**Endovascular Therapies in Acute DVT**

Jeff Tam and Jim Koukounaras *The Alfred Hospital Australia* 

#### **1. Introduction**

58 Deep Vein Thrombosis

[21] Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants in the

(2011) 46–58

prevention and treatment of thromboembolism. *Pharmacology & Therapeutics* 130

Deep venous thrombosis of the lower limb is a common disease with an incidence of 80 per 10000 (Patel et al 2011) and has potential fatal consequences in the form of pulmonary embolism.

It is usually seen in patients undergoing major surgery particularly orthopaedic surgery, trauma, prolonged immobilisation or hypercoagulable states (such as in the context of malignancy). There are associations with drugs such as the oral contraceptive pill and hormone replacement therapy (tamoxifen) that predispose to hypercoagulability.

#### **2. Pathology and clinical presentation**

Deep venous thrombosis of the lower extremity can occur anywhere from the ankle to the IVC, however it is those that occur between the IVC and femoral veins that most often lead to venous hypertension, resulting in the more severe symptoms. They are also more likely to recur (Vendatham 2006).

The clinical spectrum can range from being completely asymptomatic to post thrombotic syndrome: ulceration, pain, and intractable oedema.

Traditionally, DVTs have been treated with the use of oral anticoagulation medication (such as warfarin) for a period of 6 months. However, this is associated with a high risk for recurrent thrombosis, and approximately one third will develop post thrombotic syndrome despite treatment (Prandoni et al 1996). The recurrence of DVT is thought to be related to damage to the venous valves during an episode of thrombosis and the low rate of recanalisation particularly in caval/iliac/femoral venous thrombosis, which leads to obstruction and venous hypertension. It has been suggested that anticoagulation therapy alone may be inadequate to prevent the damage to the venous valves in the setting of caval/iliac/femoral DVT. Moreover, it has been shown that early thrombus removal is associated with a lower incidence of symptoms related to post thrombotic syndrome (Sharafuddin 2003). These factors have prompted use of invasive techniques such as catheter directed thrombolysis and mechanical thrombectomy, particularly in the acute setting, for thrombus removal.

There are currently two large randomised controlled trials (TORPEDO and ATTRACT) underway investigating the efficacy of these invasive techniques and early results suggest

Endovascular Therapies in Acute DVT 61

phlegmasia cerulea dolens with contraindications to thrombolysis, surgical thrombectomy

In order to effectively deliver the thrombolytic agent, the location and extent of the affected vessels must be elucidated, and this can be performed with ultrasound in the lower extremity. For the central venous system or the peripheral system, a venogram using CT, MRI or angiography can be used, which give a better appreciation of the extent and location

Once the inflow and outflow of the occluded segment is elucidated, the access site can be selected. Early experience with access sites centred on the internal jugular vein (Grosman & Macpherson 1999). However this has technical disadvantages such as the longer route of access causing catheter migration, catheters stimulating cardiac arrhythmias, and difficulty crossing venous valves. In the past, some authors also used the brachial vein and contralateral common femoral vein, which have also fallen out of favour. The ipsilateral popliteal access later became the route of choice for most authors, being easily punctured with ultrasound guidance, having less problems with venous valves, and providing direct access to the thrombosed segment (Grossman, 1998; Sharafuddin 2003). Other common access routes include the common femoral vein (used in iliocaval disease) and posterior tibial vein (for infrapopliteal disease). Occasionally, antegrade and retrograde access is simultaneously used, with the catheters crossed, to treat both up and downstream disease (Molina et al 1992, Raju et al 1998, Tarry et al 1994). In extensive and severe disease, particularly in the calf, selection of the smaller veins with the catheter is extremely difficult, and sometimes impossible, which leads to poor inflow and higher rates of rethrombosis. Comerota (1993) described infusion through the ipsilateral femoral artery to push the thrombolytic agent through the capillary bed and into the small veins of the calf, and potentially improving



Once access is achieved, usually via ultrasound guided micropuncture (Cook Inc, Bloomington, IN) of the popliteal vein, a vascular sheath is inserted (6Fr or larger to allow

may be considered (Sharafuddin 2003).

clearance of thrombosis in those very small veins.


mechanical thrombectomy devices)

The equipment required in CDT includes:



tapered, Bern) - Infusion catheters - Thombolytic agent


of the clot.

that early intervention in the setting of acute DVT is associated with lower recurrence rates, lower incidence of post thrombotic syndrome and lower rates of fatal PE.

