From trial data to DVT care: Dr. Suresh Vedantham on the C-TRACT study

Episode Transcript

Behind every case there’s a story. Behind every story there’s a lesson, and behind every lesson learned, there’s a trusted mentor. This is Prepped + Draped with Dr. John Kaufman, where candid conversations, actual cases, and bold new professionals shape medicine.

Welcome to Prepped + Draped. I’m really honored to have today Suresh Vedantham, who is the professor of radiology and surgery, assistant dean of clinical research, and medical director of clinical studies at WashU Mallinckrodt Institute of Radiology, but the first author of the recently published in April results of the pivotal C-TRACT trial, and here we are talking in May about that. I’m really honored, Suresh, that you’re going to join us on this podcast.

I also understand that you are a diamond-level U2 fan, but we’ll leave that for the end of the podcast. So, just before we get started, we’ll be talking about C-TRACT, obviously. Just tell us just a little bit about the trial and yourself, and how you got to the point of running a NIH multicenter national trial on treatment of chronically obstructive iliac veins.

Well, thanks, John. Real pleasure to be here with you. Always admired all the things that you’ve done over the years. And so, it’s great to have a chance to talk about the results of the trial and all that. So, thank you very much. So, as you might imagine, just about none of this was planned by me upfront, but like many interventional radiologists and other vascular providers, I started seeing patients who have chronic venous disease in my clinic and in the course of doing procedures.

And of course, that natural thing that comes to your mind is, “Well, gosh, how is it that we let patients get so sick, so disabled without intervening at an earlier time and trying to help them?” And how is it that even once they get into the chronic phase, how is it that they can bump in and talk to multiple providers before anyone really has a recognition of what they’re dealing with and refers them to appropriate care?

So, early on that clinical reality was kind of there. I was curious and had wanted to ask those questions and was kind of willing to ask them in a very objective way, I guess, as to, okay, just how effective are these procedures that we do? They certainly seem to be very effective when we are seeing them clinically in the short term. We see patients come in and their legs are very swollen and painful. And then our immediate feedback we get is that we’ve opened the vein up, whether it’s in the acute or chronic phase, and immediately, at least in most patients, those legs seem to be better. So, it seemed to me that there was a potential to have a larger impact in this disease state. In terms of how one goes about these things, by no means did I expect to be running a large multicenter trial.

Honestly, I wrote some retrospective papers. I started to interact with colleagues, and as I started to interact beyond interventional radiology, I realized that there was just such a large evidence gap between what we seem to be observing and what was going to be accepted by non-procedural providers in terms of routinely referring patients for these types of procedures. And so that’s kind of what sparked my interest in figuring out, okay, can we work together to try and answer some of these questions?

We see these patients, they get better on the table sometimes and we feel like, “Good, we’re done.” But you obviously are thinking much more about the long term. Tell us a little bit about the structure of the C-TRACT trial and many people will know you from the ATTRACT trial. So this is, I wouldn’t say a follow-on, but a very important study in this area. So, tell us a little bit about the structure of the trial, and then we’ll talk about some of the results and then maybe dig a little deeper.

Yeah. So C-TRACT, again, it’s funded by the National Heart, Lung, and Blood Institute. Medi USA was kind enough to donate compression stockings to study patients, but beyond that, those are the sources of support for the study. It is led by a multidisciplinary steering committee, and it was conducted in 29 United States sites, each of which has a multidisciplinary local team that involves, it could be interventional radiologists, it could be vascular surgeons, medical physicians, hematologists as well, vascular internists, cardiologists.

And this was a multicenter randomized trial. We included patients who have moderate or severe post-thrombotic syndrome. So they’ve had to have a previous history of DVT, and they have to have chronic symptoms of sufficient severity where doing an endovascular procedure would be reasonable. They also have to have iliac vein obstruction as demonstrated on imaging. So, at least a 50% narrowing or a total occlusion of the iliac vein.

And we randomized them to receive or not receive endovascular therapy, but all the patients in both arms got active standard management of post-thrombotic syndrome, including compression stockings, including other local allowed therapies, including ulcer care if the patient had an ulcer. And the endovascular therapy protocol was really two main elements. One was stenting of the iliac vein, and then secondly, augmented antithrombotic therapy. So whereas in the control group, patients received usual DVT care, you could say—so, a lot of them did receive anticoagulation after randomization—in the endovascular therapy group after stent placement, patients were required to receive anticoagulation and antiplatelet therapy with aspirin to start.

