Venous News Thrombolex supplement – October 2020

October 2020 | Educational Supplement

venousnews.com

This educational supplement has been sponsored by Thrombolex

Introduction

A paradigm shift in the treatment of arterial and venous thromboembolic disorders The Bashir Endovascular Catheter offers a safe and easy to use platform technology, creating immediate blood flow, accelerating thrombolysis, and dissolving large volumes of thrombus burden. This article explores the use of various advanced catheter-directed therapies, including their respective risks and potential long-term benefits.

VENOUS THROMBOEMBOLISM (VTE) is a vascular condition that affects about 10 million patients worldwide each year. Deep vein thrombosis (DVT) most often forms in the deep veins of the legs, groin, or arms. If they break loose, they can travel to the pulmonary arteries in the lungs and result in a pulmonary embolism (PE), with potentially fatal outcomes. Together, DVT and PE are known as VTE.

Anticoagulation therapy

The majority of VTE patients have traditionally been treated with anticoagulation alone. However, up to 50% of patients who present with lower extremity DVT develop post-thrombotic syndrome (PTS), despite being treated with anticoagulation therapy and compression therapy, while 35–50% of patients with PE who are treated with anticoagulation therapy go on to develop some form of functional limitation (post-PE syndrome).1 The mainstay of treatment for patients with both forms of VTE is systemic anticoagulation.4 This is aimed at preventing extension of the clot. Advanced therapies like systemic thrombolytics are effective at lysing the clot but carry a high risk of bleeding, including a 2–3% risk of intracranial haemorrhage. This has led to a quest to identify treatments that carry a much better risk–benefit ratio that are directed more locally at the culprit thrombus without the risks of severe bleeding complications.

Advanced catheter-directed therapies

Clinical data from several large studies suggest that the use of catheter-directed interventions for the treatment of acute proximal DVT may help to reduce acute

symptoms and improve quality of life.2 Likewise, several different catheter-directed thrombolysis (CDT) and percutaneous mechanical thrombectomy trials have shown prompt improvement in right ventricular function when treating patients with massive and/or submassive PE. The primary goal of catheter-directed interventions for DVT should be to prevent or reduce the likelihood of developing PTS and improve quality of life.3 The primary goal of catheter-directed therapy of massive/

Clinical data from several large studies suggest that the use of catheter-directed interventions for the treatment of acute proximal DVT may help to reduce acute symptoms and improve quality of life.” submassive PE is to relieve right heart strain as quickly as possible and restore the patient to a haemodynamically stable condition.

However, a longer-term goal should also be to reduce the incidence of post-PE syndrome, chronic thromboembolic disease (CTED), and chronic thromboembolic pulmonary hypertension (CTEPH). More

complete resolution of thrombus burden is widely thought to have a positive impact in reducing the incidence of these longer-term negative side effects. It is also thought to have a positive impact on reducing hospital readmissions.

Two broad approaches have evolved to resolve the clot: localised CDT, and mechanical extraction of the clot (mechanical thrombectomy). Each approach has its own pros and cons that merit discussion.

With regard to long-term treatment results, increasing volumes of residual thrombus are associated with higher rates of PTS, and complete clearance of thrombus may prevent moderate to severe PTS in patients with iliofemoral DVT.5,6 The challenge is how to achieve the greatest degree of clot burden reduction while limiting bleeding risks and optimising perfusion. Many of the current CDT devices available in the market today have a direct dose-response relationship to clot burden reduction and at times do not provide sufficient thrombus resolution at lower doses or shorter infusion times.

Mechanical thrombectomy therapies

While mechanical thrombectomy (MT) without thrombolytics helps to reduce the risk of systemic bleeding, there are other risks related to the use of these devices that should be considered, particularly for large bore devices. These risks include worsening PE, pulmonary vascular injury, cardiac injury, cardiogenetic shock, respiratory arrect, risk of haemolysis, and the consequent damage to the kidneys. Also, repeated and prolonged aspiration can lead to a high volume of blood loss, which may require blood transfusion.

While MT devices may be able to remove a significant volume of visible clot, the clot burden in these patients is so high that the distal perfusion often remains suboptimal post treatment.

