VENOUS REFLUX

BIOPROSTHETIC VENOUS VALVE: ‘WE WANT TO KNOW THAT THIS IS REALLY WORKING’

A key investigator in efforts to tackle chronic venous insufficiency (CVI) with an bioprosthetic venous valve replacement talks about progress being made with surgical and endovascular versions of the device—and surgical community skepticism.

JORGE ULLOA, MD, HAS NOT LONG since produced the latest data from a firstin-human (FIH) trial for emerging stainless-steel frame-based surgical implant, the VenoValve device, intended to treat patients with C5–C6 disease on the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification scale.

He is talking on the sidelines of the 2023 annual meeting of the American Venous Forum (AVF) in San Antonio, Texas (Feb. 22–25), where he has just presented the latest update on what the 36-month data from the FIH is showing.

Those results, he says, for the investigational device continue to be promising, but the U.S. pivotal trial, the SAVVE study, or Surgical anti-reflux venous valve endoprosthesis, is also approaching a crucial tipping point, he tells Vascular Specialist. “We’re getting into 40-plus patients, more than half of what is required by the Food and Drug Administration [FDA],” he explains. “We’re at 24 sites. The goal is to end up with 75 cases. That data needs to be analyzed in order to know that the experience we had with the small number [of FIH patients] we got in Colombia, which was 13 at the beginning and now eight under the last cut of the follow-up, is replicated. That is the position we are in right now.”

Attention is turning, too, to the early

By Bryan Kay

stages of a catheter-delivered version of the valve, Ulloa says. The Fundacion Santa Fe-Universidad de los Andes, Bogota, Colombia, vascular surgeon has, of course, been at the vanguard of the early research efforts around the surgical valve replacement. He will play a similar role as the FIH trial of the endovascularly delivered bioprosthetic gets underway, also in Colombia.

“This endovascular approach, which is a miniaturization of the valve—the same one that we placed and have been placing in Colombia and the U.S.—in order to accommodate it in a catheter and allow it to be placed, involves a different process in that it goes under nitinol, the material of stents. It will go into a catheter and then be delivered via the popliteal vein, and then deployed at the femoral vein level, in the very same way that we are doing so far with the open and surgical approach.

“The advantages of this are that, of course, delivery is an endovascular process— the morbidity of the surgical approach goes almost toward zero—we don’t make inci sions, we don’t do dissections, we don’t have to deal much with bleeding.”

If all goes to plan, the TAVVE (Transcatheter anti-reflux, venous valve endoprosthesis)

FIH trial will commence within a couple months, potentially with up to 20, Ulloa adds.

Yet, he is aware of skepticism over results recorded thus far among some within the vascular surgical community. “There have been a series of attempts for the last 60 years or so, with the first report of a prosthetic valve going back to the 1960s,” he says. “The first implantation in the human body was sometime around the late 1980s, early 1990s. The number of cases was very low, and the follow-up was very short and not very promising. Therefore, I understand, we all understand, that there is going to be a whole field of skeptical surgeons.”

Rather, Ulloa argues the medical landscape is more conducive to success now. “Materials are way better than they were 20, 30, 40 years ago,” he continues. “The surgical approaches are better now. We understand physiology way better. We can assess the behavior of a valve right after and during the surgery, and right after the surgery we can check it and can see it; we can measure it, we can get a lot of physiological data out of each and every one of the patients or cases. Also, the numbers we got are a little higher than the historical average, and the follow-up we got [in the FIH VenoValve trial] is the longest we’ve got in history—the longest we had before was six months.”

The valve, Ulloa says, is not going to be perfect, nor cure the underlying problem—“but it will manage the problem, and will improve the quality of life, and the data is supporting all those ideas.” He points to decreased reflux, reduced pain and healed ulcers. “Of course, we have to continue the follow-up to see what is going to happen, and continue to add numbers.”

