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BackTable / VI / Article
Update on the Safety & Efficacy of Drug-Eluting Stents & Drug-Coated Balloons
Rajat Mohanka • Updated Aug 12, 2024 • 34 hits
Due to the lack of rigorous clinical data in the late 2010s, there has been significant controversy regarding the safety and efficacy of drug-eluting technologies for treating peripheral arterial disease (PAD). Clinicians have faced challenges in obtaining patient consent and optimizing treatment in PAD while uncertain of the precise role and benefit of drug-eluting endovascular devices.
However, we have since learned more about the safety, efficacy, and appropriate use cases of contemporary drug-eluting technologies. With renewed interest, endovascular specialists should understand which situations lead to technical and clinical success when deploying drug-eluting technology.
Interventional cardiologist Dr. Eric Secemsky from the Beth Israel Deaconess Medical Center provides further insights into the safety and efficacy of drug-coated balloons (DCB) and drug-eluting stents (DES), and discusses recent advancements in clinical data and regulatory appraisal. This article includes excerpts from the BackTable Podcast. You can listen to the full episode below.
The BackTable Brief
• When using drug-coated balloons, 70% of the drug is absorbed off, with only 30% remaining on the balloon upon delivery. 10-20% of the drug effectively transfers to the vessel wall.
• Operators should aim to "tattoo" the drug into the vessel wall for deep penetration and prolonged effect.
• Calcific disease may hinder adequate drug transfer, affecting therapeutic outcomes.
• Paclitaxel is a highly effective anti-proliferative agent that is successful in large peripheral vessels, as it moves effectively through the vessel wall, ensuring long-term efficacy. Limus is effective in coronary stents but faces challenges in peripheral application.
• Predictive models, such as the Cook Zilver PTX Prediction Model, can help identify high-risk patients who may benefit from specific treatments.
Table of Contents
(1) Mechanisms of Drug Delivery in Drug-Coated Balloons
(2) Paclitaxel vs Limus in Peripheral Arterial Disease
(3) Paclitaxel Safety Profile: Controversy & Resolution
(4) Data-Driven Decision Making in Peripheral Artery Disease Treatment
Mechanisms of Drug Delivery in Drug-Coated Balloons
Unlike drug-eluting stents, drug-coated balloons (DCBs) rely on a single opportunity to transfer the drug to the vessel wall. Approximately 70% of the drug does not reach the target, with only 10-20% effectively embedding into the vessel wall. Different proprietary technologies aim to optimize this transfer, including nanoparticles and microspheres. The concept, as described by Elazer Edelman, is akin to tattooing the vessel wall with the drug to ensure deep penetration and long-lasting antiproliferative effects. However, the absence of a polymer means no sustained release, making the initial transfer critical for therapeutic efficacy, particularly in calcified vessels.
[Dr. Sabeen Dhand]
How is [drug delivery] different in drug-coated balloons where obviously the "scaffold" is the balloon, but are they also using a polymer and then the same drug?
[Dr. Eric Secemsky]
Yeah, so the drug-coated balloons are a little bit different, because there's no scaffold to elute any medication or antiproliferative agent over time. You really have this one opportunity for a transfer of drug from balloon into the vessel wall. As we know, when you put a drug-coated balloon in the body, about 70% of that drug goes elsewhere, and about 30% of it-- Not in a dangerous way, but just it absorbs off. By the time you get the balloon actually delivered to the vessel wall, about 30% still on the balloon, and probably only about 10 to 20% get against the vessel wall, but all the different drug-coated balloons have different proprietal ways of packaging the paclitaxel onto the balloon. Again, now we've seen this with the limus technology, talk about nanoparticles and other microspheres, other ways to transfer, but the goal is that you got to package the meds to transfer into the vessel wall.
If you talk to Elazer Edelman, who made one of the first coronary stents, he likes to say that it almost tattoos the wall with the drug, so that you get as much of it pressed up against the wall, and then you expect for that to transfer into the vessel wall, deep in the vessel wall, and really contribute to the anti-proliferative properties of the paclitaxel for the currently marketed DCBs. But there's no polymer, there's no long-term elution, you don't leave anything behind. As much gets transferred on that one therapy, that's what you're left with, and hopefully it's enough, but I'm sure there's some situations where not enough is transferred, and we know that with calcific disease.
