This transcript has been edited for clarity.
Rajiv Gulati, MD, PhD: Hello and welcome back to the Mayo Clinic Medscape video series. I am Rajiv Gulati, interventional cardiologist and professor of medicine at Mayo Clinic. Today we will be discussing the controversy surrounding the use of paclitaxel-coated devices in peripheral arterial disease. I am joined by my colleague, Sanjay Misra, vascular interventional radiologist and professor of radiology at Mayo Clinic, and a renowned expert in this area. Welcome, Sanjay.
Sanjay Misra, MD: Thank you, Rajiv.
Gulati: Sanjay, what are these devices, and what are they used for?
Misra: Paclitaxel-coated devices are being used primarily in the lower extremity for revascularizing atherosclerotic disease. They also have been used to limit restenosis. Currently, there are different formulations of the technology and delivery methods that are being used.
Gulati: Balloons and stents. Why was there such a rapid uptake of these devices compared with previous technology?
Misra: Several randomized controlled trials in patients with occlusive disease showed that restenosis rates are reduced when you use these devices. The blood vessels stayed open longer and the patients had better outcomes.
Gulati: Better outcomes in terms of limb function and symptoms?
Misra: Yes. Patients were able to walk farther and have fewer interventions once these devices were used.
Gulati: Let's fast-forward to now. There is a controversy based on a systematic review and study-level meta-analysis suggesting a mortality concern. Perhaps you could outline the controversy and where we are now.
What's Behind the Controversy?
Misra: In December 2018, a meta-analysis by the Katsanos group, published in Journal of the American Heart Association, reported an increased all-cause mortality in patients who received paclitaxel-coated technologies. The authors lumped all of the technologies together, looked at the available data, and found that patients who received the devices had higher all-cause mortality. The authors were unable to provide us with the reasons why this was happening or a possible hypothesis.
Gulati: If I'm correct, this was a meta-analysis of randomized trials of the balloons and stents and 5-year outcomes showing mortality, but the mortality signal did not emerge early on.
Misra: Yes. There was no signal at 1 year, a ramping up of the signal at 2 years, and a larger signal at 5 years. One of the challenges of this meta-analysis is that at that time, two studies had completed 5-year enrollment,and the majority of the studies—approximately two dozen or so—were in the 1- to 2-year follow-up range. So, many of the patients were not included in the longer-term data.
Gulati: That is important to note. None of these studies of interventions for peripheral arterial disease are powered for mortality. Mortality is not generally considered an endpoint in the primary outcome, correct?
Misra: That is a good point. The trials are all powered for restenosis and target lesion revascularization. Mortality is censored; however, we do not know the cause of the mortality. What I tell my patients is that if you have one of these devices and you walk across the street and are hit by a car, you would be associated with the all-cause mortality group. As you know, Rajiv, all-cause mortality can be anything from cardiovascular events to noncardiovascular events. What is unclear in this dataset is how many deaths were linked to the device and were true cardiovascular events, or plausible cardiovascular events, and how many were not. So the cause of mortality is really not known.
Gulati: This meta-analysis was a study-level meta-analysis and not a patient-level meta-analysis, so that would not account for changes that might have occurred during the follow-up period—cross-overs, for example—and it would not account for patients lost to follow-up. Is that correct?
Misra: At the time of the meta-analysis, approximately 20% of the patients were lost to follow-up. We did not know what happened to them. So if you are looking at small datasets, approximately 4000 patients or so, 20% is 800. Thus, it was not powered for mortality, a significant amount of patients were lost to follow-up, and we did not know at a patient level what happened to these patients, what were their outcomes.
Gulati: That is an important caveat when we interpret that meta-analysis. But despite the methodologic issues, there is still a signal, and I believe our bar for concern should be very low when it comes to a signal for harm. As a result of that meta-analysis, several groups have gotten involved. Perhaps you can enlighten us as to what the discussions have been, who has been involved, and where we are right now.
Misra: A number of groups are working in synergy on this problem. I will mention only the two I am working with. One is the VIVA Vascular Leaders Forum. They have obtained all of the data at an individualized patient level from all randomized controlled trials done in the United States. We are in the process of looking at whether there is a signal; that paper will be coming forward soon. The second group is multisocietal, a paclitaxel coalition of different specialists including, in no particular order, the American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Radiology, American Heart Association, Society for Vascular Medicine, Society of Interventional Radiology, and Endovascular Surgery Society. The goal of that group is to partner with the US Food and Drug Administration (FDA) to understand what we should do next now that we have some concerns about this technology: which patients should be treated, what the consent process should look like, and what the follow-up process should look like. Those are three major inquiries happening in the background.
