Targeting Intervention in PE & DVT

With numerous studies under-way, researchers and manufacturers are busy readying for the next wave of procedures and devices to combat the rise in chronic venous insufficiency (CVI).

VEIN Magazine recently asked U.S. thrombolysis device manufacturers to provide their latest news, products, research, approvals and updates in order to provide a current snapshot of this rapidly growing industry as we watch the targets shift in interventional venous disease care.

Clot management – in both pulmonary embolism (PE) and deep vein thrombosis (DVT) – is arguably the hottest topic in venous disease management, and potentially one of the fastest-growing segments in the medical device industry. Competing with both surgical interventions and medical management for thrombosis treatment, percutaneous clot management devices are predicted to become the favored standard of care for interventions over the next three- to five-year period.

Market Research and Market Share

With an aging population, increases in both obesity and diabetes (see BMI Study article), and an increase in chronic vascular disease, a tremendous unmet need exists for new medical technologies to treat potentially dangerous CVI and blood clots. according to Arshad Ahmed, a partner at Scientia advisors, a life science consulting firm located in Cambridge, Massachusetts, “Most vascular devices currently on the market treat only symptoms, have low patient compliance or are highly invasive, with significant side effects or risks. There are great needs for novel methods of compression and ablation to treat varicose veins and for minimally invasive catheter technologies that can safely and easily do away with potentially deadly blood clots.”

Recent research indicates that the US clot management device market – including thrombectomy devices, Inferior Vena Cava filters (ivc Filters), thrombolytic infusion catheters, and neurovascular embolectomy devices – generated nearly $570 million in revenue in 2010.

In February, Scientia advisors released findings within the overall vascular device market, reporting that the $5B vascular device market (worldwide) is a relatively small piece of the $300B medical device market (worldwide), and it has shown a sustained compound annual growth rate of 10% since 2007.

The report goes on to say, “with most major cardiovascular players focused elsewhere, smaller companies have an important presence in the venous submarkets. Hence, emerging companies can impact what is currently a fragmented marketplace and there is opportunity for larger, anchor companies to acquire or license.”

To date, Covidien is the market frontrunner as they recently saw their share of market jump to an estimated 22%. covidien acquired Bacchus Vascular’s familiar Trellis system – one of two Catheter-Directed Thrombolysis (CDT) devices being used in the attract trial (see below) – in addition to other vascular technologies. VNUS medical technologies was acquired in September, 2009, and EV?, inc. was purchased late last June – the immediate result of a series of moves in an effort to focus on faster-growing, more profitable businesses.

Interventions in Deep Vein Thrombosis

Each year, 2 million Americans are affected by DVT. nearly 6% of those with DVT die within one month of diagnosis, primarily due to PE. Oral anti-thrombotics costing between $2,000-$3,000 annually per patient, can cause increased bleeding and they often do not prevent the recurrence of thrombosis. The intravenous injection of thrombolytic drugs can substantially increase the risk of major hemorrhage and does not fully recannalize the vein in 66% of patients.

DVT and the ATTRACT Trial

In an attempt to address problems with the presence and severity of Post Thrombotic Syndrome (PTS), relief of pain and swelling, quality of life, safety and costs of treatment in DVT patients, the Sir Foundation formed a DVT research consensus panel to discuss the need for interventional DVT procedures. ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis) is a NIH-sponsored trial developing the case for early intervention through Pharmacomechanical Catheter-Directed Thrombolysis (PCDT).

“We know that there are 250,000-300,000 new people who develop a first episode of dvt each year; that is a lot of people that are at risk of the long term complications of DVT”, says Suresh Vedantham, MD, Washington University School of Medicine, Radiology, St. Louis,Missouri, president-elect of the venous disease coalition and lead investigator for the trial.

“This trial is really a paradigm study testing the general concept of catheter-based clot removal and determining whether patients should routinely undergo clot removal treatments when they have a blood clot or DVT. The purpose is to determine if clot removal procedures prevent the long term problem known as PTS, which causes significant leg pain, swelling, and disability. If these procedures can prevent them, then we would like them to be used.”

