present) or for indefinite period (where predisposing factors were absent or following venous stenting), after completion of CDT. The International Normalized Ratio (INR) was maintained within 2–3.¹

Follow-up

Patients were followed up during their hospital stay, at the end of first month and after six months following CDT. After six months, patency of the deep venous system was investigated by using duplex ultrasound. The PTS was assessed using the Villalta scale, which consists of five patient-rated venous symptoms (pain, cramps, heaviness, paresthesia, and pruritus) and six clinician-rated physical signs (pretibial edema, skin induration, hyperpigmentation, pain during calf compression, venous ectasia, and redness). Each is rated on a four-point scale (0 – none, 1 – mild, 2 – moderate, and 3 – severe). Points were totaled to produce an overall score (range, 0–33). Subjects were classified as having PTS if their score was >5 or if a venous ulcer developed in the leg with DVT.¹⁶ The Villalta scale is a reliable, validated, and responsive measure of PTS.¹⁷

Results

Thirty patients with proximal lower limb DVT received CDT and mechanical thromboaspiration. Among these 30 patients, two patients died during hospital stay due to suspected massive pulmonary embolism. Twenty-eight patients were followed up prospectively; data were collected, compiled, and analyzed.

Baseline demographic profile (Table 1)

The mean age of study patients was 41.7 ± 15 years, and Male:Female ratio was 1 : 1. Mean duration of symptoms at presentation was 13.3 ± 12 days. The most common risk factor of our patients was prolonged bed rest mostly due to trauma or fracture of lower limb (20%) and postpartum period (20%). Obesity/dyslipidemia and diabetes were seen in 16% of cases. Thirteen percent of study patients were smokers and 6% patients had history of malignancy and another 6% patients did not have any obvious reason for DVT. In our study, 67% (20/30) patients had involvement of right lower limb, 17% (5/30) had involvement of left lower limb, and 16% (5/30) had involvement of both lower limbs (Table 1). Twenty-three percent (7/30) of our patients had extension of DVT up to inferior vena cava (IVC) and/or renal vein (three patients).

Table 1.

Baseline demographic and clinical profile of study groups.

Variable	n = 30
Age (mean, range)	41.7 ± 15 years; 20–70 years
Sex (M:F)	15:15
Risk factors
MI/LVD	2 (6%)
Smoking	4 (13%)
Diabetes	5 (16%)
Tumor/malignancy	2 (6%)
Trauma/fracture/prolonged bed ridden	6 (20%)
Pregnancy/postpartum	6 (20%)
Obesity/dyslipidemia	5 (16%)
Nephrotic syndrome	1 (3%)
Idiopathic	2 (6%)
Duration of symptoms (mean, range)	13.3 ± 12 days, 2–60 days
Affected limb
Left	05 (16.5%)
Right	20 (67%)
Bilateral	5 (16.5%)
IVC/renal vein involvement	7 (23%)

IVC: inferior vena cava.

Short-term (in hospital and at discharge) treatment outcome after CDT

Mean duration of CDT with STK infusion was about 4.5 ± 1.3 days, and the average dose of STK given to a patient is about 11 million units. All of our patients received CDT along with mechanical thromboaspiration which was done just prior to and during thrombolytic therapy. Thirty-three percent of patients had Grade III lysis, and 67% patients had Grade II lysis at the end of only CDT. Additional PTA along with CDT and mechanical thrombectomy was done in 40% (12/30) patients who had residual stenosis with partial clot lysis. These patients received CDT for another 24–48 h. All these cases improved clinically following PTA-assisted CDT with good venous patency. PTA and venous stenting were done in 27% (8/30) patients who had persistent symptomatic venous obstruction following PTA-assisted CDT. Three of our study patients had May–Thurner syndrome which was diagnosed angiographically and in these cases PTA and stenting of left common iliac vein were done successfully. Five patients with right sided proximal venous residual obstruction underwent successful stent implantation. In all eight patients who underwent venous stenting had immediate relief of obstruction with good venous run off. Among seven patients those who had thrombus extension into IVC, five received IVC filter implantation prior to mechanical thromboaspiration and CDT (Table 2).

Table 2.

Short-term (in hospital and at discharge) treatment outcome after CDT.

