Clinical Trials

ATTRACT Trial Signals Reduction in Post Thrombotic Syndrome Severity with Interventional Treatment of Acute Deep Venous Thrombosis

Cath Lab Digest talks with venous specialist Timothy E. Yates, MD, Mount Sinai Medical Center, Miami Beach, Florida, about his DVT treatment results and how they compare to ATTRACT.

 

Cath Lab Digest talks with venous specialist Timothy E. Yates, MD, Mount Sinai Medical Center, Miami Beach, Florida, about his DVT treatment results and how they compare to ATTRACT.

 

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) Trial 

The ATTRACT study1 sought to determine whether the use of adjunctive pharmacomechanical catheter-directed thrombolysis, which includes the intrathrombus administration of rt-PA (alteplase), in addition to standard treatment (anticoagulants and the use of elastic compression stockings), can prevent post-thrombotic syndrome (PTS) in patients with symptomatic proximal deep vein thrombosis (DVT) as compared to standard anticoagulation therapy alone. This NIH-funded, Phase III, multicenter, randomized, open-label, assessor-blinded, parallel two-arm, controlled clinical trial enrolled 692 patients. The primary endpoint was cumulative incidence of PTS out to 24 months. 

At the 2017 Society of Inteventional Radiology (SIR) conference in Washington, DC, the 24-month data was presented by the ATTRACT principal investigator, Suresh Vedantham, MD. The trial results demonstrated that while there was no difference in the primary outcome between the two arms, DVT patients who received pharmacomechanical catheter-directed thrombolysis were 25% less likely to develop moderate to severe PTS. It also suggested that patients with larger clots, such as those with iliofemoral DVT, may benefit most from this procedure.

The ATTRACT trial results identified a suggested benefit with interventional therapies of iliofemoral DVT compared to the femoral popliteal segment. Do you feel this is an accurate representation of what you see in terms of success in treating DVT patients?

Absolutely. Both in surgical and endovascular literature, there is evidence that removal of thrombus is effective for both a reduction in post-thrombotic syndrome (PTS) and a reduction in postthrombotic morbidity. The femoropopliteal segments have always been traditionally more difficult to treat — it is less effective, irrespective of what the employed strategy may be, and ATTRACT offered further evidence that this is in fact the case. The post-thrombotic incidence was the same in both the treatment arm and the anticoagulation-alone arm, irrespective of whether it was iliofemoral or isolated femoropopliteal disease. On the flip side, the occurrence of moderate to severe post thrombotic syndrome trended to be less in iliofemoral disease, along with the overall pain and swelling. These clinical complaints are really what the patient cares about, not where the DVT is, or what it looks like on a venogram or intravascular ultrasound (IVUS). In the ATTRACT trial, acute symptoms of pain and swelling were also improved out to 30 days in the interventional treatment arm. That is important and adds further support to the CAVENT (Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis) trial and other surgical trials, where the iliofemoral segment was the target. 

My paradigm is to aggressively treat patients with acute iliofemoral DVT (less than 14 days old). I typically treat patients who are active, relatively healthy, and less than 65 years of age. If, in this same active, healthy population, the DVT is older than 14 days, my decision to treat usually hinges on continued iliac involvement, not the fempop segment. I don’t usually go after isolated femoral popliteal disease, because there is just no defined role for treatment. You only add cost for the patient, and  potential for procedural morbidity and mortality.   

What are the challenges with treating fempop disease?

