Comparison of Long-term Outcomes Between TADV vs Standard of Care Therapy for No-Option CLTI Patients

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Anahita Dua, MD, MS, MBA, FACS, vascular surgeon at Massachusetts General Hospital in Boston, shares background and insights on the abstract she presented at VAM25, "Comparison of Long-term Outcomes Between TADV vs Standard of Care Therapy for No-Option CLTI Patients."

Anahita Dua: Hello, everyone! My name is Anahita Dua. I'm a vascular surgeon at the Massachusetts General Hospital, and an associate professor of surgery at Harvard Medical School. It's such a pleasure to be here today. We are going to be talking about an abstract that we presented at the Vascular Annual Meeting titled “Comparison of Long-term Outcomes Between TADV vs Standard of Care Therapy for No-Option CLTI Patients.”

Tell us about the PROMISE I, PROMISE II, and CLariTI studies: what did they evaluate, and what were the primary endpoints?

Anahita Dua: Absolutely, the PROMISE I, PROMISE II, and CLariTI studies are all related. Let me explain, first, about the PROMISE studies. So essentially in the world today there are several patients that are considered what we call “no option.” No option means that no conventional options of open surgery, endovascular procedures, or combinations allow you to get enough blood flow in the leg for these types of patients. So ultimately, what happens is, even if you do something to get a little bit more blood flow, they end up amputated. Those are our no-option patients, and unfortunately, there are more and more of these patients out there because of the rise in diabetes.

So, the PROMISE I and PROMISE II studies were evaluating a new procedure, a novel procedure called deep venous arterialization, which basically focused on taking a fistula-like creation, and pushing blood from the arterialized system into the venous system of the foot and ultimately breaking the valves in the foot, so that all that arterialized blood gets down into the foot. This is all done endovascularly, using a kit called the LimFlow kit that is made by Inari and Stryker.

Now, what we evaluated in the PROMISE I and PROMISE II studies is, we took a bunch of patients that had Rutherford 5 and 6 diseases. So, the worst of the worst in terms of their options. They were either considered no option, because out the gate a doctor evaluated them and said that they were no option, or they had more than 2 revascularizations that had failed within 6 months. So again, the worst of the worst that were looking at amputation. If they had the correct anatomy, we performed a deep venous arterialization on them and then we followed them for up to a year to see how many of these patients had their limbs salvaged.

Now the CLariTI study is a different study that looked to see what the natural history of disease without deep venous arterialization in a patient’s life is. So, in other words, what we did is, we took the same criteria that we used in the PROMISE study, and then we look to see what happened to them once they were just subjected to conventional options over the course of a year, and what we found in our endpoints. Our primary endpoint essentially was limb salvage. That was the primary endpoint. We had other endpoints in the secondary endpoints, including survival, amputation-free survival, and wound healing pain. But the main thing was limb salvage for patients in the PROMISE studies. 

When we grouped all the data together, the rate of limb salvage at 1 year was 82%, which is good if you think about these patients who likely would have been amputated. In the CLariTI data, the rate of limb salvage at a year was 50%. So essentially a coin toss.

Now, we have data out to 2 years for the PROMISE patients, and at 2 years the rate of limb salvage pretty much maintains itself at about 70%.

We haven't yet collected the 2-year data for the CLariTI patients because we designed the CLariTI study after we did the PROMISE studies, because we really wanted to make sure that the inclusion criteria were very similar to the PROMISE patients, so that we could do a head-to-head comparison, even though it's not a randomized controlled trial.

Can you summarize the limitations of current standard-of-care treatments for no-option CLTI patients?

Anahita Dua: The limitations for patients that are no-option CLTI really fall into 2 categories. One, they're limited by their own physiology. A patient may be unable to get a long bypass because their heart may not be able to take it. For example, a patient may have an ejection fraction of just 15% and just be unable to get a bypass.

The second thing, which is more common, is if they're unable to have one of the conventional options that we have for them succeeding in getting enough blood flow to the leg. Historically, patients would have a blockage, maybe in one of the tibial vessels or the SFA. Either through a surgical option or through an endovascular option, we were able to bypass around that blockage or go through the blockage with a wire and reestablish blood flow. But one of the tenets of vascular procedures is that you must have inflow, and you must have outflow.