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Paclitaxel vs Limus in Peripheral Arterial Disease
While both paclitaxel and limus have roots in coronary stent technology, their application in the peripheral space has distinct challenges and advantages. Paclitaxel, known for its aggressive anti-proliferative properties, has been particularly successful in larger peripheral vessels due to its effective transfer through the vessel wall. Limus, although highly effective in coronary stents, faces challenges in packaging and delivery for peripheral use. Advances in technology may eventually improve limus's efficacy in the peripheral context, particularly in below-the-knee applications where paclitaxel has been less effective. This discussion highlights the importance of drug selection based on vessel size and location, as well as the evolving nature of stent technology.
[Dr. Sabeen Dhand]
You mentioned paclitaxel and limus-taxol and limus are really the two drugs that have been used on stents. As they're anti-proliferative agents, are there other agents that have been looked at too or are those are the only two that are shown to be effective?
[Dr. Eric Secemsky]
I'm sure there's been interest in many different agents for decreasing anti-proliferative properties of restenosis. A lot of what we're doing in the periphery has been driven by how drug technology has evolved in the coronary space. Back when the first-generation coronary stents were made, they were Taxol, they were taxus-based, and the stents themselves worked really well. They prevented early and midterm restenosis that we're seeing with bare metal stents, but the problem in the coronary stents is that it almost worked too well that there was risk of late occlusion, we call it-stent thrombosis, because of potentially paclitaxel being too aggressive and not letting the stent really endothelialize into the vessel wall. Then that metal scaffold was a nidus when it came off your antiplatelet therapy for thrombosis.
That's why in the peripheral world, two things happened. One, we started using dual antiplatelet therapy much longer to prevent that late occlusion. Then we evolved from paclitaxel to limus based, and there's a couple different limus drugs. That really- the limus with the polymer and the coronary space allowed for this more consistent elusion and more really successful long-term reduction in thrombosis rates, that's become the standard of care in all our stent style or limus space. In the periphery, you have to think of the peripheral space a little bit differently. First off, it's a larger vessel, so occlusion rates are going to be different. Coronary vessels are three millimeters, and SFA is six to eight millimeters. You don't have the same small vessel that you worry about with the scaffold.
The other thing is it's in a very aggressive area for atherosclerosis, as we all know. You need a really effective agent there, and so that's where paclitaxel has been so successful is it's an aggressive anti-proliferative agent. It moves through the vessel wall very successfully. It's a very aggressive anti-proliferative agent, and that has made paclitaxel really an incredibly successful drug in the peripheral vascular space.
[Dr. Sabeen Dhand]
That's interesting. I was always thinking, I was like, why aren't- the limus has shown to be so effective in coronary. Why isn't just all the peripheral stents limus too? It's interesting that paclitaxel's stronger, and that's why. It's a bigger vessel.
[Dr. Eric Secemsky]
Yeah, there's a lot of differences between the two of them, and we can nerd out about it, I'm sure, for a while. I think the thing that I think about a lot is they've looked at limus in the periphery before, and some of the biggest issues is just it's harder to package and deliver successfully through the vessel wall. The older technology, and there's been some other stents also that have had limus on them, haven't been successful. Now the newer technology, we know there's a lot of interest in this across industry, has different mechanisms for packaging that limus that could, in theory, be successful. Most of that's being advanced in the below-the-knee space right now, where paclitaxel hasn't shown benefit. I'm sure we'll see more above the knee as well and on stents. The last comment there is that when you put the limus with a polymer, it's much easier to deliver, just like in the coronary stent. That might be in the future also, is that paclitaxel stents work great, we'll see maybe some limus stents, we'll have to see if they work as well as a paclitaxel stent.
Paclitaxel Safety Profile: Controversy & Resolution
Initial concerns surrounding the safety of paclitaxel-coated devices arose from a meta-analysis suggesting a potential link between paclitaxel and increased mortality, though the study was not designed to measure this outcome. The vascular community, including industry, clinicians, and regulatory bodies, collaborated to reassess the evidence, leading to a pivotal FDA review in 2023. Updated data from independent analyses and long-term studies ultimately restored confidence in the safety of paclitaxel-coated devices. This process underscored the importance of rigorous data analysis, patient safety, and collaborative problem-solving in advancing vascular interventions.
