Pharmacomechanical Thrombolysis

Historical Background

Venous thromboembolism (VTE) remains a significant health problem with over 900,000 new episodes each year in the United States alone. VTE, which comprises both deep venous thrombosis (DVT) and pulmonary embolism (PE), is responsible for up to 300,000 deaths each year and continues to be a leading cause of in-hospital mortality. Postthrombotic syndrome (PTS) is the most common complication of DVT, with 25% to 50% developing PTS despite anticoagulation (AC) after their first episode of DVT. The complications of DVT are well known, yet treatment continues to revolve around conservative therapies (AC and graded compression) aimed primarily at PE prevention while there remains resistance to endovascular treatments. Intravascular thrombus removal however, attempts to prevent both PE and PTS, while focusing on restoring the vein to its prethrombus state. PTS is a chronic condition that adversely affects a patient's quality of life (QoL) while remaining a significant burden socioeconomically.

Etiology and Natural History

The pathogenesis of DVT formation is believed to be caused by Virchow's triad, which suggests that thrombosis occurs as a result of alterations in blood flow (stasis), endothelial injury, and hypercoagulability (inherited or acquired). There are several possible outcomes of acute DVT, which include resolution with or without recurrence, propagation, pulmonary embolism, and PTS. PTS develops as a result of venous hypertension from increased resistance and venous obstruction, as well as reflux secondary to valvular incompetence. In fact, those patients who develop both venous reflux and residual obstruction following their DVT have the greatest risk of developing PTS. When considering DVT location, it is important to differentiate those patients with iliofemoral DVT versus those with infrainguinal only (femoropopliteal-tibial) DVT because the former carries a significantly higher risk of developing not only recurrent DVT and PTS but also a more severe PTS. Studies on patients with proximal (iliofemoral) DVT treated with AC showed poorer complete (4%) and partial resolution (14%) respectively. In fact, Raju and Fredericks demonstrated that when venous thrombosis occurs in the common femoral vein (CFV) or above, the more severe the outflow obstruction, the higher the ambulatory venous pressures, and the more severe the PTS. That is not to say that infrainguinal DVT does not cause PTS and QoL issues, particularly in those with residual venous obstruction and valvular damage of the popliteal vein.

Treatment Options

The rationale behind endovascular treatment of acute DVT is for rapid and complete thrombus removal to enhance the possibility of quickly restoring flow and preserving the vein, as well as the valves, and returning them to a normally functioning state. Theoretically, this will help prevent venous hypertension from residual venous obstruction and/or venous incompetence.

There are several categories of intervention, which might be considered after the first line of treatment, therapeutic AC, has been executed. These endovascular options include: catheter directed thrombolysis (CDT), percutaneous mechanical thrombectomy (no thrombolytic agent used), and pharmacomechanical thrombolysis (PMT; thrombolytic agent added to the mechanical device at the time of thrombectomy) also known as pharmacomechanical catheter directed thrombolysis (PCDT). The focus of this chapter will be on pharmacomechanical thrombectomy and the various forms of treatment techniques.

Patient Selection

In the hopes of preserving complete vein and venous valve function, early and complete resolution or removal of thrombus is important. Given the natural history of proximal DVT and its poor rate of complete resolution with higher risk for PTS, it is an important subset of DVT that warrants early intervention to restore patency. Any patient being evaluated for DVT treatment should undergo rigorous, preprocedural evaluation including a thorough history, physical examination, and appropriate imaging. This includes identifying any contraindications or potential bleeding risks. The Society of Interventional Radiology (SIR) quality improvement guidelines for the treatment of lower extremity DVT recommends thrombus removal in patients with the following :

• Image-proven symptomatic DVT in the inferior vena cava (IVC), iliac, common femoral, and/or femoral vein

• Recent ambulatory patient

• DVT symptoms for less than 28 days or in whom there is a strong clinical suspicion for recently formed (<28 days) DVT.

Variations in patient selection exist, such as those from the recent 2016 CHEST Guidelines, which propose that patients who are most likely to benefit from CDT have the following :

• Iliofemoral DVT

• Symptoms for less than 14 days

• Good functional status

• Life expectancy of 1 year or more

• Low risk of bleeding.

One must keep in mind that this list represents suggested guidelines and that case reports exist on treating patients whose status fell outside these guidelines. A physician's decision to treat any patient with DVT must be made after a number of individual factors, not the least of which is the individual's risk/benefit ratio, as well as the overall clinical status. In my practice, the use of RAPID ( r heolytic a ccelerated p harmacomechan I cal d irectional) lysis PMT has broadened the ability to treat patients suffering from acute DVT because patients previously deemed as having absolute contraindications for CDT have been safely and successfully treated using PMT techniques ( Fig. 14.1 ). This point illustrates one of the theoretic benefits of PMT over CDT in the ability to downgrade absolute contraindications for CDT to relative contraindications for PMT.