Pending the results of these trials however, clinicians should assess the need for invasive measures on a case by case basis, based on the timing of the DVT, associated risk factors for development of DVT, risk factors for thrombolysis related bleeding, age and prognosis of the patient.

#### **3. Endovascular techniques**

The goals of endovascular treatment of acute DVT include: prevention of PE, early symptom relief, and prevention of post thrombotic syndrome (Vendatham 2006).

The endovascular techniques available to achieve these goals include catheter directed thrombolysis, mechanical/rheolytic thrombectomy and stent placement. IVC filters can theoretically be used in conjunction with these techniques to reduce the rate of PE during therapy, although this is controversial.

These techniques require knowledge of, and skills in, ultrasound guided needle punctures, wire and catheter manipulation, thrombolysis drug administration, placement of endovascular stents, and familiarity with the use of various mechanical/rheolytic thrombectomy devices. The specific equipment will vary according to their availability and preference.

#### **3.1 Catheter directed thrombolysis**

Thrombolytic agents activate plasminogen which leads to the breakdown of clot. Systemic thrombolysis results in better short and long term clinical results (Comerota & Aldridge 1993; Gallus AS 1998; Schweizer J, et al 2000; Wells PS 2001) when compared with anticoagulation, but this is at the expense of an increase in serious bleeding and PEs.

Catheter directed thrombolysis (CDT) has developed in response, in an effort to reduce the dose of systemic thrombolytic by delivering the agent at the site of thrombosis, allowing a relative higher concentration to reach the thrombus with a lower systemic dose. This also reduces the duration of the therapy and complication rates. In addition, this technique allows the simultaneous treatment of underlying lesions that are often the cause of the thrombosis itself.

Indications for CDT should focus on patients who ideally are young and active and have a normal life expectancy. In older patients, CDT should be performed in cases of an acutely threatened limb. Both these groups should have acute symptomatic DVT or severe clot burden that involves the IVC. Threshold for thrombolysis in iliofemoral DVT should be lower than that for femoro-popliteal DVT, due to the higher risk of developing post thrombotic syndrome in the former group (discussed in previous sections). Patients who have propagation of clot despite anticoagulation should also be considered for treatment. CDT is most effective when instituted within 4 weeks of thrombosis.

Contraindications are similar to thrombolysis of any site, and include recent major surgery, recent cerebrovascular bleed, recent CPR, pregnancy or coagulopathy. In cases of

that early intervention in the setting of acute DVT is associated with lower recurrence rates,

Pending the results of these trials however, clinicians should assess the need for invasive measures on a case by case basis, based on the timing of the DVT, associated risk factors for development of DVT, risk factors for thrombolysis related bleeding, age and prognosis of

The goals of endovascular treatment of acute DVT include: prevention of PE, early symptom

The endovascular techniques available to achieve these goals include catheter directed thrombolysis, mechanical/rheolytic thrombectomy and stent placement. IVC filters can theoretically be used in conjunction with these techniques to reduce the rate of PE during

These techniques require knowledge of, and skills in, ultrasound guided needle punctures, wire and catheter manipulation, thrombolysis drug administration, placement of endovascular stents, and familiarity with the use of various mechanical/rheolytic thrombectomy devices. The specific equipment will vary according to their availability and

Thrombolytic agents activate plasminogen which leads to the breakdown of clot. Systemic thrombolysis results in better short and long term clinical results (Comerota & Aldridge 1993; Gallus AS 1998; Schweizer J, et al 2000; Wells PS 2001) when compared with

Catheter directed thrombolysis (CDT) has developed in response, in an effort to reduce the dose of systemic thrombolytic by delivering the agent at the site of thrombosis, allowing a relative higher concentration to reach the thrombus with a lower systemic dose. This also reduces the duration of the therapy and complication rates. In addition, this technique allows the simultaneous treatment of underlying lesions that are often the cause of the

Indications for CDT should focus on patients who ideally are young and active and have a normal life expectancy. In older patients, CDT should be performed in cases of an acutely threatened limb. Both these groups should have acute symptomatic DVT or severe clot burden that involves the IVC. Threshold for thrombolysis in iliofemoral DVT should be lower than that for femoro-popliteal DVT, due to the higher risk of developing post thrombotic syndrome in the former group (discussed in previous sections). Patients who have propagation of clot despite anticoagulation should also be considered for treatment.