The question whether the MT alone has the ability to increase pulmonary perfusion, and thereby potentially improves longterm outcomes, is raised by data from two recently approved devices for the treatment of submassive pulmonary embolism.7,8 While both devices met the primary endpoints of their respective clinical studies, namely a reduction in right ventricular (RV)/left ventricular (LV) ratio of >0.2 at 48 hours, one of the pivotal studies reported less than 10% reduction in the Modified Miller Index (MMI) at 48 hours, a key assessment of clot burden reduction. This is a much lower reduction in clot burden as assessed by the

All rights reserved. Published by BIBA Publishing, London T:+44 (0)20 7736 8788, publishing@bibamedical.com.

The opinions expressed in this supplement are solely those of Thrombolex and the featured physicians and may not reflect the views of Venous News.

2

October 2020

Bashir Endovascular Catheter

MMI than what has been reported in the CDT trials.

The Thrombolex solution

A recent addition to the percutaneous devices is a pharmacomechanical catheter-directed thrombolysis (PMCDT) device developed by Thrombolex. The company has developed a platform technology around their family of Bashir Endovascular Catheters. Since its inception in mid-2016, Thrombolex has received US Food and Drug Administration (FDA) clearance, via a 510(k) premarket regulatory pathway, for seven PMCDT devices. These devices are cleared for infusion of physician specified fluids, including thrombolytics in the peripheral vasculature.

Thrombolex successfully completed a first-in-human (FIH) trial in December 2019, treating patients with acute submassive PE. This study met its primary safety and feasibility endpoints, and showed a robust reduction in right heart strain as evidenced by a mean reduction in RV/LV ratio of 37% (P<0.0009), as well as a 37.1% mean reduction (p<0.0005) in pulmonary clot burden, as measured by the MMI score following a mean infusion of only 13.7mg of r-tPA over eight hours. There were no adverse or major bleed events. “The Bashir

Endovascular Catheters have demonstrated an excellent early safety profile and Thrombolex has launched a pivotal singlearm, multicentre clinical study of acute submassive PE patients under an IDE [investigational device exemption] to further evaluate the safety and efficacy of this device, using less than 14mg of r-tPA over five hours,” said Brian Firth, chief scientific officer of Thrombolex.

The mechanical action of the Bashir Endovascular Catheter establishes multiple channels of blood flow through the thrombus, which brings the patient’s endogenous fibrinolytics into the clot. This action, coupled with dispersion of exogenous thrombolytic across a broad cross-sectional area of the thrombus, promotes immediate blood flow and enhances fibrinolysis. “The ability to achieve robust clot resolution with very small doses of fibrinolytics, coupled with the lack of bleeding complications in the patients (both PE and DVT) treated to date with the Bashir Endovascular Catheters, challenges the notion that the administration of small doses of thrombolytic (less than 15mg of r-tPA) is inevitably associated with major bleeding complications,” said Mike Cerminaro, president and CEO of Thrombolex. The Bashir Endovascular Catheter early safety is enhanced by no

reported major bleeds and no reported major adverse events across both its FIH data and all its real-world cases to date. Its mechanical action on thrombus makes it eligible for the new “fragmentation” ICD-10 codes leading to higher paying DRGs than for thrombolysis alone.

References 1. Kahn SR, Hirsch A, Beddaoui M, et al. “Post-pulmonary embolism syndrome” after a first episode of PE: Results of the E.L.O.P.E. study. Abstract #650. Presented at the 2015 ASH Annual Meeting, 7 December 2015; Orlando, USA. 2. Kahn SR, Hirsch A, Beddaoui M, et al. Dyspnea, quality of life and walking capacity during 1-year follow-up after a first episode of pulmonary embolism: Results of the E.L.O.P.E. study. Abstract #750. Presented at the 2015 ASH Annual Meeting, 7 December 2015; Orlando, USA. 3. Vedantham S, Thorpe PE, Cardella JF, et al. Quality improvement guidelines for the treatment of lower extremity deep vein thrombosis with use of endovascular thrombus removal. J Vasc Interv Radiol 2006; 17:435–47; quiz 448.

4. Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2017; 388:3060–73. 10.1016/ S0140-6736(16)30514-1.

5. Comerota AJ, Grewal N, Martinez JT, et al. Post-thrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg 2012; 55:768–73. 10.1016/j. jvs.2011.10.032.

6. Enden T, Haig Y, Kløw NE, et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the Cavent study): A randomised controlled trial. Lancet 2012; 379:31–8. 10.1016/S0140-6736(11)61753-4.