Yeah. And that’s actually been one of the points people have made about the differentiation of the results, is there was potentially some differences in the medical therapy. But could you tell us, we both know how many patients, but maybe listeners won’t know, how many in each arm and then how long the follow-up was. And then let’s talk about the results.

Yeah. So 225 patients were randomized, equally distributed in two arms. One patient was excluded because they didn’t meet the criteria. So, it was 112 versus 112. And again, patients were followed. Most of them were followed for 24 months. In this first report, we’re reporting on all of the patients that were followed for six months, and the primary outcome was the venous clinical severity score at six months adjusted for baseline. We also assessed health-related quality of life and a number of other secondary outcomes, including safety, and we’re doing a cost-effectiveness analysis as well.

So what were the results, Suresh?

Well, what we found is that through six months, patients who had their iliac vein stented and received the augmented antithrombotic therapy did experience a reduction in their severity of their post-thrombotic syndrome scoring on the venous clinical severity score by more than what was seen in the no-stent arm. And that was a statistically significant difference. In addition, there were pronounced improvements in health-related quality of life that were larger in the stented group, both in terms of venous disease-specific quality of life and generic health-related quality of life. And these weren’t small differences. These were really pronounced differences that are more than twice the size of the kind of minimally clinically important difference on those scales. And then we also did find though that patients had more bleeding who were stented, and that was largely probably due to the antithrombotic regimen given the timing of the bleeds, which was really mostly beyond three months after the index procedures.

And most of the bleeds were non-major bleeds. There were only a total of five major bleeds of which four were in the endovascular therapy arm, one was in the control arm, and all of the major bleeds occurred beyond three months.

Yeah, I was just going to ask you about that. So, I was really struck by figure two where you compare the pre- and post-VCSS and Villalta scores. And what struck me was the degree of improvement in the non-intervention arm or the non-endovascular arm. And I think if you compare the degree of improvement from the stented arm to baseline, it’s a very dramatic difference. I mean, for those who haven’t seen it, it’s a stacked bar graph. So, you can kind of measure up the different levels, but significant improvements in the conservative management, or what would say conventional management group, over where they were at baseline. I don’t know if you want to talk about that a little bit. I mean, I think it sort of points to a gap in our overall care of these patients.

Absolutely. I think that really patients hopefully should be getting multi-modality care for their— When they have post-thrombotic syndrome this severe, it really should be you’re doing multiple things, and at a minimum compression therapy. If they have an ulcer, they should be in a professional wound care clinic, and there are other things that one can try as well that may be helpful. And then of course, endovascular therapy for those that have iliac vein obstruction. But certainly it’s the multi-modality care overall that’s helpful here. And I think we’ve all considered probably post-thrombotic syndrome as a relatively stable disease after the first few months at least, but it does wax and wane over time, and there are other dimensions, other than just opening up the vein, of care that may be very important for patients. And so, hopefully going forward, we can do more to educate along those lines.

Yeah. That’s one of the things I wanted to ask you about because when you see the differences— There’s significant differences in the six-month reports between the two arms, but also I think if you were to compare each arm individually to its baseline, big improvements as well. And you’re a big proponent of the open vein hypothesis and recently published a really interesting article in Circulation, I believe, on revisiting this.

Does this, figure two, in a sense support the idea, as you’ve just said, that there is really much more than just the plumbing. It’s more than just opening up the vein in order to treat these patients. And this may be a much more complicated process than even we think of it as now.

Oh, absolutely. I mean, there’s clearly different elements to chronic venous disease. There’s lymphatic obstruction in some patients. There are cardiovascular comorbidities that may interact and produce more swelling than you expect. There can be other conditions that cause pain in a particular patient. And then even on the venous side, there’s inflammation that’s occurring. And we all know from our clinical practices that it’s remarkable how some people have such pronounced inflammation with their venous disease and other people just don’t.

Some people present with a lot of pain and only a little swelling. Others present with a hugely swollen leg, but they’ll tell you that it doesn’t really hurt that much. So, we see a tremendous diversity of phenotypes really, I guess you could say, among these patients. And one of the sub-analyses that we do plan to do is to really go line by line, in terms of within these kind of measures like the Villalta scale, the venous clinical severity scale, there are individual items. And trying to understand what improved, which parts of it improved and which parts of it didn’t with this intervention, I think will be very helpful in mapping some of that out.