According to Vedantham, there are a number of preliminary studies that point in that direction, although he stresses the need for a large scale randomized trial to establish that for sure. “The results of the attract trial will really determine the future of DVT treatment – if they suggest that these treatments are effective with acceptable safety, it will be very important for us to work with the organizations out there that create clinical practice standards to make sure that physicians know that when you have a blood clot, you should be thinking clot removal.”

The most recent (2008) venous thromboembolic (VTE) disease guidelines from the American College of Chest Physicians (ACCP) recognize that the potential benefits of combining thrombus removal with traditional pharmaceutical therapies as a first-line strategy in treating DVT may be significant. Not only can the benefits be measured by the thrombus removal itself, but also by permanence of results, patient quality of life, procedure cost and treatment times.

“DVT care is slowly trending towards becoming an outpatient treatment,” says Vedantham. “A possibility for the future, if the ATTRACT trial is positive, is that when a patient is admitted in the ER with a blood clot, it gets diagnosed, patient gets put on blood thinning drugs, is sent directly to the procedure area where the clot is removed and then sent back to the er and discharged. the ideal situation is that they wouldn’t have to stay in the hospital and they would have had the clot removed.”

The ATTRACT trial utilizes the trellis Peripheral infusion System and AngioJet Solent catheters, and aims to enroll nearly 700 patients at 50 sites to monitor their venous health for a period of two years.

New Devices for DVT

It has already been a very busy year for MEDRAD Interventional. This April, MEDRAD announced the release of the Solent Proxi Thrombectomy Catheter, and right on its heels, in June, came the Solent Omni Thrombectomy Catheter - the most recent additions to the AngioJet Solent Family of products designed for large, difficult-to-remove thrombus for peripheral vasculature.

The Solent Omni provides a new 120 cm length, offering a longer reach as compared to the 90 cm Solent Proxi. The new catheters are enabled for Power-Pulse delivery, allowing them to be used to power-infuse lytic into the thrombus. The Solent family is part of the growing portfolio of specialized thrombectomy devices available for use with AngioJet’s Ultra System.

Mark J. Garcia, MD, FSIR, Section Chief of Christiana Care Health Services Vascular & Interventional Radiology, Newark, Delaware, has used the new Proxi since its release in April. “Our practice has been using the AngioJet system for more than 12 years, so we have extensive experience in DVT with it, both acute and chronic, as well as arterial thrombosis. The new Solent catheters are more comparable to the older DVX catheter, in their ability to remove clot, while causing less hemolysis, so it seems that their result is certainly better than the older systems.”

In response to requests from interventionalists, the Solent catheters offer the highest clot-removing power in the AngioJet range. Garcia says that to him, the improvements are significant. “A big change came first with the drive unit. For our techs and nurses, the system is so much simpler to set up compared to the older system. And with the old system, the DVX was the really powerful gun, but it had a lot of hemolysis. That can be an issue. For example, in a patient with renal disease, it can worsen renal insufficiency although usually transient. The Xpeedior was less powerful and therefore, caused less hemolysis. I think that Solent has married the best qualities of both where I feel it has the added power with less of the side effects.”

The Solent catheters are also the first to allow guide-wire exchange during the procedure. Garcia recalls his practice’s old “in-house” technique before this new advancement. “We developed a technique we called the ‘rapid Lysis’ technique where we use a hockey stick guiding catheter that has a 45-60˚ angle and we would put the older AngioJet catheter through it. We would take the wire out and then spiral it around the vessel wall as we manipulate the system forward and backwards, allowing us to get wall-to-wall, 360˚ circumferential apposition and we saw a tremendous improvement in thrombus removal. The problem with the older system was that once you took the wire out, you couldn’t put it back in.

If you retracted it all the way through the clot and you needed a wire to get back through the vessel, we would have to take the whole system out and start over with a basic catheter and wire and exchange everything back out again. With the new Solent system, if you need to exchange the wire or put a wire back in, you can just feed it right back through the wire port and you feed the catheter right back up to where you want to be. The new design made it very easy for us.”

