A Moving Target

Questions abound about use of catheter-directed therapies for venous thromboembolism.

The proliferation of novel catheter-directed therapies for pulmonary embolism and deep vein thrombosis has spurred rapid development in the treatment of venous thromboembolic disease. As the field rushes forward, however, physicians in some ways are left playing catch-up.

“This whole field of treatment of PE and VTE is particularly challenging because, as we establish new therapeutic goals, the ground is shifting rapidly. The development of new innovative devices, alternative pharmacologic agents and new models of care — such as Pulmonary Embolism Response Team (PERT), a multidisciplinary team-based approach to PE — makes for a rapidly evolving field and thus a moving target. It is challenging for clinicians and scientists to keep up with what’s happening and to integrate new therapies into the existing paradigms,” Kenneth Rosenfield, MD, MHCDS, FACC, FSCAI, Cardiology Today’s Intervention Editorial Board Member and section head of vascular medicine and intervention at Massachusetts General Hospital, said in an interview.

The problem lies less in the devices and more in the lack of data available to inform decision-making, experts told Cardiology Today’s Intervention. As these novel therapies come onto the market or, in some cases, inch toward FDA approval, physicians require more information about for whom these treatments are most appropriate.

This is particularly true for patients with PE, according to Jay S. Giri, MD, MPH, director of peripheral intervention and assistant professor of medicine at the Hospital of the University of Pennsylvania.

“There are going to be a lot of tools in the toolbox for PE before too long, but just because those tools exist, it is important to know that we may not be helping patients by uniformly, routinely or algorithmically treating large swaths of patients with PE,” he said in an interview. “In the absence of evidence, the onus is on us, as clinicians, to try to select those patients who are going to benefit most and be least likely to be harmed with utilization of aggressive therapy. As a research community, the onus is also going to be on us to try to produce evidence to more scientifically guide the employment of these therapies.”

Potential Benefits of Catheter-based Thrombolysis

For both PE and DVT, the longstanding standard of treatment is anticoagulation, which generally works well alone in low-risk patients. However, for patients who require escalation of therapy, catheter-directed thrombolysis may be a viable alternative to the traditional next step of systemic thrombolysis.

Systemic thrombolysis is most often administered at a high dose and carries a significant risk for bleeding, including the potential for a fatal intracranial hemorrhage, according to Andrew Klein, MD, FACC, FSCAI, interventional cardiologist at Piedmont Heart Institute. Because catheter-directed thrombolysis delivers the thrombolytic agent directly to the thrombus via a catheter and at a much lower dose, some of this risk might be mitigated.

“The advantage of delivering clot-busting medicine directly to the clot is that you’re able to use a lower dose than you would if you were administering it through an IV as you would with systemic thrombolysis. In fact, the dose can be reduced to one-fifth of that given during systemic thrombolysis,” Klein told Cardiology Today’s Intervention.

Giri pointed out, however, that data are lacking on whether catheter-directed thrombolysis is superior to systemic thrombolysis.

“We tend to think that catheter-directed lysis has theoretical benefits in terms of potentially having less bleeding risk and maybe more efficacy, but it is important for us to recognize that we have not proven that in any kind of significant way. There have been no comparative studies that are of any value that compare the two approaches to one another. Therefore, when we are using catheter-directed lytic approaches vs. a systemic lytic approach, we’re doing it based on faith, not evidence,” Giri said.

Novel Catheters

Catheter-based thrombolysis can be performed using a standard infusion catheter or a catheter with an ultrasound transducer at its core (EKOS; EkoSonic Endovascular System, BTG). In theory, Rosenfield said, ultrasound-assisted catheter-directed thrombolysis enhances the effectiveness of the thrombolytic agent by delivering ultrasound energy that enables molecular bonds, such as those between fibrin molecules, to be broken down and allows better penetration of the drug.

Furthermore, data support ultrasound-assisted catheter-directed thrombolysis in PE, which actually comprises a significant portion of the overall data on catheter-based approaches to thrombolysis, have been largely positive, Klein said.

For instance, the ULTIMA trial, published in Circulation in 2014, showed that ultrasound-assisted catheter-guided thrombolysis was superior to anticoagulation with heparin alone in reversing right ventricular dilatation without increased bleeding complications in patients with intermediate-risk PE (See Table). Similarly, results from the single-arm SEATTLE II trial, published in JACC: Cardiovascular Interventions in 2015, linked ultrasound-assisted catheter-directed thrombolysis to improved RV function in acute PE, decreased pulmonary artery angiographic obstruction and reduced pulmonary artery systolic pressure (Table).