Thrombus Removal Devices

Thrombus removal can occur in a variety of ways. The devices that are US Food and Drug Administration (FDA) approved for mechanical thrombectomy can be categorized by their respective mechanism of action. These include rotational thrombectomy, rheolytic thrombectomy, aspiration thrombectomy, or ultrasound-accelerated thrombolysis. Rotational devices physically macerate the thrombus using a basket or helix configuration that rotates at a high velocity to macerate the clot. These devices include the Trerotola device ( Fig. 14.2 ) (Arrow International, PA), the Cleaner Rotational Thrombectomy System ( Fig. 14.3 ) (Argon Medical, Plano, TX), and the Amplatz thrombectomy device (Microvena, MN).

The Trellis device (Covidien/Medtronic, MN) is no longer commercially available.

Rheolysis is unique to the AngioJet device ( Fig. 14.4 ) (Boston Scientific, MN), which uses the Bernoulli-Venturi principle and generates high velocity saline jets to create a central, low pressure or vacuum zone within the catheter lumen. At the tip of the catheter, the affluent saline jets also produce a physical maceration or fragmentation of the thrombus, which is then aspirated and evacuated via the catheter through the effluent port. The original rheolytic technique described uses heparin in the affluent saline solution instead of a lytic agent. The PMT or PCDT technique substitutes heparin for a thrombolytic agent added directly into the affluent saline solution. Once the lytic agent has been added to the saline solution, there are several different PCDT techniques that use the AngioJet catheter. The 8-Fr Zelante DVT thrombectomy set is intended for use to break apart and remove thrombus, including DVT, from the iliofemoral and lower extremity veins 6.0 mm or greater in diameter. The 6-Fr AngioJet SOLENT Proxi & Omni thrombectomy sets are intended for use to break apart and remove thrombus from peripheral veins 3.0 mm or greater in diameter.

The first technique to be described is the use of the AngioJet catheter over the guidewire, as its original intended use, while in the thrombectomy mode, allowing for the outflow port to remain open for thrombus evacuation. The second technique is the power pulse technique, which is selected on the console unit. By selecting this technique, the console automatically closes the effluent port while in use. The catheter is advanced through the thrombus at 1 to 2 cm increments while “pulsing” the lytic/saline solution into the clot. The outflow port is closed, allowing for the lytic agent to “dwell” in the clot for an appropriate time, usually 20 to 30 minutes. Once the dwell time is completed, the catheter is again advanced through the thrombus, this time in the thrombectomy mode (selected on the console, which opens the effluent port), where both the combination of the mechanical action and vacuum removes any residual clot. The third technique is called the RAPID lysis technique, which was originated in 1997 and uses an 8-Fr hockey-stick guide catheter with the guidewire retracted inside the AngioJet, allowing the guide catheter to angle the tip of the AngioJet catheter along the periphery of the vessel wall. The operator then slowly retracts the coaxial system from central to peripheral aspects of the DVT, with the device in the thrombectomy mode. While retracting the system through the clot, the operator rotates the guide catheter hub in a slow 360-degree circle, allowing for the AngioJet treatment zone to gain full circumferential coverage of the vessel. This optimizes removal of wall thrombus in addition to luminal clot and, in my opinion, greater overall thrombus removal.

Another thrombectomy technique is termed aspiration thrombectomy and is achieved by creating suction in the catheter device once it is placed into the thrombus. Suction created in the closed system is accomplished with the aid of an in-line pump. Two FDA-cleared devices exist, the Indigo device (Penumbra, Alameda, CA) and the Angiovac system (Angiodynamics, Latham, NY).

The EKOS Endowave system (EKOS/BTG, Bothell, WA) combines the use of a thrombolytic agent delivered via a thrombolytic infusion catheter that contains an inner ultrasound core, which emits ultrasound energy or waves that aid in dissolution of the thrombus. This combination technique is termed ultrasound accelerated thrombolysis (USAT) or acoustic pulse thrombolysis.

RAPID Lysis Technique

The treatment technique of choice for patients presenting with acute to subacute DVT is the RAPID lysis technique. As stated earlier, this technique combines the mechanical and rheolytic properties of the AngioJet system with that of the thrombolytic agent in addition to gaining circumferential, wall-to-wall apposition to enhance the ability for complete clot removal and thrombectomy in a single session. An additional advantage is the opportunity to downgrade absolute contraindications to relative contraindications, as has been established time and again in my practice. Before discussing the details of the technique, one must be prepared with the appropriate imaging equipment and procedural instruments to safely, effectively, and successfully complete the case.