7. Thomas Tu, MD, Catlin Toma, MD, et al. A prospective, single-arm, multicentre trial of catheter-directed mechanical thrombectomy for intermediate-risk acute PE, the Flare trial.

JACC 2019; 12.

8. Sista A, et al. Late-breaking clinical trials. EXTRACT PE trial.

Presented at VIVA 19, 4–7 November 2019; Las Vegas, USA.

Bashir Endovascular Catheter basket Bashir Endovascular Catheter basket and handle

Bashir Endovascular Catheter Plus 40 full device

October 2020

3

Case report

Characteristics and applications of the Bashir™ Endovascular Catheter

The Bashir™ Endovascular Catheter was invented by Riyaz Bashir (Temple University, Philadelphia, USA) in order to (a) create a channel for immediate blood flow through the culprit clot and (b) allow for precise and targeted delivery of thrombolytics and other agents directly into multiple cross sectional areas of large thromboses. This innovative platform technology has been found to be safe, effective, and remarkably easy to use in early human studies. The main characteristics of the technology are shown in Figure 1A–C. Presented herein are two illustrative cases of the use of the Bashir Endovascular Catheter platform for the treatment of (1) a large deep vein thrombosis (DVT) of a lower extremity with May-Thurner syndrome, and (2) a massive bilateral pulmonary embolism (PE).

Case study one: A DVT of a lower extremity with May-Thurner syndrome

By John Moriarty, MD, RPVI Patient presentation

A 65-year-old man with a history of hypersensitivity lung disease and gastrooesophageal reflux presented to the emergency department after experiencing a first, 12-hour episode of swelling of the left lower extremity and moderate, dull pain aggravated by weight bearing. He reported no fever, shortness of breath, chest pain, recent trauma, change in activities, or relevant family history. On initial presentation, his body mass index was 26.4kg/m2, body temperature 36.6ºC, heart rate 107bpm, blood pressure 132/69mmHg, and blood oxygen saturation was 95% on room air.

The admission laboratory tests revealed a peripheral blood white cell count of 16.2x106/µl and a D-dimer plasma concentration >10,000ng/ml. He had a negative COVID-19 test three days before admission.

A venous duplex of the left lower extremity revealed the presence of a thrombosis involving the left common, femoral, and deep femoral veins, as well as the popliteal, posterior tibial, peroneal, gastrocnemius, and greater saphenous veins.

As per protocol for an acute femoropopliteal DVT, an intravenous heparin infusion was started. On computed tomographic venography, the thrombosis was seen to extend into the common and external iliac veins, with fat reticulation surrounding the

4

John Moriarty

left femoral and iliac veins consistent with thrombophlebitis.

A focal narrowing of the left common iliac vein as it passes behind the right common iliac artery, was indicative of underlying MayThurner syndrome.

Procedural overview

The patient was taken to the cardiac catheterisation laboratory where he underwent diagnostic venography, which confirmed the presence of (a) an extensive, acute thrombosis involving the left common, internal and external iliac veins, and the common femoral vein, (b) a focal narrowing of the left common iliac vein as it travels behind the right common iliac artery, and (c) multiple pelvic, collateral veins. The inferior vena cava and renal veins were patent.

No evidence of PE was found on thoracic computed tomographic angiogram.

A decision was reached to perform thrombectomy and thrombolysis of the very symptomatic, extensive DVT of the left leg. Venous access was obtained from the left popliteal vein. Venography confirmed the presence of a large thrombus burden, extending from the common iliac vein,

which was occluded at the site of MayThurner vascular compression, down to the common femoral vein. The image also revealed abundant collateral vessels around the region, and several other characteristics of acute, as well as chronic thrombotic obstruction (Figure 2A). A Bashir +40 endovascular catheter was introduced and advanced through the thrombus. The infusion basket was expanded at the site of common iliac vein occlusion (Figure 2B, arrow).

Recombinant tissue plasminogen activator (r-tPA), 0.25mg/h, was then administered for 24 hours through the ports of the expanded infusion basket, and an additional 0.25mg/h was administered for 24 hours through the infusion ports along the distal length of the catheter shaft, for a total dose of 12mg over 24 hours. Venography performed the next day revealed the complete resolution of the acute and the chronic thrombotic occlusions.