Variable	Value	Patency rate (>90% clearance) at six months by duplex venography (n = 20)
Duration of CDT, h (mean, range)	4.5 ± 1.3 days; 2–7 days
Dose of streptokinase (mean, range)	11 m.u; 4–17 m.u
Immediate lysis grade after CDT + mechanical thrombectomy (n = 30)
Grade I	0 (0%)	0 (0%)
Grade II	20 (67%)	12 (60%)
Grade III	10 (33%)	8 (80%)
Further intervention
Only CDT	10 (33%)	8 (80%)
CDT + PTA	12 (40%)	6 (50%)
CDT + PTA and stenting	8 (27%)	6 (75%)
CDT + IVCF implantation	5 (21%)
Adverse events
SAE
1. Death	2 (6%)
2. Pulmonary embolism	4 (13%)
3. Anemia requiring blood transfusion	7 (23%)
MAE
1. Local site bleeding/hematoma	11 (37%)
2. Anemia not requiring blood transfusion	4 (13%)
3. Thrombocytopenia	4 (13%)

PTA: percutaneous transluminal angioplasty; IVC: inferior vena cava; m.u: million units; CDT: catheter-directed thrombolysis.

AE of CDT

Among the serious AE as per definition in our study, four (13%) patients developed clinical features of acute pulmonary embolism during CDT and among them two patients had confirmed diagnosis by CT pulmonary angiogram. Two patients who died suddenly were diagnosed to have suspected acute pulmonary embolism. Both of them were elderly female (age > 65 years) and one of them was treated previously for breast carcinoma. Both these patients did not have thrombus extension into IVC and IVC filter was not implanted. About 23% (7/30) patients received blood transfusion as they had significant blood loss during mechanical thrombosuction with drop of hemoglobin >2–3 gm/dl from baseline to a value of total hemoglobin less than 8 gm/dl. Among minor AE, 37% patients had local site bleeding or hematoma and 13% had anemia not requiring blood transfusion. About 13% of patients had thrombocytopenia without requirement for platelet transfusion which started after a median of four days after initiation of treatment, possibly related to continuous infusion of UFH (Table 2).

Efficacy outcome at six months after follow-up

After six months of follow-up, 72% of patients after CDT had patent lower limb veins diagnosed through duplex venography. PTS diagnosed by Villalta scoring system was seen in 21% of study patents. Another two patients died within six months of follow-up from non-cardiac causes. One of them was suffering from nephrotic syndrome and another patient had malignancy. Among 10 patients who received only CDT and mechanical thromboaspiration, eight of them had venous patency and another two patients died following CDT. Among 12 patients who underwent PTA without venous stenting, only six (50%) patients had venous patency, five patients developed PTS, and one patient died during follow-up due to nephrotic syndrome. Eight patients who underwent PTA and venous stenting, six (75%) had patent vein during follow-up, one patient expired due to malignancy and one patient had stent restenosis during follow-up (Table 3).

Table 3.

Final clinical outcome at six months’ follow-up.

Variable	n = 28
Total death	2 (7%)
Venous patency (>90% clearance) at six months	20 (72%)
PTS (Villalta score >5)	6 (21%)

PTS: post-thrombotic syndrome.