There are also additional clinical trials and other dimensions of study that are ongoing to evaluate different types of anti-inflammatory strategies, either medical in the form of pills or in the form of endovascular-type treatments that could be delivered to patients. And so, there is a lot of work to still be done to really fully address all components of this disease process.

Yeah. And I definitely want to come to the subgroup analysis in the TRACT trial, some of the subgroup analyses were very influential in altering clinical practice. Before I do that, just I know we’re talking about several things at the same time, but in your article about open vein hypothesis, you talk about the omics, genomics, proteomics.

Do you feel, or would you agree with the idea that we’re going to have to approach this like we approach cancer patients, that the instruments we have right now, the drugs we have right now are relatively blunt? We think this blood thinner should work for everybody, but maybe there are genetic differences in individuals and how they’re going to respond to different medications, how their clot will progress. And we’re going to have to adjust and even have different combinations, neoadjuvant, adjuvant therapies in addition to anticoagulation, a very multidisciplinary complex process.

You seem to be pointing to that in the article. I don’t know if that’s a way you’ve been thinking.

Oh, absolutely. I think that it also gets to, we’ll need bigger data sets than— C-TRACT is a randomized interventional treatment trial. The challenge there is that you just can’t enroll in numbers. When you want to identify some of these additional predictors, whether they’re genetic or other biomarkers, the numbers can be a little bit of a limitation. But I think going forward, you have the SIRs promoting the VIRTEX registry, and there are other sources of big data. And if you add on top of that some either blood collection or whatever it is in specific study environments, we may be able to do a little bit better in terms of the numbers and trying to establish some of these relationships.

And everything doesn’t have to be a randomized trial. Some of that observational data can be crucially helpful in understanding the disease process and segmenting the population into these different groups that might benefit from different adjunctive therapies.

Right. The randomized trial is really good for therapies, but in sort of understanding differences in populations, maybe not, as you point out, as important. Let’s just circle back to the subgroup analyses. I think everyone’s going to be really interested. I think one of the big criticisms that has been pointed out, or I would say one of the current limitations is a six-month follow-up. And we all know, many of us follow these patients for decades if you’ve been in this business long enough, because they are often young patients who have a chronic process. So, if you can, talk about some of the subgroup analyses that you’re thinking about that we can look forward to.

Yeah, I’ll tell you what’s currently planned. So, two projects that are already underway, one of them is reporting on the 24-month outcomes of patients, in particular quality of life, and that analysis is active and ongoing and it’s right now our top priority really. A second thing that’s going on that will go on in parallel with the quality-of-life assessment is the cost-effectiveness analysis that’s being done as well. So, that’s ongoing as well.

We plan to report a descriptive paper on focusing on people who presented with venous ulcers. That will also happen probably within the next year or so. We will also be doing some analyses looking at the imaging that we got in the study and correlating that with clinical outcomes. So, what type of venographic result predicts better outcomes, what type of ultrasound results were achieved, and to what extent— what changed on the ultrasounds?

Is it just the status and openness of the veins or is it also valvular reflux? Did that change six months after you got stented? And then does that predict or correlate with the six-month and two-year clinical outcomes that we see? That’s coming as well.

I mentioned the kind of factor analysis looking at the specific symptoms and signs. We’ll also be looking at predictors of bleeding. There’s a lot, I think that now with the finding that there was more bleeding, I think people would love to understand exactly are there ways that we can optimize the risk-benefit ratio? So, understanding in which patients we got the best benefit and also in which ones the risks seem to be a little more accentuated where we have to be a little bit more careful with what we do afterwards, I think we all want to understand those things as well.

As with your previous trials, as I said, the subgroup analysis has just been very interesting, and as a forthcoming and helping us understand how to manage these patients. So, I may want to change tack, but not direction, come back to where we started at the beginning of the podcast about clinical trialists.

And I’ll embarrass you a little bit and say you are probably, if not the top, one of the top clinical trialists, especially in interventional radiology and certainly in venous diseases in general, you are an absolutely top clinical trialist with multiple NIH-funded grants. For people who are thinking about taking— They’re in a procedural specialty, which I think makes it really challenging for clinical trials, and want to follow your role model. Talk a little bit more about how you sort of navigated the challenges of being someone who may be perceived as just the plumber, but you really have a much deeper interest and broader interest in the pathology that you’re treating and you want to do something like a national multicenter trial.