Furthermore, brisk blood flow was observed through the site of the previously obstructed left common iliac vein, with distinct visualisation of a mild residual stenosis (Figure 3A&B).

A Venovo® (BD Bard) venous stent system was placed at the site of previous iliac vein occlusion (Figure 4A), with brisk flow observed through the stent (Figure 4B). The procedure was uncomplicated and associated with minimal blood loss. The patient was discharged from the hospital 23 hours after completion of the infusion on a regimen of enoxaparin, 1mg/kg twice daily for 10 days, before transition to apixaban 5mg twice daily, and aspirin, 81mg daily.

Discussion

The key take-away from this case is that the Bashir +40 endovascular catheters, which allowed (a) the immediate restoration of

This case illustrates a very impressive, complete clot resolution and flow restoration, achieved using a total of only 12mg of r-tPA overnight.” blood flow by opening the basket (for up to an additional 45mm in diameter) in the thrombus, and (b) the simultaneous infusion of low doses of thrombolytic through the infusion basket and the shaft infusion October 2020

Bashir Endovascular Catheter

segment, provide a valuable, effective treatment of large and long DVT. This case illustrates a very impressive, complete clot resolution and flow restoration, achieved using a total of only 12mg of r-tPA overnight, in a patient with an extensive acute-onchronic iliofemoral DVT. This patient experienced no bleeding or other adverse complications relating to the procedure.

In our experience, patients presenting with such cases are often treated with other

catheter-directed thrombolysis (CDT) technology, requiring much larger doses of r-tPA, for much longer infusion periods, with variable success and increased risk of bleeding complications. Furthermore, no adjunctive mechanical thrombectomy, using expensive aspiration devices was needed. As is often the case in patients with the May-Thurner syndrome. Complete treatment required the insertion of a stent in the left common iliac vein. The Bashir +40

endovascular catheter removed the large volume of thrombus in a short time period without complications. We view it as a valuable new option to remove extensive clot burden found in large vessels.

John Moriarty is a specialist in vascular and interventional radiology and director of the PE Response Team at UCLA Medical Center, Los Angeles, USA.

C

A

B

Figure 1. Bashir Endovascular Catheter (BEC). A. Actuator (slider) located on the handle at the proximal end of the device. B&C. The infusion segment can be expanded to form a basket and collapsed by the actuator. Therapeutic agents are administered through the infusion line. The device size is 7F, 92.5 cm in length. The length of the infusion segment is 12.5 cm, accommodating a 0.018â&#x20AC;? guidewire.

Figure 2. Before thrombolysis

Figure 3. Post lysis, using BEC+40 and a total of 12mg of r-tPA was infused via the basked and shaft.

September 2020

Figure 4. Post lysis, using BEC+40 and a total of 12mg of r-tPA was infused via the basked and shaft. A VenovoÂŽ venous stent system has been placed inside the iliac vein.

5

Case report

Case report two: a massive bilateral pulmonary embolism (PE) with an RV/LV rate of 5:3:1

By Brian Tweddale, MD Patient presentation

A 79-year-old, previously healthy, nonsmoker man presented with a four-day history of dyspnoea, which began during moderate exercise and worsened on the day of presentation, associated with new onset of mild chest pain. He had observed swelling of his right lower extremity for several months but had not sought medical attention. He presented to the emergency department in acute respiratory distress; his heart rate was 123bpm, systemic blood pressure 90/47mmHg, respiratory rate 40 breaths per minute and oxygen saturation 90% on room air. The laboratory tests revealed a brain natriuretic peptide blood concentration of 3,200pg/ml (normal <450), and blood troponin concentration of 0.079ng/ ml (normal <0.034). Emergency thoracic computed tomographic venography showed a massive saddle embolism and large bilateral PE. His right ventricle (RV) was abnormally large, with an RV/left ventricular (LV) ratio of 5.3:1, and marked hypo perfusion of both lungs (Figures 1A and 2). The normal RV/LV ratio is under one and the death rate increases progressively as the ratio increases. He received an intravenous bolus of heparin and the PE response team was activated. Pulmonary angiography showed a massive saddle embolus and large bilateral PE. The initial pulmonary artery pressure was 50/23mmHg and a mean of 33mmHg. Intravenous fluids were administered liberally to maintain his blood pressure.