[Dr. Sabeen Dhand]
Yeah. So 2018 was a big year for paclitaxel, and the whole debate came up about the risk-safety profile. What are your thoughts, now you've done so much work. What are your whole thoughts and overall opinion about the safety profile of drug-eluting stents and technology?
[Dr. Eric Secemsky]
Yeah, absolutely. I think that it's fun to sit here almost four years later. That was, December 2018 when it was published or five years later now, gosh. It's crazy to have lived through it, and we all lived through it together, and it's so awesome to see in our careers that there was this big controversy and that we almost got to live through the resolution of it as well. I think oftentimes these things linger, and they don't have the same ending, and it was really awesome. I'll just comment on that. The first thing is, I grew up learning peripheral intervention with drug-coated balloons and drug-coated stents as part of my daily practice. I always use this analogy when I speak about paclitaxel, is if you went to the cath lab and told me during coronary intervention, "Guys, I really need to get rid of every drug-eluting stent off the shelf, you can either bring back bare metal stents or you can only balloon." We would shut down. I think, and no one would agree that we can do our procedures anymore in the same way, and benefit our patients.
To come in and say, all drug-coated technologies needs to halt because of this alarm signal from this analysis is challenging. It was challenging for my own practice. I got involved because I'm interested in this, but obviously I got more involved, because it was affecting my patient care and I saw that it was going to affect patient care throughout the world. Now, something that a lot of us brought up from the beginning is this whole controversy was started on some shaky data. It's not that the trial data isn't sound. It's just that the trial data never was meant to examine mortality. When you introduce all these variables like loss to follow-up, repeat treatment, crossover, I think that it would create a very complex scenario where you don't really know what you're measuring in the end, because you don't know what that pathway, the journey of that patient was. The person who got randomized to balloon angioplasty in the original Zilver trial potentially went and got a Zilver stent. We saw that happened in a meaningful amount of patients, but they weren't being treated that way. They're treated as only in the balloon arm.
So there's a lot of nuance to that meta-analysis that wasn't adding up. Then we never could really demonstrate a mechanistic fashion of how a one-time treatment with what is relatively low-dose paclitaxel can cause such a high risk of death, 7%. That's just a number that- it's hard to think of things that can because 7% mortality.
[Dr. Sabeen Dhand]
7%.
[Dr. Eric Secemsky]
Right? Unless you're trying to kill someone. I think the most important thing though, and the FDA said this themselves is if it wasn't death, there would've maybe been a different response. Death is such an important endpoint to everyone, patients, to clinicians, to regulators, to the population level. Because it was such a important endpoint that was being presented as associated with these devices, the FDA had to take it seriously. Again, it was a really unique process watching industry come together and find out how to work together and then solve this issue. Clinicians and societies working with the FDA to find ways to support the process and independent investigators generating data to help guide the regulatory process.
Really a remarkable time for the vascular field. I think everybody should be proud how people came together, trying to do what's best for the patient, make sure the patient risks weren't there with everything, that we care about our patients first, that we're doing things with them in mind. In July of this past year, the FDA finally reviewed all the updated data. They had an updated independent patient data meta-analysis. They got the individual trial data with all these updated trials that had lost a follow-up, some newer trials that have longer term data. This was published in Lancet in October by Sahil Parikh, Bill Gray, Peter Snyder, and others. That really gave the FDA the confidence to say, we don't have a true sense that this association is actually real and that these devices are causing harm, and really reversed all their stances on paclitaxel.
[Dr. Sabeen Dhand]
Yeah. That was a very important article and stance. It was an interesting time to live through, because we all knew drug-eluting stents were working great and drug-eluting technology is working great. Having those challenges or saying, oh, having those conversations with those patients at that time five years ago, four years ago was difficult.