Contraindications are similar to thrombolysis of any site, and include recent major surgery, recent cerebrovascular bleed, recent CPR, pregnancy or coagulopathy. In cases of

CDT is most effective when instituted within 4 weeks of thrombosis.

anticoagulation, but this is at the expense of an increase in serious bleeding and PEs.

lower incidence of post thrombotic syndrome and lower rates of fatal PE.

relief, and prevention of post thrombotic syndrome (Vendatham 2006).

the patient.

preference.

thrombosis itself.

**3. Endovascular techniques** 

therapy, although this is controversial.

**3.1 Catheter directed thrombolysis** 

phlegmasia cerulea dolens with contraindications to thrombolysis, surgical thrombectomy may be considered (Sharafuddin 2003).

In order to effectively deliver the thrombolytic agent, the location and extent of the affected vessels must be elucidated, and this can be performed with ultrasound in the lower extremity. For the central venous system or the peripheral system, a venogram using CT, MRI or angiography can be used, which give a better appreciation of the extent and location of the clot.

Once the inflow and outflow of the occluded segment is elucidated, the access site can be selected. Early experience with access sites centred on the internal jugular vein (Grosman & Macpherson 1999). However this has technical disadvantages such as the longer route of access causing catheter migration, catheters stimulating cardiac arrhythmias, and difficulty crossing venous valves. In the past, some authors also used the brachial vein and contralateral common femoral vein, which have also fallen out of favour. The ipsilateral popliteal access later became the route of choice for most authors, being easily punctured with ultrasound guidance, having less problems with venous valves, and providing direct access to the thrombosed segment (Grossman, 1998; Sharafuddin 2003). Other common access routes include the common femoral vein (used in iliocaval disease) and posterior tibial vein (for infrapopliteal disease). Occasionally, antegrade and retrograde access is simultaneously used, with the catheters crossed, to treat both up and downstream disease (Molina et al 1992, Raju et al 1998, Tarry et al 1994). In extensive and severe disease, particularly in the calf, selection of the smaller veins with the catheter is extremely difficult, and sometimes impossible, which leads to poor inflow and higher rates of rethrombosis. Comerota (1993) described infusion through the ipsilateral femoral artery to push the thrombolytic agent through the capillary bed and into the small veins of the calf, and potentially improving clearance of thrombosis in those very small veins.

The equipment required in CDT includes:


Once access is achieved, usually via ultrasound guided micropuncture (Cook Inc, Bloomington, IN) of the popliteal vein, a vascular sheath is inserted (6Fr or larger to allow

Endovascular Therapies in Acute DVT 63

between proximal and distal balloons for control and to prevent PE. Rotational devices have direct contact with the endothelium and subsequently have the potential for endothelial damage. However there have been no studies to analyse their efficacy compared with

Rheolytic devices include the Angiojet (Possis, Minneapolis,MN). The device uses highpressure saline jets to fragment the thrombus. The jets also create a negative pressure zone which draws the fragmented thrombus toward the catheter where it is aspirated and removed. A possible advantage of the Angiojet device is that there is no contact of the maceration component of the device with the vessel wall. However, its use of high-pressure saline jets carries a theoretical risk of haemolysis and the release of adenosine and potassium. (Zhu, 2008) This has been linked to the incidence of bradyarrhythmia in cardiac

Ultrasound enhanced devices include the EKOS Endowave (EKOS Corporation, Bothell, WA, USA) and Omniwave (Omnisonics Medical Technologies, Wilmington, MA, USA). These are catheters that contain multiple ultrasound transducers, which radially emit high-frequency, low-energy ultrasound energy. The ultrasonic energy expands and thins the fibrin component of thrombus, exposing plasminogen receptor sites, and the ultrasound forces thrombolytic into the clot and keeps it there (Francis et al, 1995). This technique may be associated with fewer haemolytic effects than rheolytic thrombectomy (Lang et al, 2008) and has a lower potential for endothelial damage than rotational