Treating isolated femoropopliteal disease is very challenging. I think you set yourself up for failure by treating those segments alone. DVT or venous disease is a very different monster than arterial disease. Veins behave differently in terms of flow; they are highly distensible and collapsible, and vein diameter constantly changes, because venous flow is a dynamic process. The diameters in the femoral popliteal segment are much smaller than they are in the cava or iliac segments — anywhere from 5-10 mm compared to up to about 16-20 mm in the common iliacs. Adding to that, the below-the-knee veins are incredibly small. Below the knee is a complicated network of multiple veins, and these veins are very dependent on calf and muscular function to essentially squeeze the flow upward. After DVT, there is scarring in the veins related to the deposition of fibrin, and ultimately there is conversion to collagen. After this, the veins can’t dynamically distend and have suffered irreversible damage. It probably also explains why we run into problems with venous recoil when we treat with balloon angioplasty in these segments alone. It hasn’t been particularly effective. Stents in these segments haven’t been particularly effective either, because of another factor in venous disease, which is flow. When we put in a stent — a rigid metal cage — the conductive forces related to the distension and rapid collapsing of the veins, such as muscular pumping, can’t occur. Based on Virchow’s triad, stasis of flow is one of the three cardinal risk factors for development of thrombus. Stents without flow will clot. We are unlikely to be successful in treating isolated femoral popliteal venous thromboembolism, at least with current techniques. Treatment success (angioplasty, stenting, thrombolysis, thrombectomy) is more likely in the iliofemoral segment and all of these trials have shown that to be the case.

Do you feel that the ATTRACT study adequately represents the DVT patient pool that you currently see?

Yes, the general study population was fairly similar. ATTRACT studied patients that were 16-75 years old with what they defined as proximal DVT. ATTRACT excluded pregnant patients, patients with active cancer, those with recent major surgical intervention, obstetrical delivery, or brain lesions, or if they already had thrombotic syndrome. In my practice, I typically do not treat pregnant patients or those with active cancer either, at least not with thrombectomy. There are isolated cases, however, where I will deviate from this. The above contraindications are standard for most types of thrombolytic therapy. Here in Miami Beach, we do have an older population, so I see a lot of patients that are in the 80 to 90, or even 100-year-old range, and obviously we are not treating those patients unless there is a specific reason to do so. The patient has to be incredibly active patient and with an iliofemoral DVT for me to consider treatment.

How do you see ATTRACT study results affecting your patient selection and treatment approach for DVT patients?

For those of us treating a lot of DVT, the trial reinforced what we already knew. ATTRACT basically gave us further support to treat iliofemoral disease, because even though there wasn’t an overall reduction in post-thrombotic syndrome incidence, there was a reduction in symptoms out to 30 days and this continued out to a year. There was also a statistically significant reduction in the occurrence of moderate to severe PTS, which is really what we are after in these patients. These patients are the ones with chronic venous stasis, ulcerations, severe varicose veins, chronic edema, and pain, and if we can reduce that occurrence by 25%, it is a significant reduction in the cost burden to the health care system.  ATTRACT will also help to exclude patients who aren’t likely to benefit, who are the isolated femoral popliteal disease patients or the below-knee DVT patients that are very likely to partially or completely recanalize on their own, statistically speaking. They are unlikely to derive any other significant benefit in terms of post-thrombotic syndrome or its morbidity. ATTRACT tells us to avoid exposing these patients to a costly procedure or the risks associated with thrombolysis, and to just treat them with the standard of care. 

ATTRACT demonstrated a statistically significant reduction in the severity of PTS at two years for the iliofemoral patient population. How impactful is this data point?

Again, it supported what was seen in CAVENT and the surgical literature. And this was with thrombectomy, which is usually a single-session treatment strategy. In terms of impact, it supports us further in what we are doing for these patients from the standpoint of doing an invasive procedure. What’s disappointing is that the overall post thrombotic syndrome incidence wasn’t any different in either group. In CAVENT, the catheter-directed thrombolysis trial, there was a 28% absolute risk reduction in PTS incidence. The control arm had 71% and there was a 43% incidence in the catheter-directed thrombolysis group. What is interesting about that study is that despite the fact that they had those gains, they didn’t see an overall increase in the quality of life for these patients, which again calls us to continue to study this disease. DVT is a chronic disease state, even if you have an isolated acute event. It is something that most patients are going to be dealing with, in some shape or form, for the rest of their lives. Even though we talk about acute DVT, it really is the initiation of a chronic disease state. Identifying and treating these patients early is crucial. And in terms of “bang for the buck”, the iliofemoral population is where we have to focus initial efforts. 

What impact have you personally seen from an interventional therapy for DVT in patients in terms of both short- and long-term quality of life?