There might be no more skeptical a group than those investigating the device themselves, Ulloa says. “We want to know that

THREE-YEAR FIRSTIN-HUMAN RESULTS

During the AVF 2023 Ulloa provided attendees with updated data on improvements in venous reflux of 63%, revised venous clinical severity score (rVCSS) of 64%, and visual analog scale (VAS) of 83% compared to presurgery levels.

The VenoValve device has been developed to be surgically implanted in the femoral vein of patients with C5–C6 disease.

Ulloa, principal investigator of the first-in-human trial, said the findings demonstrated the VenoValve “appears to be safe with continued significant benefit.” this really working, we want to see how it is working, we want to assess each and every measurement that we can, and that’s what we have been doing so far with it. Yes, prob ably we are approaching the end of the road, and we are getting into the field of a lifelong problem that has been facing vascular sur geons—really difficult to manage—which is the post-phlebitic syndrome. For the first time, it has real possibility of treatment that will, at least for three years, see a dramatic improvement in symptoms and dramatic increase in quality of life.”

The two-year findings, presented at the 2021 Vascular Annual Meeting (VAM) in San Diego, showed 63% improvement in venous reflux time, 60% improvement in VCSS score, and a 93% improvement in recorded pain, or VAS, when compared with preoperative levels.

At AVF 2023 in San Antonio, Ulloa said the remaining eight patients showed “continued and stable improvement” for three years, with no ipsilateral ulcer recurrence. “It appears that long-term anticoagulation may be necessary,” he added.

An analysis of venous usage trends in the United States from 2014 through 2021 showed a “significant increase” in stents per day placed over time, despite high-profile recalls of two dedicated venous stents from the market.

Those were among the observations of Karem Harth, MD, associate professor of surgery and director of the Center for Comprehensive Venous Care at University Hospitals in Cleveland, Ohio, who led the study, which looked at the total eight-year period and three distinct timeframes within it: before Food and Drug Administration (FDA) approval of dedicated venous stents, from FDA approval through to the date of the first recall, and the period after the recall. Harth delivered the results at 2023 annual meeting of the American Venous Forum (AVF) held in San Antonio, Texas (Feb. 22–25).

In an interview with Vascular Specialist afterward, she said the increase in usage was not surprising but did highlight a number of areas in need of evaluation. “We found that there was a significant increase in stenting since FDA approval, which is not surprising because this therapy is exciting and long-awaited,” she explained. “But what we also found was that the top three diagnoses included acute DVT, NIVLs or non-thrombotic iliac vein lesions, as well as mild chronic venous insufficiency [CVI], which came as a surprise to us when we looked at this data, and that trend remained over time.” Analyzing venous stent usage rates both overall and across the three time periods by demographics, indications for stenting and overall mortality, significant differences were identified in gender, race and overall mortality (p<0.05), Harth said. The top four indications for venous stenting were acute deep vein thrombosis (DVT), chronic DVT, NIVL and CVI with no inflammation.

In addition to the increase in stent usage overall (p<0.00001), on multivariate regression analysis Harth and colleagues recorded an increase from the period prior to FDA venous stent approval to the period between that afterward until the first stent recall among more white and female patients (p<0.005), and both acute and chronic DVT patients

(p<0.01). Meanwhile, in the same timeframe trend showed decreased usage in patients with NIVLs, CVI with no inflammation, and CVI with inflammation. From the second time period (FDA approval–first recall) to the third (after the recall), no changes occurred across indications for stenting (p>0.05), Harth told AVF 2023. Risk factors in the first and second periods for overall mortality at more than two years post-stenting included age, male sex and chronic DVT, NIVL, and CVI with ulceration, while African-American race was a risk factor in the period prior to venous stent approval, she added.

Harth concluded her podium presentation by stating that “significant increases in venous stenting occurred after U.S. FDA approval and remained unchanged after FDA recall.” Indications are broad and “may not all be appropriate use of venous stenting,” she said, highlighting the need for further work to understand the venous stent landscape, usage and to minimize unnecessary stenting.—Bryan Kay