Constructed with flexible, polymer-clad spiral shafts and hydrophilic coating on the distal section to improve handling compared to earlier designs, Garcia shares that “The trackability of the catheter over the wire with this system seems to be smoother and easier. It doesn’t get hung up as easily as it used to.”

A side port with stop cock has also been added to the catheter’s hub to facilitate in situ contrast injection. “The newer system allows you to inject contrast through a side port which is a huge improvement. Say you treat the iliacarea in the pelvis and you don’t know whether you got all the thrombus. With the old system, you had to take detach the outflow system or take the catheter out to do an injection and see what was remaining. Now all you have to do is inject into the side port and get a good study and you’ll know if you need to do more or not. If you do, you’re already there, so you just go back through and it makes it much easier. The more you exchange, the more cumbersome it is.”

Like the other AngioJet thrombectomy catheters, the Solent catheters use the AngioJet cross-stream technology—utilizing high-speed saline jets contained inside the catheter tip to create a powerful low pressure zone that entrains and removes clot.

Garcia sums it up by saying, “The power of the newer system, the guidewire exchangability, a shaft system that tracks easier and doesn’t kink as easily with the ability to inject contrast and evaluate your results are all significant improvements allowing for greater success of the procedure – it all adds up to a system that is far greater.”

Interventions in Pulmonary Embolism

Research Strengthens the Case for Rapid Removal of Clots in PEEKOS pioneered the development and clinical application of ultrasound-accelerated thrombolysis, introducing its first system for the treatment of vascular thrombosis in 2006. In 2008, the company introduced its second generation EkoSonic Mach4 endovascular System with Rapid Pulse Modulation followed in 2009 with the even faster EkoSonic System with Mach4e.

What is unique about the EKOS’ approach is its inherent safety. Unlike mechanical thrombectomy catheters, which can fragment or partially aspirate thrombus material that can result in fatal outcomes, EKOS’ gentle diagnostic-intensity ultrasound conditions the clot in the targeted treatment area to more rapidly absorb the delivered thrombolytic agent which then dissolves blood clots up to five times faster. Because of the natural biochemical mechanism of dissolution, the lysis speed and the resulting low drug dose, adverse events normally associated with thrombolysis, such as distal embolization, blood cell fragmentation, and bleeding, are virtually eliminated.

Bob Hubert, President and CEO of EKOS corporation explains that EKOS technology is receiving more attention and focus within peer reviewed publications these days, mainly because the device really does work in speeding up the process of removing the clot.

One major area of focus for EKOS is in the treatment of massive and sub-massive pulmonary embolism which is currently a significant unmet medical need. Hubert commented that EKOS was prepared to invest in clinical trials but needed to be assured that should the outcomes be positive, the interventional treatment would rapidly follow.

“Before we decided to raise the millions of dollars necessary for PE trials we conducted extensive market research. We wanted to know if interventional adoption for this application would be faster than the interventional adoption of DVT. All of us in the market expected the interventional advancements in the treatment of DVT would move more rapidly in adoption than it has; particularly in light of the changes in the ACCP guidelines and focus by the Surgeon General’s office. The results from the PE market study were unequivocal. DVT is generally a quality of life issue while PE can be life and death; thus adoption of interventional therapy for PE will be much more rapid.”

In researching the literature with principal investigator for EKOS’ U.S. trial, Samuel Goldhaber MD, Brigham & Women’s Hospital cardiovascular division in Boston, Hubert goes on to state, “We did a lot of data mining of the peer reviewed publications and there is a plethora of papers addressing sub massive PE and the poor prognosis of morbidity and mortality that these patients will probably face if they leave the hospital with an enlarged right heart due to a pulmonary embolism, including the risk of permanent pulmonary hypertension.”

A summary of articles about data previously published on sub massive Pe patients and right ventricular dysfunction (RVD) provided ample ammunition for Tod Engelhardt, MD, Assistant Professor of Surgery at Tulane University School of Medicine in New Orleans Louisiana Heart, Lung and Vascular Institute, to return to his records to tally up his own data. (See Why Treat Sub massive PE Patients?)