Most recently, in the OPTALYSE PE study, published in JACC: Cardiovascular Interventions in 2018, ultrasound-assisted catheter-directed thrombolysis was associated with a reduction in the RV/LV ratio and clot burden, at lower doses and shorter durations than prior regimens (Table).

Giri noted, though, that it remains unclear how these ultrasound-enhanced catheters stack up against infusion catheters, as no randomized comparisons have been performed in PE and one done in DVT showed no difference.

The ongoing SUNSET trial, which is comparing ultrasound-enhanced catheters with infusion catheters for thrombolysis, seeks to answer that question, Klein added.

Advances in Thrombectomy

Whereas catheter-directed thrombolysis centers around dissolution of the clot, thrombectomy focuses on removal of the clot by aspiration or suction.

Most recently, the FlowTriever System (Inari Medical) — a catheter-directed mechanical thrombectomy device that combines aspiration and mechanical disruption — was approved by the FDA for use in PE based on results of the FLARE trial, which were presented at the Society for Cardiovascular Angiography and Intervention Scientific Sessions in April. In this prospective, single-arm, multicenter study, use of the device without thrombolytics reduced RV strain at 48 hours in patients with acute submassive PE (Table).

One potential downside to this device, according to Rosenfield, who was the primary investigator for the FLARE trial, is the large size of the current iteration — 20F — and the learning curve, as an operator must navigate through the RV out into the correct pulmonary branch. He noted, however, that a smaller version of the device that may mitigate some of these issues is in development.

Another aspiration device that has been used in DVT and is now being investigated for use in PE is the Indigo System Continuous Aspiration Mechanical Thrombectomy 8F (CAT8) catheter (Penumbra).

Other available devices include the AngioVac mechanical thrombectomy device (AngioDynamics) and the AngioJet rheolytic thrombectomy device (Boston Scientific), but they are not often used in PE. The AngioVac, for instance, is a large device that requires veno-venous bypass and not well-designed yet for use in the pulmonary arteries, Rosenfield said. “It still has potential to be a game-changer, with appropriate modifications,” he said. The AngioJet now carries an FDA black box warning after the device was associated with morbidity and mortality when used in the pulmonary arteries.

For DVT, however, AngioVac and AngioJet appear to have an important place in clinical practice. AngioJet is useful and efficient in acute iliofemoral DVT and AngioVac is most useful in clearing cases of catastrophic inferior vena cava and right atrial thrombus, according to Charles B. Ross, MD, FACS, chief of vascular and endovascular services at Piedmont Heart Institute and Piedmont Atlanta Hospital.

In terms of newer technologies for DVT, a device that is comparable to FlowTriever, dubbed ClotTriever (Inari Medical), has been developed for use in DVT and the JETi Thrombectomy System (Pyramed) has generated interest for treatment of DVT as well.

Despite these new devices, physicians still do not fully understand when they should escalate therapy beyond anticoagulation and which therapies would be best in various clinical situations.

“We need systematic collection of data and development of an evidence base, both by randomized and single-arm clinical trials, as well as thorough collection of registry data; this will help us parse out what is the best therapy for any given patient,” Rosenfield said.

Patient Selection is Key

Currently, identification of patients with DVT or PE who would fare best with catheter-directed therapy is complicated, experts told Cardiology Today’s Intervention.

In terms of DVT, the CAVENT trial, published in The Lancet in 2012, indicated that catheter-directed thrombolysis in addition to anticoagulation, compared with conventional care, was shown to reduce the risk for postthrombotic syndrome, at the cost of a small increase in bleeding, in patients with acute iliofemoral DVT (Table on page 12). However, in the ATTRACT trial, published in The New England Journal of Medicine in 2017, adding pharmacomechanical catheter-directed thrombolysis to anticoagulation did not lower the risk for postthtrombotic syndrome and increased risk for major bleeding in patients with acute proximal DVT (Table).

Those findings, however, should be placed in context, according to Lawrence (Rusty) Hofmann, MD, FSIR, professor and chief of interventional radiology at Stanford University School of Medicine; medical director of cardiac and interventional radiology at Stanford Hospital and Clinics; and medical director of Digital Health Care Integration for Stanford Health Care.