Procedural overview

The patient was transferred directly to our cardiac catheterisation laboratory, where heparin infusion and intravenous fluids were continued. The patient underwent pharmacomechanical thrombolysis using the Bashir Endovascular Catheter. Boluses of 2mg of recombinant tissue plasminogen activator (r-tPA) were injected into each pulmonary artery, followed by bilateral infusions at a rate of 0.65mg/h, to a total dose of 14mg, including the initial 2mg bolus. It is worth noting that the US Food and Drug Administration (FDA) has approved the use of systemic anticoagulation in a dose of

6

100mg of r-tPA over two hours, for the treatment of massive PE. However, there is up to a 30% risk of systemic bleeding and 3% risk of intracranial haemorrhage with the systemic Brian Tweddale administration of such a high dose of r-tPA. Within one hour of the first pulmonary arteriogram, the patient’s heart rate had decreased to 86bpm and his systemic blood pressure had increased to 110/74mmHg. Procedure duration in the cardiac catheterisation laboratory was about 55 minutes. The patient was transferred to the medical intensive care unit and within two hours of the start of the procedure, the patient was recovering comfortably. Follow-up pulmonary arteriography, performed 16 hours after admission, revealed a decrease in pulmonary artery pressures to 43/12mmHg

This unique device provides us with rapid results that we have not found with any other advanced catheterdirected therapy.” (mean=23), and a marked increase in the pulmonary arterial perfusion bilaterally compared to pre-procedure (Figures 3 and 4A&B). His heart rate at that time was 57bpm, respiratory rate 17 breaths per minute and oxygen saturation 99% on 3-L of nasal cannula. One hour after discontinuation of the r-tPA infusion, the patient was transitioned to an 80mg subcutaneous dose of enoxaparin therapy.

The patient was discharged from the hospital 48 hours after the thrombolytic

procedure, on a regimen of apixaban, 5mg twice daily. A two-month follow-up, thoracic computed tomographic angiography showed complete resolution of all emboli, and a RV/ LV ratio of 1.3:1 (Figure 1B).

Discussion

This case illustrates the very impressive outcome of a critically ill patient presenting with a massive PE and RV/LV ratio of 5.3:1, treated with Bashir Endovascular Catheters in both pulmonary arteries. An RV/LV ratio of this magnitude is very rarely documented, and usually fatal if untreated. PE is the third leading cause of cardiovascular death behind myocardial infarction and stroke. It is also the number one cause of in-hospital mortality.

The patient’s clinical and haemodynamic status improved markedly during the procedure, following a total of only 2mg of r-tPA pulse sprays in each pulmonary artery, after repeatedly expanding and collapsing the infusion basket of the Basher endovascular catheters in each pulmonary artery. I like the ability to expand and contract the infusion basket as it helps to restore blood flow immediately and allows the device to conform to the size of large vessels up to 45mm in diameter. The low-profile design of only 7Fr makes it easy to steer and very compliant in tortuous parts of the anatomy. In addition, this unique device provides us with rapid results that we have not found with any other advanced catheter-directed therapy.

As an example, in only 16 hours following the procedure in this case the pulmonary angiograms revealed a marked increase in pulmonary blood flow.

There were no bleeding complications or adverse events of any kind related to this critically ill patient. The fact that the patient was well enough to leave the hospital two days later is a testament to the effectiveness and safety of the Bashir Endovascular Catheter in combination with a low-dose r-tPA regimen. The marked reduction in the RV/LV ratio to near normal at two months is another noteworthy finding that augurs well for the future of this patient. Alternative devices I have used in the past have not been adequate for quick resolution of the clot.

Using the Bashir Endovascular Catheter, we have been able to get results that we have been unable to achieve with any other device.

Brian Tweddale is an interventional radiologist at Doylestown Hospital in Doylestown, Pennsylvania, USA.

October 2020

XXXXXXXX

Figure 1: Pre- and post-procedural thoracic computed tomographic venography, crosssectional views. A. Initial presentation. B. Two months post pharmacomechanical thrombolysis.

Bashir Endovascular Catheter

Figure 2. Pre-procedural computed tomographic angiography, saggital view.

Marked pulmonary hypoperfusion.

Figure 3. Left pulmonary angiography. A. Preprocedure. B. 16 hours post procedure.

Figure 4. Right pulmonary angiography. A. Preprocedure. B. 16 hours post procedure.

September 2020

7