As a result, in "Thrombosis Research" (Elsevier), Engelhardt et al presented their findings in support of the use of EKOS’ patented catheter-directed Ultrasound-Accelerated Thrombolysis (USAT) for the treatment of pulmonary embolism. Their particular focus was the retrospective analysis of 24 PE patients who were treated with USAT and the efficacy of its usage in the reversal of right ventricle (RV) dysfunction.

The study goes on to list several of its own limitations, beginning by pointing out the retrospective nature of the study and the small sample number of patients. However, the conclusion was intriguing enough - in patients with intermediate (sub-massive) and high risk (massive) PE, low-dose USAT rapidly reverses right ventricular dilatation and pulmonary clot burden.

This certainly doesn’t hurt EKOS’ push towards standard of care and early interventions in clot management in sub-massive or massive PE.

EKOS device has the CE Mark approval for use of the EkoSonic Endovascular System in Europe to treat both massive and sub-massive pulmonary embolism, which they received in December 2010. This includes patients with ≥ 50% clot burden in one or both main pulmonary arteries or lobar pulmonary arteries, and evidence of right heart dysfunction based on right heart pressures or echocardiographic evaluation.

“In the U.S., more than 600,000 patients a year are diagnosed with PE, of which 40% are sub-massive,” Hubert explains.

“These pulmonary emboli are usually bilateral, placing a lot of strain on the heart. Typically when a patient is diagnosed with sub-massive PE they are treated in the ICU with blood thinners in hopes that the body will resolve the clot by itself. Unfortunately in many patents that does not happen and the outcome is not good. Our expectation is that the data generated using EKOS therapy will demonstrate excellent outcomes for these patients.”

The company states that the EkoSonic System is FDA cleared for controlled and selective infusion of physician-
specified fluids, including thrombolytics, into the peripheral vasculature, and for placement into the pulmonary artery for infusion of solutions.

Clinical Data

The early peer-reviewed studies of EKOS (Parikh, et al, JVIR 2008) demonstrated that the first generation EKOS systems dissolved venous clot in half the time and with half the drug dose as standard catheter directed thrombolysis.

Using the latest generation EKOS System, early results from the FAST trial arterial clot lysis (Ramaiah, et al, icon 2011) proved that EKOS thrombolysis completely clears (>90%) of arterial clot in 79% (11/14) of patients in a median time of 4.5 hours.

Other global research studies involving the EKOS System include the "Cava Trial: a randomized multi-center studyof EKOS vs anticoagulation for DVT patients" (principal investigators C. Wittens, H. Ten Cate; Maastricht, NL); the DUET trial: a randomized multi-center, controlled study of EKOS vs. standard catheter directed thrombolysis in patients with arterial occlusions (principal investigators, JP De Vries, A.M. Schrijver; Nieuwegein, NL, and M. Reijnen; Arnhem, NL); "The IMS iii Trial: a randomized, controlled, multi-center study of EKOS MicroSonic Small Vessel System and other devices to treat ischemic stroke" (principal investigators: J. Broderick, T. Tomsick, Univ. of Cincinnati); and the recently completed "SLEUTH Trial: a Phase 2 safety study of patients with hemorrhagic stroke treated with thrombolytic and EKOS ultrasound to reduce hematoma size" (principal investigators: D. Newell, Seattle, WA, and D. Hanley, Baltimore, MD).

To more completely characterize the benefit of EKOS in the treatment of pulmonary embolism, VEIN Magazine learned that EKOS is sponsoring a European, multi-center, randomized clinical trial called ULTIMA which compares sub massive PE patients treated with EKOS vs. the medical standard of care - anticoagulation. Study completion is targeted for late 2012. (Principal investigator: N. Kucher Bern, Switzerland).

EKOS owns or has licensed 39 U.S. patents and has 26 pending which protect its unique ultrasound drug acceleration technology. Supporting patents are issued in Europe and Japan.

The Future of Intervention

It is said, “necessity is the mother of invention.” As more and more attention is given to clot removal and early intervention, it is certain this segment will see plenty of change over the coming months and years. New players are already beginning to emerge, and with them, more options will come to light that will continue to provide physicians and their patients better treatment for these life-threatening diseases, no doubt borne from the advancements we are beginning to see today.