We prefer the use of the Angiojet system at our institution, as an adjunctive modality to CDT. The timing of its use is dependent on the case, and preference of the interventionist. However, the method is the same in either situation. The Angiojet catheters come in a range of sizes and lengths, we prefer the 5 and 6Fr systems. The device is passed several times across the thrombosed segment over a wire and under fluoroscopic visualisation. In order to minimise the risk of haemolysis, each pass is limited to 30 seconds with 10 second rests in

The potential added benefit of the Angiojet system is the ability of the catheters to 'pulse spray' thrombolytic agent using high pressure jets into the thrombus itself, improving

To date, the largest DVT thrombolytic database is the venous registry (Mewissen 1999), which is a prospective registry of patients with a DVT who underwent CDT with urokinase. 473 patients were enrolled with 287 patients followed up at 1 year. 83% of patients had thrombolysis >50%. There were also a strong relationship between early thrombus removal and 1- year patency (primary patency rate of 60%). Major bleeding complications occurred in 11%, most often at the puncture site. 1% of patients developed a PE. Two patients (<1%)

applications of the device (Lee et al, 2005) or haemoglobinuria.

rheolytic devices.

thrombectomy devices.

between.

delivery.

**4. Results** 

**4.1 Catheter directed thrombolysis** 

died (one from PE and one from intracranial haemorrhage).

passage of an infusion catheter), and a diagnostic venogram performed either via the sheath or via a catheter. This may or may not be sufficient to visualise the extent of thrombosis. In either case, this is followed by a wire and angiographic catheter (usually 0.035in system, such as glidewire (Terumo, Somerset NJ) and a 5Fr angled tapered glidecatheter), which traverses the occluded segment. A venogram past the level of the occlusion is performed, usually in the IVC, to confirm intraluminal position, and absence of more centrally located clot.

The thrombolytic agent is usually injected at this point, and a number of different thrombolytic strategies have been described. At our institution, we would lace the length of the thrombosed segment using 200,000IU of Urokinase as the diagnostic catheter is being retracted. An infusion catheter with an infusion length that covers the occluded segment is then selected, and is inserted over a wire. The active infusion segment of the catheter is placed over the thrombosed segment of vein, which allows direct delivery of thrombolytic agent throughout the length of the thrombus. An infusion of Urokinase would then be commenced, at a rate of between 100,000-150,000 IU per hour. A Heparin infusion through the vascular sheath side arm is also commenced. The infusion is continued overnight, and patient nursed in a High Dependency Unit or Intensive Care Unit with one to one nursing. If the case arrives early in the morning, the infusion is left running until the mid afternoon. The patient will then return to the angiography suite for a venogram to reassess the degree of thrombosis and treat any underlying lesions.

If significant thrombus remains after the initial infusion, the infusion can be continued if it is felt that the clot will continue to disintegrate. However, this increases the dose and the duration of therapy with the associated increased risks of thrombolysis. It also increases the length of hospital stay and potentially increases the costs of treatment. Currently, CDT combined with mechanical thrombectomy is the preferred treatment (Sharaffudin 2003).

#### **3.2 Mechanical thrombectomy**

Mechanical thrombectomy devices disturb and break up the thrombus and allow rapid clearance of a large clot burden without the risks of pharmacological thrombolysis. They can be used alone, in situations where rapid debulking of thrombus is crucial, without the need for pharmacological therapy. However, adjunctive use of mechanical thrombectomy with thrombolysis is the preferred option. They can be used before, after or both before and after thrombolytic therapy.

The mechanism employed in the device can be divided into rotational devices and rheolytic devices.

Rotational devices include the Amplatz Thrombectomy Device (Microvena, White Bear Lake, MN), and Trerotola Percutaneous Thrombectomy Device (Arrow International, Reading, PA). These employ a high-velocity rotating helix or nitinol cage to macerate thrombus. The Trellis device (Trellis-8; Bacchus Vascular, Santa Clara, California, USA) employs a sinusoidal nitinol wire to disintegrate thrombus and with thrombolytic agent

passage of an infusion catheter), and a diagnostic venogram performed either via the sheath or via a catheter. This may or may not be sufficient to visualise the extent of thrombosis. In either case, this is followed by a wire and angiographic catheter (usually 0.035in system, such as glidewire (Terumo, Somerset NJ) and a 5Fr angled tapered glidecatheter), which traverses the occluded segment. A venogram past the level of the occlusion is performed, usually in the IVC, to confirm intraluminal position, and absence of more