Sure, sure. I think the first thing is just that self-awareness that there are lots of pieces to designing and running trials that we simply aren’t trained to do. At the end of the day, we are trained to be great doctors. We’re trained somewhat in kind of practice building and positive collaboration, but almost no one is trained in how to implement a trial.

People get trained in design, but implementation, it doesn’t almost exist really. And that’s not just within our fields, that’s even beyond endovascular procedural fields really. It’s a big gap out there. So, I was able to thankfully perceive early on that there were lots of parts of this I was going to need a lot of help with. And I think the things I did best just by accident starting off is that I wasn’t satisfied just reading the IR literature. I went out and read all this stuff about DVT in the medical literature, the surgical literature.

I became familiar with some of the names and was able to sort of start to adopt the language. Because when you hear an IR talk about DVT, you hear a hematologist talk about DVT, it’s like Mars and Venus. It’s not even the same thing that it sounds like you’re talking about. But in order to really build the allies and get the help and the collaboration, there needs to be the ability to at least understand that language, start to speak it a little bit, understand the concerns that other providers might have around the things that we’re doing.

And once you start to have that, then you can enlist them as partners, I think. And I was very lucky to find amazing, amazing mentors from both inside and outside the field of IR to support what I’m doing. They were really egoless people, frankly, who were a lot more accomplished than me and could have led the ATTRACT trial, for example, on their own really, but really wanted to be part of a group process.

I think I just learned a lot from that. The challenges were equally external and internal because within our field, as you know, John, first of all, the concept that research is a profession, not a hobby, that’s the first thing that you have to get past. The fact that research takes time to do well, just like clinical practice takes time to do well, that research benefits from a quality improvement mindset just like clinical care does, each is a bridge that has to be crossed in perceptions.

And it wasn’t easy. I can’t claim that I did everything right, or God knows that I was very headstrong at times, but ultimately was able to do enough of that and convey enough of that to be able to create space to be able to actually put the time into it, but it wasn’t necessarily an easy process. I think we’re doing better now in terms of— I’ll mention real quickly that the SIR Foundation, the Society of Interventional Oncology, some of the other subspecialty areas do have research programs that are geared towards trying to train clinical trialists, RSNA does as well. And I encourage young investigators to really take advantage of these kinds of opportunities.

As you alluded to, it’s hard work, and I know it’s hard work because you had to work with me a couple times and—

Got to work with you a couple times. Yeah.

I should just mention that the C-TRACT was run± COVID was right in the middle of C-TRACT. So, as in many of some of these big trials, it was a big issue for that. It’s just really hard work. And when you say you’re running a trial, there’s a ton behind that. I mean, very, very few words to describe the enormous amount of work. Just talk a little bit about what the nitty-gritty is of running a trial like this.

Yeah. Well, and I didn’t know it upfront, it was all learned by bumping my head, honestly. But most of the trials that we run are obviously sponsored trials from industry where there’s a CRO that runs the trial really, that administers it in a operational sense.

When you get a publicly funded trial launched or funding from another source, oftentimes you’re in the position as you’re running an investigator-initiated trial where you have to put in place the implementation mechanism. And then you’ll go to your own institution and you’ll learn that, boy, on the one hand, there’s tons of resources here, but on the other hand, they’re not all necessarily apt or suited to what I’m trying to accomplish.

But ultimately with the help of the NIH grant, I was able to hire clinical research professionals, so project managers and financial managers and coordinators, and those kinds of people who provided their own expertise to help.

And so I learned tremendously from those kinds of folks as well, as well as from some of the experts on our steering committee that had run the road, that had run trials. But the bottom line is that it’s a hands-on enterprise. Really, if you’re running a trial as an investigator, you really need to be much more hands-on than you would be for a trial that’s administered by an external body, and it requires being very interactive with your co-PIs and your other colleagues.

And interactive means being very respectful and appreciative to what they’re doing and the effort it takes at their end, but also being willing to say, “Hey, how can we improve? What have we learned from other sites that everyone can learn from? What about this idea? What do you think about trying to implement this there?” And it requires flexibility. It requires, one, to run a multi-site trial, you have to understand the variances in clinical practice.