But what's happening in these? No-option patients are kind of carpet bombing of all the tiny little blood vessels in the foot. So even if you do a connection around the blockage at the thigh level, or the calf level, the blood has nowhere to go because there's no blood flow into the foot. So, what ends up happening is a patient shows up with a little toe wound. You do an angiogram on them, and you see that there's barely any blood flow. No main blood vessels down into the foot, and the tibial vessels have a lot of disease. You try to get better inflow pressure by opening, maybe an SFA lesion, even opening up a tibial down to the ankle, but you just can't get that flow into the foot.

So, what will end up happening to that patient is over the course of a year, the toe may be amputated, then the toe amputation site won't heal. Maybe you try another angiogram, to try to get a bit more flow, but the toe amputation site doesn't heal. So now they're looking at a TMA, which is half the foot, and ultimately, they end up with a below-knee amputation over the course of the year.

And the reason is because again, these conventional options cannot get blood flow into that carpet-bombed area. So, the beauty of the DVA is you can say, “okay, we've lost all the itty, bitty, tiny arterioles. Why don't we use the little venules that are sitting there, that are sitting empty?” Because if no blood is getting down to the foot, then obviously blood doesn't need to come back from that area. So those little veins are just sitting doing nothing. So, we hijack them to deliver oxygenated blood into the foot.

Given the promising results, how do you see TADV being integrated into current CLTI treatment algorithms?

Anahita Dua: Given that there's such promising results for DVA, I think that a few things are going to happen. First, I think that we're going to further decipher who is the right patient to get a DVA.

When we did the PROMISE studies, one of the inclusion criteria was that the patient had to have a wound on their foot already. But you could argue that in a patient with rest pain, who also has critical limb ischemia and no options, that maybe a DVA is the appropriate thing to prevent a wound from ever forming. So, I think we're going to tease that out a little bit more as the years pass.

But in terms of algorithms, I think for patients that are facing amputation because they have no options, DVA is going to become an option for these patients to at least have a discussion. For the right patient, we are already seeing the guidelines from the Vascular Surgery Society, the Cardiology Society, and the Interventional Radiology Society that DVA is mentioned as a possible option if the operator is comfortable with doing it, and if the patient understands the risks and benefits, and would like to move ahead. So, I think, as we go further, we're going to pick up nuances and be able to really decipher who the patients are, and then ultimately get that into the guidelines. So, patients are afforded this option, if they have otherwise no conventional options.

What training or procedural considerations would clinicians need to adopt TADV in routine practice?

Anahita Dua: One of the absolute beauties of DVA is that it is so easy to do. It really is. Anybody who has the endovascular skills of today to do the procedures that we standardly do in vascular surgery can certainly do a DVA. But doing the DVA is just one component of it.

The reason that that PROMISE was so successful, and the reason that DVA is so successful, is not the procedure. It's the entirety of the procedure and the wound care, and the understanding of how to manage these patients over the 6 months it takes to get them to fully salvage their leg.

So, what really needs to be learned, in the case of a provider who wants to learn DVA, is you're going to be able to do the surgery immediately, but what needs to be picked up is, when do you do the amputation of the toes? If the patient has had a DVA and has necrotic gangrenous toes, when do you move forward? And the answer is, 3 months. 

You must wait approximately 3 months for the circuit to kind of build itself up before you go ahead with the TMA. And then, when you do that TMA, when do you do the wound care? What is the type of wound care that you need to be doing?

There are some principles like, you don't want to debride too much. You want to just hold and wait until the circuit has matured. When you do a TMA, you usually want to do it open.

You don't want to close the TMA because eventually, you want to skin graft that TMA, because that'll give the DVA the best chance of being successful. When you finish doing your DVA, what blood thinners do you put the patient on?

Personally, I put the patient on triple therapy to begin with, so I usually put them on Xarelto 2.5 BID, aspirin, and Plavix for the first 3 months, and then at the end of those 3 months, I'll drop off the Plavix and then maintain them on the 2.5 Xarelto and aspirin. That's my algorithm. 

