The Case for Duplex Endpoints
The right clinical endpoint for assessing patency was discussed on Wednesday afternoon in a VIVA@LINC session by Raghu Kolluri, MD, System Medical Director at OhioHealth and President of Syntropic Core Lab in Ohio. Importantly, Dr Kolluri, who has been involved in numerous chronic limb-threatening ischemia (CLTI) trials, was one of the authors of the LIFE-BTK trial,1 a multicenter, randomized controlled trial that treated CLTI and infrapopliteal artery disease with an everolimus-eluting resorbable scaffold or angioplasty.
The case for duplex ultrasound (DUS) as a composite endpoint in clinical trials was presented by Dr Kolluri. “DUS has been used in above-the-knee clinical trials and peripheral arterial disease clinical trials for a long time. Binary stenosis assessment is an endpoint in most of the investigational device exemption [IDE] trials,” he explained. “But there has been resistance to DUS, and the most prominent trial that used DUS binary stenosis as one of the composite endpoints was LIFE-BTK.” Here, the primary efficacy endpoint was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion.
Traditionally, patency is assessed using angiography or computed tomography angiography (CTA). Only a few trials have used DUS, said Dr Kolluri, and these have only looked for occlusions, not stenosis. But there is still a strong case for using it. “I am a proponent of DUS because it is widely used in contemporary CLTI care,” he explained. For example, many patients who come into Dr Kolluri’s hospital, Riverside Methodist Hospital, do so with critical limb ischemia. “Most of them also have renal insufficiency,” he noted. “We generally bypass the CT scan because it uses dye, and then we do a duplex mapping of the leg, get an ankle-brachial index, and then the patient goes to the cath lab.”
This, he emphasizes, is standard of care. Subsequent follow-ups are also done with DUS, rather than invasive angiography. At a recent meeting of the Vascular Leaders Forum in Washington, DC, Dr Kolluri asked the audience how many use duplex mapping of the leg. “Except for two, everyone raised their hands,” he said. “DUS is standard of care. We are doing it in our clinical lives, but we’re not bringing it to research, in trial settings, as an endpoint.”
DUS should not be the only primary endpoint, said Dr Kolluri, who stated that other primary endpoints are more important. “Duplex should be included, at least, in the composite endpoint, or in the hierarchical model using win ratio,” he added.
Dr Kolluri concedes that the technology has had limitations. The femoral-popliteal segment above the knee, where arteries are larger, is easier to visualize on DUS, Dr Kolluri explained. Below the knee, where arteries are smaller and there is more calcium, DUS has been less accurate in the past. “But I think duplex technology has matured enough where we really can get good images in the clinical world,” he explained.
As the director of vascular medicine at OhioHealth, Dr Kolluri manages 16 vascular labs, and every single day, they image arteries below the level of the knee using DUS. Important evidence comparing DUS with angiography below the knee has been published by Eiberg, et al.2 “This evidence, with hundreds of segments, demonstrated correlation to be moderate to strong, which is what we see in our clinical practice,” said Dr Kolluri. “Therefore, we decided at the LIFE-BTK leadership level that we should include DUS as one of the composite endpoints.”
Of course, correlation in a more systematic way must be established, said Dr Kolluri. “LIFE-BTK is going to look at that,” he added, saying that a paper should be published on this issue imminently. “But it’s a maturing of our thought process and improving duplex technology enabling this.”
Addressing the controversy over peak systolic velocity ratio (PSVR), which in the femoral-popliteal segment is widely agreed to be 2.4, Dr Kolluri spoke about approaches in LIFE-BTK. Here, PSVR was 2.0—or a doubling of velocity before and after the stenosis—based on the Eiberg paper. “Now, a lot of people question that. They think that there might be too many false positives that will lead to clinically driven target lesion revascularization,” he explained. “To that end, in LIFE-BTK, we actually included some other ultrasound characteristics, including Doppler characteristics, in addition to the 2.0. We can be confident that at 2.0 there is a blockage/stenosis there.”
Dr Kolluri also talked about the effect on PSVR when a scaffold or a stent is placed within an artery that is already tiny. “If we put the stent or scaffold in there, that is circumferentially going to crowd the artery,” he explained. “So, because the lumen is so small to start with, the velocity here may go up.”
Dr Kolluri explained how the core lab uses DUS in such difficult areas. “We can measure the thickness of the wall,” he said. “We may not be able to see the scaffold because it blends in the greyscale, but at least we know how thick it is.” Three months later, if the scaffold has been absorbed, the team should see the velocities go down as the thickness decreases. “We have a fair idea of why initially there might have been a larger velocity and then why it then decreases,” he said.
Therefore, said Dr Kolluri, DUS has a place within trials. “Ignoring DUS is like throwing the baby out with the bathwater,” he explained. “I don’t think we should give up on it, because it is the standard of care. It is noninvasive. It does take training and, in a clinical trial setting, requires independent adjudication, oversight, and site training. But it could be done just like LIFE-BTK was done.”
References
1. Varcoe RL, DeRubertis BG, Kolluri R, et al. Drug-eluting resorbable scaffold versus angioplasty for infrapopliteal artery disease. N Engl J Med. 2024;390(1):9-19.
2. Eiberg JP, Grønvall Rasmussen JB, Hansen MA, et al. Duplex ultrasound scanning of peripheral arterial disease of the lower limb. Eur J Vasc Endovasc Surg. 2010;40(4):507-512.