“The decision was made to construct the trial as first-line therapy for all proximal DVTs, which include femoral popliteal DVT as well as iliofemoral DVT. However, in clinical practice for the past 20 years, the vast majority of treated patients were iliofemoral DVT patients that underwent catheter-directed therapy, often due to progression of symptoms while on anticoagulation,” he told Cardiology Today’s Intervention. “Subsequently, it was not surprising that ATTRACT was a negative trial. But the secondary endpoint showed that patients who benefited most from the intervention were those with iliofemoral DVT and the belief has been that those are patients who have a much larger thrombus burden and really do need adjunctive measures to remove the clot, restore patency and prevent the postthrombotic syndrome.”

Consequently, Hofmann said the ATTRACT results haven not changed his practice because he would not have treated many of those patients enrolled in the trial.

For PE, appropriate patient selection is further complicated by the fairly crude risk-stratification system that classifies patients as having massive, submassive or low-risk PE, Rosenfield said.

Generally, patients with low-risk PE fare well on anticoagulation alone and those with massive PE definitely require more aggressive therapy, either with systemic thrombolysis, surgical embolectomy or catheter-directed therapies with or without mechanical circulatory support. The appropriate therapy for patients with submassive PE, though, is more difficult to pinpoint, Klein said. These patients, he explained, show evidence of right heart strain on CT scan or echocardiography and have elevated troponin and B-type natriuretic peptide (BNP), but, unlike patients with massive PE, are not dying.

“For submassive PE, you have to watch the patient and see what their trajectory is,” Akhilesh Sista, MD, FSIR, section chief and associate professor of vascular and interventional radiology at NYU Langone Medical Center and national principal investigator for the trial of the Penumbra device in PE, told Cardiology Today’s Intervention. “If they look like they’re heading toward decompensation — if they look ill, if their lactic acid is going up, if they have signs of RV failure or impending RV failure — those patients should receive something more.”

Understanding the Risks

When considering which patients to treat, it is important to also consider the rare, but significant, risks associated with catheter-directed therapies for VTE.

Bleeding events, including those associated with thrombolysis and those associated with the procedure itself, are a concern with catheter-directed therapies in both DVT and PE, but with PE, the need to navigate the heart while working in the pulmonary arteries creates the possibility to cause damage to the cardiac structures or lung, according to Sista.

“You’re passing catheters and wires through the right heart in the pulmonary circulation, so you can cause arrhythmias or perforations,” he said.

Other risks include the potential for hemodynamic collapse due to further embolization during intervention, Ross added.

“Clinical deterioration and even death in PE intervention has been reported in cases where saddle emboli have been broken up only to embolize into the more distal pulmonary arteries, thus immediately increasing RV afterload with deterioration to shock,” he wrote in an in email to Cardiology Today’s Intervention.

There are also a number of other complications, such as access-site bleeding, that are characteristic of any interventional procedure, Ido Weinberg, MD, MSc, FACC, assistant professor of medicine at Massachusetts General Hospital, said in an interview. Also, if unwarranted, the treatment itself becomes the problem.

“There are patients who may have otherwise done well with anticoagulation alone who undergo a procedure and then experience bleeding or respiratory decompensation that may not have otherwise occurred,” Weinberg said. “These issues are rare, but they can happen once you start using catheters in the heart and pulmonary arteries and you never know what the cause and effect was.”

A Need for More

Although the field of catheter-directed therapies has no shortage of new devices or technologies, more is needed in terms of data, there is a call for more involvement from physicians and researchers, and collaboration across specialties.

“Catheter-directed therapies, in multiple trials, have been shown to rapidly reverse RV dysfunction while also reducing the expected rate of clinical deterioration,” Ross said. “Improvement in these two endpoints, when viewed as surrogates for mortality reduction, supports the value of these treatment modalities. At the bedside, such physiological improvement is manifested in patients by symptomatic relief that seems to be achieved much more quickly compared with anticoagulation alone.”

Outside the advantage of faster resolution of symptoms, the potential benefits of catheter-directed therapy are more theoretical and not supported as strongly by hard evidence, Giri noted.

“We hope that if we select patients properly, we actually may extend their lives, but the evidence behind that is softer. Also, many patients with PE are left with long-term symptoms, such as frank pulmonary hypertension or persistent functional status decline, so we also hope that we can improve these long-term symptoms. However, we haven’t yet shown that with perfect data for any of our catheter-based therapies at present,” he said.