The thrombolytic agent is usually injected at this point, and a number of different thrombolytic strategies have been described. At our institution, we would lace the length of the thrombosed segment using 200,000IU of Urokinase as the diagnostic catheter is being retracted. An infusion catheter with an infusion length that covers the occluded segment is then selected, and is inserted over a wire. The active infusion segment of the catheter is placed over the thrombosed segment of vein, which allows direct delivery of thrombolytic agent throughout the length of the thrombus. An infusion of Urokinase would then be commenced, at a rate of between 100,000-150,000 IU per hour. A Heparin infusion through the vascular sheath side arm is also commenced. The infusion is continued overnight, and patient nursed in a High Dependency Unit or Intensive Care Unit with one to one nursing. If the case arrives early in the morning, the infusion is left running until the mid afternoon. The patient will then return to the angiography suite for a venogram to reassess the degree of

If significant thrombus remains after the initial infusion, the infusion can be continued if it is felt that the clot will continue to disintegrate. However, this increases the dose and the duration of therapy with the associated increased risks of thrombolysis. It also increases the length of hospital stay and potentially increases the costs of treatment. Currently, CDT combined with mechanical thrombectomy is the preferred treatment

Mechanical thrombectomy devices disturb and break up the thrombus and allow rapid clearance of a large clot burden without the risks of pharmacological thrombolysis. They can be used alone, in situations where rapid debulking of thrombus is crucial, without the need for pharmacological therapy. However, adjunctive use of mechanical thrombectomy with thrombolysis is the preferred option. They can be used before, after or both before and after

The mechanism employed in the device can be divided into rotational devices and rheolytic

Rotational devices include the Amplatz Thrombectomy Device (Microvena, White Bear Lake, MN), and Trerotola Percutaneous Thrombectomy Device (Arrow International, Reading, PA). These employ a high-velocity rotating helix or nitinol cage to macerate thrombus. The Trellis device (Trellis-8; Bacchus Vascular, Santa Clara, California, USA) employs a sinusoidal nitinol wire to disintegrate thrombus and with thrombolytic agent

centrally located clot.

(Sharaffudin 2003).

thrombolytic therapy.

devices.

**3.2 Mechanical thrombectomy** 

thrombosis and treat any underlying lesions.

between proximal and distal balloons for control and to prevent PE. Rotational devices have direct contact with the endothelium and subsequently have the potential for endothelial damage. However there have been no studies to analyse their efficacy compared with rheolytic devices.

Rheolytic devices include the Angiojet (Possis, Minneapolis,MN). The device uses highpressure saline jets to fragment the thrombus. The jets also create a negative pressure zone which draws the fragmented thrombus toward the catheter where it is aspirated and removed. A possible advantage of the Angiojet device is that there is no contact of the maceration component of the device with the vessel wall. However, its use of high-pressure saline jets carries a theoretical risk of haemolysis and the release of adenosine and potassium. (Zhu, 2008) This has been linked to the incidence of bradyarrhythmia in cardiac applications of the device (Lee et al, 2005) or haemoglobinuria.

Ultrasound enhanced devices include the EKOS Endowave (EKOS Corporation, Bothell, WA, USA) and Omniwave (Omnisonics Medical Technologies, Wilmington, MA, USA). These are catheters that contain multiple ultrasound transducers, which radially emit high-frequency, low-energy ultrasound energy. The ultrasonic energy expands and thins the fibrin component of thrombus, exposing plasminogen receptor sites, and the ultrasound forces thrombolytic into the clot and keeps it there (Francis et al, 1995). This technique may be associated with fewer haemolytic effects than rheolytic thrombectomy (Lang et al, 2008) and has a lower potential for endothelial damage than rotational thrombectomy devices.

We prefer the use of the Angiojet system at our institution, as an adjunctive modality to CDT. The timing of its use is dependent on the case, and preference of the interventionist. However, the method is the same in either situation. The Angiojet catheters come in a range of sizes and lengths, we prefer the 5 and 6Fr systems. The device is passed several times across the thrombosed segment over a wire and under fluoroscopic visualisation. In order to minimise the risk of haemolysis, each pass is limited to 30 seconds with 10 second rests in between.

The potential added benefit of the Angiojet system is the ability of the catheters to 'pulse spray' thrombolytic agent using high pressure jets into the thrombus itself, improving delivery.