Discussion

Early thrombus debulking by CDT and/or mechanical thromboaspiration is currently standard of care in the management of proximal DVT. CDT and mechanical thromboaspiration have shown promising results, rapid removal of clot burden, and decreased incidence of PTS and PTE, though currently considered as 2B recommendation due to lack of randomized control studies.¹ About 25–82% of patients with iliofemoral DVT treated with anticoagulants alone suffered from the PTS.⁸ CDT has been performed by using either urokinase or alteplase as thrombolytic agents; we report our experience with STK as thrombolytic agent for treatment of proximal DVT.¹¹ Systemic use of thrombolytic agents has been shown to be no more effective than heparin in achieving clot lysis.² The use of local and regional thrombolysis (infusing the thrombolytic agent in a dorsal foot-vein or popliteal vein) demonstrated significantly fewer clinical symptoms of PTS with fewer complications due to thrombolytic agents.¹¹ CDT therapy has been studied recently and has been shown to be safe and effective in achieving early, intermediate, and long-term venous patency.^18–22 The ipsilateral popliteal venous approach is preferred because it is often difficult to penetrate an occluded superior iliofemoral vein from the internal jugular vein or the contralateral common femoral vein, and venous valves may prevent safe catheterization.¹¹ This approach also clears the distal veins. Among the 12 studies in a systematic review on thrombolysis for acute DVT, only six reported on patency after six months, including one study on local administration of a thrombolytic agent. In the six studies combined indicated patency in 43% after thrombolytic therapy vs. 17% in the control group, and the trial of Elsharawy and Elzayat reported complete lysis in 72% after CDT.¹¹ Numerous studies have reported positive outcomes for CDT in acute DVT.^12–22 Mewissen et al.¹⁵ documented a complete resolution rate of 31%, a partial rate of 52%, and a failure rate of 17%, whereas other studies have found 6–12 months patency in 38–50% after standard treatment.¹² Three case series on CDT reported six months patency to be 83%, 85%, and 100%.¹¹ These efficacy estimates are consistent with our study findings. In our study, the CDT was successful in the treatment of proximal lower limb DVT. About 33% of patients had complete Grade III lysis and another 67% patients had partial Grade II lysis of clot following CDT and mechanical thromboaspiration which was less than the previous study which used STK as thrombolytic agent¹¹ and other studies like CaVenT study.^12,15 In the present study, patients with partial clot lysis and residual venous obstruction (67%) were further treated with PTA and/or proximal lower limb venous stenting.^11,12,15 Though the early results of CDT were dissimilar to previous studies but final venous patency immediately after assisted CDT and at six months’ was very similar with the previous studies because of PTA and/or stent implantation for residual lesion.¹¹ The study of Elsharawy and Elzayat¹¹ differed from the present study in some aspects though in both studies STK was used. Even though CDT included STK and heparin infusion through local popliteal vein, mean duration of STK infusion was longer in the present study and it was similar to CavenT study where alteplase was used.¹² As our study included patients with DVT up to eight weeks of onset of symptoms compared with <10 days in the previous study so this could be the reason for need of longer duration of thrombolytic infusion and having more number cases with partial clot lysis.¹¹ In our study, only 21% of CDT-treated patients developed PTS which was also comparable with the previous studies.^11,12 In our study, only three (10%) patients had May–Thurner syndrome which was lesser than the previous studies.^11,12 Though numerous devices have been recently developed for pharmacomechanical thrombolysis, we performed a mechanical thrombectomy by manual aspiration using guiding catheters, as newly developed catheters such as the Trellis catheter, the AngioJet system, or an ultrasound incorporating system are not available to us. However, a study by Lin et al.²¹ showed no statistical difference between thrombus removal rates for the pharmacomechanical thrombectomy using the AngioJet system and CDT. Acute pulmonary embolism is a major morbidity of acute DVT.²¹ In our study cohort, we used a retrievable IVC filter (Cordis, Optease) in five (21%) of the patients with thrombus extension into IVC from deep vein to prevent thrombus embolization during the procedures. IVC filter insertion is recommended in patients with a free floating IVC thrombus that is longer than 5 cm.²² The reported complications of CDT are bleeding, pulmonary embolism, and death.²⁰ The incidence of pulmonary embolism in hospital during treatment in our study was 13% (4/30), which was equivalent to previously reported series (10–26%).^22–24 The biggest concern which we observed in the present study was two sudden deaths due to suspected pulmonary embolism. About 23% (7/30) patients had developed anemia due to aspiration of blood and thrombus during mechanical thromboaspiration which required blood transfusion. About 37% of patients developed a minor bleeding complication like oozing from local site or hematoma which was more than the previous studies^11,12 and no case had severe life-threatening bleeding. In contrast to previous studies,¹¹ 13% of patients of our study developed thrombocytopenia after 4–5 days of CDT. This could be due to heparin-induced thrombocytopenia, though none of them required therapy for it. We observed that patients with residual venous obstruction and partial clot lysis who underwent venous stenting had more venous patency (75%) than who underwent only PTA (50%) at the end of six-month follow-up.

Limitation of this study

Firstly, it was a prospective study so chance of selection bias was more. Secondly, sample size in our study was small as it was a single center-based study.

Conclusion

CDT and conventional manual aspiration thrombectomy are an effective and safe treatment for lower extremity proximal DVT. STK infusion can be used safely for CDT up to five days to achieve good results. However, it increases only minor bleeding rate, and addition of UFH infusion can cause thrombocytopenia. For patients with residual venous obstruction and partial clot lysis despite CDT, venous angioplasty with or without stenting increase the acute venous patency rate though during follow-up venous patency was maintained in more number of patients following venous stenting than in patients who underwent PTA only. Patients with high thrombus burden and thrombus extension into IVC need IVC filter implantation prior to CDT. Further randomized control trials are required to assess the long-term venous patency rate following venous stenting vs. PTA in patients with partial lysis following CDT.

Footnotes

Author contributorship

SBC, NCM, and BR were the intervention cardiologists involve with the management in all these cases. NCM planned the study. SP designed the protocol, collected and analyzed the data, reviewed the literatures, and drafted the manuscript. SBC, NA, and MCN corrected the manuscript. All authors approved the final version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

All the authors have no conflict of interest and nothing to disclose.

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