That kind of algorithmic approach to the entire patient is really what needs to be learned. But the actual DVA procedure is something that anyone can do, especially with the LimFlow kit, which has taken away some of the uncertain steps like crossing from the arterial to the venous system or getting into the foot to break those valves with the valvulotome. The beautiful LimFlow kit allows for that, so now the procedure is easier than ever, which comes with its own positives and negatives because, of course, again, just doing the procedure is like planting seeds in the soil. Then you've got to wait for the thing to mature for you to do the rest of the steps to salvage the leg.

Have there been any updates in this space since the completion of the study? And is your team currently engaged in any upcoming research?

Anahita Dua: There have been multiple updates in the space. For example, some of the specifics about DVA have been evolving over time. I'll give you an example. My group has done a bit of research that we just very recently published about coiling of branches.

The veins, as we all know, have a lot of little branches that go off here and there, and historically, when someone would do a DVA, they would then come back at different intervals, 2 weeks to 4 weeks, and coil off some of the branches that needed to be knocked off in order for the blood to be pushed towards the foot.

Our group recently looked at all of our DVAs, and looked at the coiling to tease out what patients needed to be coiled, and which ones didn't need to be coiled to simplify the procedure and say, “actually, it turns out, we don't need to be coiling maybe as much as we are doing, because the patients tend to do well, even without it.” The blood is in a circuit and figures out how to get to the foot. Obviously, if you have a huge stealing branch, then you do need to coil it, and we do need to tease out what that would mean when I say, “huge stealing branch.” What is the volume of flow that needs to be stolen for you to be saying, “yep, I should probably go and coil that off,” and that right now is more of an art than a science. But our team is working on figuring out some of those specific, quantifiable numbers so we can make TADV as straightforward as a process, and as homogeneous of a process across the board so that everyone's getting the same results because everyone's doing the same thing. 

Also, there are a significant amount of people working on the wound care side of things. What's the best wound care for these patients? And how do you ensure that once your TADV works that you have a good outcome?

And there's, of course, a lot of work being done by the company itself, changing some of the things like the stent or the valvulotome to make them smaller and more effective, so that the procedure is easier to do even in an OBL.

There’s a lot of work being done in this space. I've been with this story from the beginning, and we have accepted that DVA is a great option for these patients if they meet the right criteria, so it's not perfect for every patient--what surgery is?— but in the right patient it is appropriate, and what we're now seeing is some of that nuance work being dealt with to really tease out what are the differences between patients and how can you optimize it so that every patient wins.

Is there anything else you'd like to share with our audience?

Anahita Dua: I think the most important thing to share is that this is here to stay. It's a great procedure in the right patient, and it really can salvage the leg. The most important thing about it is that it's easy. It is an easy procedure, and it's something that should be in the armamentarium of anybody that does PAD, especially because we are seeing such an immense rise in the number of patients that are considered no option.

The other thing to say is, you know, I'm sitting here at Massachusetts General, and this is a great hospital with a lot of different options for me to be able to help my patients. But we know that in the United States there are large areas of “vascular deserts,” is what we call them, where there might be one provider that's doing the care of a patient for miles around.

I want to speak to those providers and say the CLariTI data really tried to look at those people as well, because at the end of the day, it's not good enough to just say, “oh, if all patients come to Johns Hopkins, or if all patients come to Mass General, they'll have great care,” because most patients are not coming to these places. Most patients are going to their local area for care, because this is peripheral artery disease, and patients don't travel over state lines to go and get PAD care. Who's to say that these centers are better than other ones? Nobody's saying that either. The point is that every provider who does PAD needs to be well versed in all the things that can help these patients, because patients stay local. This is one of the important advances that has happened in our area in a while, and every provider, no matter if they're sitting in the middle of Mississippi, or they're sitting in the middle of San Francisco, should have this skillset so that they can potentially offer it to their patients—especially the endovascular DVA that's done with the LimFlow kit. That can be done at any place if you have the right wound care available to you.

The transcript has been edited for clarity and length.