Additionally, in most of the trials involving catheter-based therapies for PE, surrogate endpoints, such as RV/LV ratio after treatment, were used instead of clinical endpoints, according to Sista. More studies showing the effect of these treatments on mortality, deterioration, long-term functional status, recurrent VTE and quality of life would be of benefit, he said.

Weinberg echoed Sista’s sentiments, noting that a recent American Journal of Medicine study he and his colleagues conducted, suggests the mortality rates for patients with acute massive and submassive PE remain high despite the introduction of advanced therapies.

“Regarding massive PE, much work remains to be done in terms of risk stratification,” Ross said. “Massive PE is defined by hypotension, but in practice, there are wide variations in the severity of illness of patients in the massive category. It is difficult to compare outcomes and design therapy when patients are stratified by such a blunt and simple instrument. The same is true in the case of intermediate-risk or submassive PE. Better stratification should lead to refinements in our understanding of best candidates for PE intervention and improvements in matching the best primary device for an individual patient.”

Finally, greater involvement on the part of physicians is essential, according to Rosenfield, who pioneered the concept of the PERT as well as the development of the PERT Consortium, a 501(c)3 organization dedicated to improvement of care and outcomes for patients with PE. The PERT concept brings together physicians from multiple disciplines at one center to evaluate and create a treatment plan for patients presenting with PE. Likewise, the PERT Consortium has created an international database of information from participating centers and is partnering with the Boston Clinical Research Institute to analyze data and try to answer some of these important questions, he added.

“We need the medical community — physicians and institutions and our industry partners — to invest in this incredible initiative, so we can actually define what’s best for patients and improve outcomes for this terrible disease,” Rosenfield said. – by Melissa Foster

• References:
• Enden T, et al. Lancet. 2012;doi:10.1016/S0140- 6736(11)61753-4.
• Kucher N, et al. Circulation. 2014;doi:10.1161/CIRCULATIONAHA.113.005544.
• Piazza G, et al. JACC Cardiovasc Interv. 2015;doi:10.1016/j.jcin.2015.04.020.
• Secemsky E, et al. Am J Med. 2018;doi:10.1016/j.amjmed.2018.07.035.
• Tapson VF, et al. JACC Cardiovasc Interv. 2018;doi:10.1016/j.jcin.2018.04.008.
• Tu T. Late Breaking Clinical Science II. Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions; April 25-28, 2018; San Diego.
• Vendantham S, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615066.

• For more information:
• Jay S. Giri, MD, MPH, can be reached at jay.giri@uphs.upenn.edu; Twitter: @jaygirimd.
• Lawrence (Rusty) Hofmann, MD, FSIR, can be reached at lhofmann@stanford.edu; Twitter: @rustyhofmannMD.
• Andrew Klein, MD, FACC, FSCAI, can be reached at andrew.klein@piedmont.org; Twitter: @DrDrewKleinMD.
• Kenneth Rosenfield, MD, MHCDS, FACC, FSCAI, can be reached at krosenfield1@mgh.harvard.edu; Twitter: @krosenfieldMD.
• Charles B. Ross, MD, FACS, can be reached at charles.ross@piedmont.org.
• Akhilesh Sista, MD, FSIR, can be reached at akhilesh.sista@nyumc.org; Twitter: @akhileshsistaMD.
• Ido Weinberg, MD, MSc, FACC, can be reached at iweinberg@mgh.harvard.edu; Twitter: @angiologist.

Disclosures: Giri reports he serves on the board of directors for the PERT Consortium and he serves on the advisory board for AstraZeneca. Hofmann reports he has financial ties to Aron Medical, Boston Scientific, Confluent Medical, Cook Medical, Medtronic and W.L. Gore and Associates and he is founder of Grand Rounds. Klein reports he serves on the peripheral advisory board for Medtronic. Rosenfield reports he serves on the advisory board for Abbott, Capture Vascular, Cardinal Health, Magneto, MD Insider, Shockwave and Surmodics; he owns equity in Contego, Embolitech, MD Insider, PQ Bypass and Primacea; he serves on the advisory board for Thrombolex; he has received research support from Inari Medical and the NIH; he has stock in Eximo; and he is a board member for VIVA Physicians. Ross reports he is a consultant for BTG and a member of the board of directors for the PERT Consortium. Sista reports he received grant or research support from Penumbra; he serves on the advisory board for Thrombolex; and he serves on the steering committee for the C-TRACT trial. Weinberg reports he serves on the scientific advisory board for Novate Medical.