Gains for my patients certainly are greatest in the first 30 days, echoed by the ATTRACT trial. The first month is when patients experience the “wow” decrease in edema and pain. The onset of post-thrombotic syndrome is typically something that develops in the course of months to years. That also speaks to why we see an impact at 30 days — carry it out to longer periods of time and you tend to see those gains level off. If they continued trial follow-up out to 5 years, I suspect that the overall gains would trend off and become, if not slightly better, at least the same as the anticoagulation-alone group. In my practice, I see a lot of uncovered iliac disease. I have also been aggressive with iliac vein stenting with patients refractory to angioplasty, based on IVUS criteria.

In terms of long-term quality of life, someone that treats DVT has to know it is like treating diabetes or hypertension, because DVT is truly a chronic disease. Though the patient presents with an acute event, I often will see, venographically and with IVUS, evidence of chronic disease, mostly in the iliac segments or the common femoral segments. Despite the existence of acute disease in the femoropopliteal segment, we will see evidence of some type of chronic venous compression, or stenosis or occlusion. I believe that several of these patients have already had multiple acute events. DVT is a stepwise disease with repeated episodes and, at some point, as the saying goes, the straw breaks the camel’s back and you thrombose the entire leg. The challenge going forward for improving quality of life is to get patients in earlier and figure out ways to keep them open for longer. These patients should have a specialist; they need somebody that understands their disease process, and that is really us, the people that are treating them. We must give patients the resources and support they need to understand that even though we are performing a procedure and removing clot, the inflammatory state and the disease state that brought them to this point is still occurring in their body. Some of these patients are hypercoagulable, while some have genetic profiles that make them more likely to thrombose. Others are mechanically obstructed. I think there is a combination that is probably true for the majority of patients. So the take-home is that we are the patients’ advocates for the long-term consequences of the disease, and we have to give patients realistic expectations. They need compression stockings, activity, to take part in walking programs, and elevate their legs when they are not active. We must try to get them into the mindset of being active in their own treatment and investing in themselves. 

What do referring physician specialties need to know about the ATTRACT data results and the benefits of intervention? What are the key points you would highlight to these physicians?

One important point is, how do we identify DVT patients? Despite the fact that what we find is often an acute femoral popliteal thrombosis,often there is preexisting iliac disease. How do we find these patients early? The truly acute patients have the best procedural results and the best long-term patency. So, is our definition of acute truly appropriate? Is 14 days really a short enough period of time? How do we get referring physicians to identify patients with DVT appropriately and how do we get them to our centers? My challenge with referring physicians is to use the CAVENT and ATTRACT trial data to show iliofemoral DVT patients are likely to derive benefit from pharmacomechanical thrombectomy or thrombolysis in terms of PTS. We are going to see at least a 25% reduction in moderate to severe disease pathology (for thrombectomy) and a definite clinical benefit up to 30 days in terms of reduction of edema and pain. These are the things that I bring to the attention of my referring physicians, and I emphasize that they need to get patients to see us as quickly as possible in order to reduce the time from the onset of DVT to procedure. We need to educate our referring physicians that DVT isn’t just “a thing that happens” where you then put patients on anticoagulation and send them away. We must educate and work with our colleagues to understand that DVT is a chronic disease state, and that treating it aggressively and early in our patient population is crucial. For us, as interventionalists, the wow moments often happen after a successful case and are both venographically and sonographically (IVUS) satisfied. But the true impact comes during the  follow-up when patients still have relief. At 6-month follow-up, they say, “Doctor, I can still walk. My leg is not swollen and I could not have done it without this procedure. I talked to several people before I got to you and you were the only one that truly understood what was going on.” I believe you have to be a patient advocate, and in this particular disease, viewing it as a chronic disease state and giving patients resources is where I found I could have an impact. 

How much of an impact does a walking program have on the progress of the disease?

A study of the association of a walking program with venous disease and venous thromboembolic disease, before and after intervention, or after anticoagulation therapy, would be very important. I do think it is a factor. Muscular contraction is a crucial flow mechanism below the knee and if we have a patient that is not going to be mobile after we have reestablished a lumen, they are still at risk, because the blood flow is static. We try to do these procedures in an ambulatory fashion, and if they are inpatient, my protocol is to get these patients into compression stockings right away. Then, immediately or as soon as they can, they are out of bed and walking. 