So, it’s not something you can pull off in your first year as an attending, for example. You have to understand, what are people doing differently out there? What needs to be harmonized and where can I accommodate? Because at the end of the day, the biggest fallacy is that I can write a scientific protocol and the world will implement it because I want it to. That’s the common fallacy we all had, and it’s just wrong. The reality is, the burden’s on me to write a clinically friendly protocol that can survive and thrive in the real world as it is.

That’s the art of it. And the art is also in implementing it, where can I be flexible? And it requires a lot of judgment. It requires both the clinical knowledge as well as an understanding of how people are motivated. And again, I’m not saying that as someone who thinks that I was necessarily so great at it to begin with, but I learned a lot of things along the way, and sometimes I was probably a little bit too forthright and pushy in what I was trying to do, but then again, some of the pushiness I suspect was probably essential to getting the job done in the end for all of these studies.

Well, you’re certainly a role model, I think across multiple specialties for a clinical trial and a procedural trial. So I think you have really accomplished a huge amount. Talk a little bit as we’re closing, there are a lot of other people that are involved, family, colleagues that have to back you up in order to do this. It’s a huge, huge effort in how you— How do you navigate your own personal life to have the time to deal with something like this?

Well, it’s tremendously challenging. I mean, any physician or provider knows just how tough it is to balance things. So, I don’t have any easy answers for you there. I’m lucky that I got through it and everything is intact, but to say that it was an easy process, I’d be lying. I do think that the NIH system, because you get protected time, the one silver lining that came out, I worked a lot more because I did the ATTRACT trial and the C-TRACT trial and the PE-TRACT as well, but the flexibility of my time was probably a little bit better than someone who is in the procedure lab every day, where when you go to work, you’re there and you’re pretty much there all the time. So, in terms of finding enough time to go to my kids’ concerts and this and that, the other thing, I was able to carve out enough, I think.

And so that was, I think, a positive side of it, but overall it really is quite demanding, but rewarding as well. I don’t want to deter people. I want to remind people that it really is rewarding to be able to represent something accurately, I guess let me say it that way.

When you do an investigator-initiated trial, you’re asking a question, the answer comes back, and you’re able to just state what you found, not always what people wanted to hear as I’ve learned, but still you are able to do that. And I think that is a really positive thing that comes out of it and people do appreciate that, I believe, down the road.

Yeah. Well, I think it’s hard questions. To ask a really good question is very hard. I don’t mean it’s a hard question, but it’s really, really difficult to ask a good question. And then the results are the results, as you just alluded to. And sometimes people are hoping for something but not always getting what they want, but maybe not hoping for the answer that’s really the evidence answer, it’s more for their perspective or their clinical practice.

You certainly had time to get your diamond-status U2 fan designation. Yeah, let’s not dissuade people from trying to do this. I’m not sure there’s anything more I can add to what you just said. I always like to give a guest at the end, just if there’s one thing you want people to remember about the conversation or about you or about the trial, just kind of offer you that opportunity before we wrap up.

Well, thank you. I think I would look to the future and say there is a difference between a set of academic researchers putting a paper into a journal and changing the world. And so, now we have data. We have data showing that in the acute phase with specifically iliofemoral DVT, there are benefits to opening up the vein.

In the chronic phase, there are benefits to opening up the vein. But what we don’t have right now is what we do have in the pulmonary embolism space, local, collaborative structures to make sure that we see the patients that may benefit and then together come up with the right way to manage those patients on an individualized basis. So we have PERT teams, but we don’t have something similar for DVT. And this is a local thing. This is something that we really need to happen. We need every provider here who cares about these patients to go and forge those bonds with your local collaborators.

And we don’t need you waking up in the middle of the night at three o’clock to talk about DVT, but is it a weekly case conference for high-risk DVT patients that come into your system? What is it? It can vary locally, but we need that collaborative care mechanism to make sure that people with DVT that’s extensive get followed, they get anti-coagulated properly, they get compression, and the ones that stay symptomatic may need an intervention. And we want that to happen at a time when it can be most helpful in their lives. So, that’s going to require all of us to do more, locally, to build those structures.

Suresh, thank you very much for joining us on Prepped + Draped. You have had an enormous impact on venous disease, venous thrombolic disease, and you will continue to have an enormous impact as we go forward. So, it’s been a pleasure as always, and thank you very much.

Thanks so much for the opportunity. Appreciate it.