[Dr. Eric Secemsky]
Absolutely. I'll tell you something Sabeen. I was at VIVA sitting through a talk about durability of drug-coated balloons and drug-eluting stents. They're reviewing all this interesting data. It was so nice and refreshing to sit there. It wasn't about mortality, and it wasn't about how do I consent my patients, and how do we get through this controversy. It was about the data and the science and the technology. It was just really refreshing for us to go back to where we started and think about what a breakthrough technology does to a space like peripheral intervention.
Data-Driven Decision Making in Peripheral Artery Disease Treatment
During the paclitaxel controversy, predictive models were crucial in identifying high-risk patients who might benefit from drug-coated technologies. Cook’s model uses a comprehensive set of variables, including patient demographics and lesion characteristics, to predict the likelihood of target lesion revascularization (TLR) over time. This tool aids clinicians in balancing the risks and benefits of different treatment options, ensuring a more personalized and informed approach to patient care. The emphasis on transparent data and predictive accuracy enhances both clinician confidence and patient understanding, ultimately contributing to better long-term outcomes.
[Dr. Sabeen Dhand]
Yeah, makes sense. Speaking of long-term outcomes, there's been a couple of predictability models, particularly one that's available online by Cook. Do you use that?
[Dr. Eric Secemsky]
Yeah, absolutely. Data is an important part of everything. In particular, these data models or prediction models to help really consult patients even before a procedure are critical. During the paclitaxel controversy, the question was, how do you identify a patient who's high-risk enough to get a drug-coated technology if you were concerned that signal was real? Cook Medical really led the way with their data. They had the longest-term data on the five-year data for the Zilver PTX stent had been published, and they were incredibly transparent. I think everybody in the field recognized that Cook took a leading position in terms of being transparent about their data and standing by their technology.
There's a gentleman named Aaron Laudis. Aaron was a statistician at Cook who's a wonderful guy. He actually went to academia, but still affiliated with Cook, but helped put this together with the Cook team, a prediction model, and they used their data and registry data to identify predictors of a higher likelihood of needing a repeat intervention. It was freedom from target lesion revasculization. They used a number of really available variables to help generate a really realistic prediction rate for the likelihood of repeat intervention. They have about eight patient demographic variables that are anywhere just from age, sex, diabetes, high cholesterol, smoking, claudication, or CLI. Easy stuff that we have on our mind when we're presenting any patient. Then if you have a diagnostic angio available, they had some lesion characteristics, length, reference vessel diameter, total occlusion, calcification, prior intervention, and runoff.
Again, there was about 15 variables in total, eight patient, seven from the lesion characteristics. You plug all these numbers in, and then they give you a really nice estimation of freedom from target lesion revasculization from 12 months through five years. When this started, I think that it was an opportunity to say, if we are going to limit how much paclitaxel we expose patients to, but balance that there is a risk of needing a repeat intervention if you use just a balloon angioplasty or non-coated bare metal stent, this is a good way to guide that conversation. If you had really high risk of restenosis, maybe it's like, let's just do it with the [unintelligible 00:28:25] with the drug-coated technology. Now, with paclitaxel being safe, it's not about reserving paclitaxel, but just thinking a little bit about how you leave a procedure. We all know that we don't want to aim for perfection, because that gets us in trouble. We also know that we got to go think about the risk, long-term risk for a patient, and that goes anywhere from their age, the severity of their disease, CLI versus claudication, to the lesion morphology.
This helps us just be realistic with our patient that you have a fairly high risk of TLR. We are going to be really aggressive with how we treat you, because the only way we know how to modify that if you're already going towards an intervention is to be really complete with our intervention. I think that's where this prediction model can be really helpful for that conversation with the patient and a reminder to the clinician about the risks of that patient.
Podcast Contributors
Dr. Eric Secemsky
Dr. Eric A. Secemsky, MD, MSc, RPVI, FACC, FSCAI, FSVM is the Director of Vascular Intervention and an Interventional Cardiologist within the CardioVascular Institute at Beth Israel Deaconess Medical Center (BIDMC).
Dr. Sabeen Dhand
Dr. Sabeen Dhand is a practicing interventional radiologist with PIH Health in Los Angeles.
Cite This Podcast
BackTable, LLC (Producer). (2024, January 22). Ep. 407 – The Evolving Role of Drug Eluting Stents in PAD [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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