What do you see as we look ahead?

I treat the vast majority of my DVT patients with either pharmacomechanical thrombectomy or suction thrombectomy. We know from surgical thrombectomy and thrombolysis trials and retrospective studies that these procedures do confer decreased morbidity and incidence of PTS. I am a strong believer in single-session therapy. I think we need to continue to investigate this option to try to minimize patient exposure to risk and cost of care. ATTRACT was trying to show that pharmacomechanical thrombectomy and catheter-directed treatments are viable alternatives. It did establish the presence of a conferred benefit in the same segments that we already were aware of. Why does it matter? While the thrombectomy treatment itself is expensive, the goal, in my practice, of single-session therapy, avoids the costly ICU utilization for both my hospital and for the patient, and decreases the potential for complications, bleeding, or overnight or multi-hour tPA infusions.  

Other things to look at are the tools now available for thrombectomy. For example, the newest generation of AngioJet, the ZelanteDVT catheter (Boston Scientific), now reports 4x more thrombus removal with the 8 French (Fr) catheter compared to their 6 Fr catheter. The ZelanteDVT catheter is directable up to 270 degrees, so you can get much better wall and clot contact (which is really what we are looking for), and aspiration in multiple directions for better clearance. Whenever we look at a trial, we are several months to years behind the current state of technology, and the question we always have is, would this new generation have caused a different result? I want us to continue to push ahead and further separate out which patients benefit the most, as well as those that don’t benefit at all. In the iliofemoral and large veins, right now, these tools are fantastic. Would the ZelanteDVT catheter and 8 Fr suction CAT-8 catheter and Penumbra Indigo system have been better in supporting the open vein hypothesis in the ATTRACT trial? In my practice, I think it would, out to about a year. Of the iliac segments I have stented, the vast majority of patients are open, while about 50% of patients who had femoral popliteal occlusions at the time of their iliac occlusions re-occlude. When the femoral popliteal segment remains occluded chronically, it does contribute to post thrombotic mortality and morbidity. Still, patency of the femoral popliteal segment isn’t necessarily crucial to the patency of the iliac segments. The distensibility and compressibility of the iliac segments are not as big of an issue either, and in my patients, I tend to be a little more aggressive in stenting early. In these patients, stenting is often necessary to maintain patency. Keeping the vein open does, in my patient population, reduce the overall PT morbidity and potentially its incidence — and also, ultimately, improve quality of life.

CAVENT showed that there was less post thrombotic syndrome in the catheter-directed thrombolysis group vs control; ATTRACT didn’t show that difference between the control and experimental arms. Some questions I am thinking about are: Is it a technological issue? Is our definition of acute DVT clinically relevant? Or is it something we don’t understand on a biochemical level, at the level of the venous endothelium, with all the inflammatory changes that occur in cascades? Those are areas we need to continue to investigate. It underscores what Suresh Vendentam, the PI for ATTRACT, said at the 2017 SIR conference, which is, do we truly understand what PTS is? Do we understand what the truly crucial factors are that send patients off into moderate to severe PTS? 

Finally, IVUS for me, is indispensable for the treatment of venous disease. It is an incredibly useful tool for identifying the involvement of various venous segments. Venograms are inherently unreliable, which has been born out in trials such as the IVUS VIDIO trial. Veins, as we talked about, don’t behave like arteries. They can collapse and they can compress. While something might look like there is flow on a venogram, it might only be in one dimension. IVUS gives you a 360-degree view of the vein lumen. I end up treating segments more aggressively because I didn’t truly see a difference venographically. The inclusion and validation of IVUS in treating venous disease is crucial. The hope is that we will eventually come up with something that will be more solid in terms of protocol, nationally and internationally. Venous disease is the frontier where we don’t have all the answers. We need to continue to  the momentum ATTRACT started, even with failed endpoints. High-quality data is needed to continue to elucidate the best treatments for our patients. This trial was a very important, Level 1, first step.

Reference

  1. Vedantham S, Goldhaber SZ, Julian JA, et al.; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017 Dec 7;377(23): 2240-2252. doi: 10.1056/NEJMoa1615066.

Sponsored by Boston Scientific.