To Use or Not to Use a Paclitaxel-Coated Device
Gulati: It is commendable how rapidly the societies got together and how inclusive the leadership forum has been. Involving the FDA is quite important. Perhaps you can tell us where we are right now. For clinicians with patients who may benefit from a paclitaxel-coated device, what should they do?
Misra: We are asked that question all the time. What would you do if you saw this patient? A lot of this is driven by the types of patients you see, and whether these patients are presenting with claudication, which is pain with walking, or with critical limb ischemia, the end product of atherosclerotic peripheral arterial disease, who need a limb revascularization. So, one consideration is how sick is the patient and what is the best therapy for them?
Gulati: That is a really interesting point. You are saying that the patient who has more to gain with the device would be someone with critical limb ischemia, for example, and you would have a lower threshold to use the device?
Misra: I believe the threshold for using the device would be lower for the patient with critical limb ischemia because you would want effective and durable revascularization, and these patients have higher mortality risks than patients with claudication. The problem with the data we have is that 90% of the dataset is from the healthier claudication patients. You would have to extrapolate from the group with claudication to the group with critical limb ischemia, and I believe that would be a subset one would consider for revascularization. The other considerations are how sick is the patient, would a repeat revascularization be more hurtful than a very good revascularization—a Cadillac procedure, a priori—and then, obviously, what are the risks and benefits of a surgical bypass and could this patient undergo a surgical bypass? It is very complex decision-making.
Gulati: So it's not as simple as banning all of the devices and waiting for more data; rather, we should be nuanced in our discussions with patients. What is Mayo doing right now in regard to the balloon and stent?
Misra: As you know, Rajiv, we are a large organization in multiple different geographic sites and multiple venues within these geographic sites, with cardiologists, surgeons, and radiologists practicing in several different centers. Given that we have such complexity and diversity of patients, we have put a moratorium on using these devices until we understand our data. We have looked at our dataset across the enterprise, which includes Scottsdale, Jacksonville, Rochester, and the Health System, and we are analyzing our results and scrutinizing them because there are center-to-center biases for these datasets.
Any time you conduct a randomized controlled trial, you are assuming that every patient is treated with the optimal medical therapy at the same level. As a cardiologist, you know that a simple thing such as taking a statin and having good hypertensive control could result in a 30% mortality difference from someone not well controlled. That is one thing we are looking at as we speak. We are also thinking about what the FDA will say. Currently, they suggest very good counseling of the patient, very good follow-up of the patient, and informed consent based on the local environment you work in. We are waiting to see whether the FDA will provide additional guidance with additional datasets that will be released.
For the short term, we do not recommend using these devices. Once our data are available, we will look at that, see where the FDA is, and then decide what to do for our patients.
Getting to the Answer
Gulati: So right now we are in limbo. What data do we need to help us make a decision about whether these devices should be used and in whom they should be used?
Misra: That's a great question. It has to be at the level of what is best for the patient. So at least for Mayo, what does our own data show and how did our patients do?
Gulati: But that is not going to be randomized data. Do you think we will be able to get a patient-level meta-analysis, patient-level information, from the initial trials?
Misra: There are a couple things we are doing locally and nationally. We are getting individualized patient meta-analyses from randomized trials; we are getting large datasets from Medicare and other providers; and we are also getting large datasets from Germany and other national datasets outside the United States. That data will help us, in conjunction with the FDA.
The local data will also help us because it will give us an idea of what our data at Mayo looks like. We will have individualized patient data, and we will also have a control group of patients who did not get coated stents, and we will be able to sort out, with some level of confidence, how our patients did. I think those two datasets will help guide the conversation at Mayo and maybe even outside Mayo.
Gulati: It certainly sounds that way. More robust data with better follow-up will be highly informative to the FDA and to our clinicians and patients. What does this mean for the field of peripheral arterial disease research? Should mortality be considered an endpoint in all future studies of device interventions?
Misra: As you know, from the coronary dataset, very few trials have been powered for a mortality endpoint, and what I think we are finding is that mortality plays a role any time we perform an intervention. The questions are: What is the optimal trial design, how long should we follow these patients, and in what way should we follow patients? Do we enroll everyone in a registry such as the National Cardiovascular Data Registry, the Vascular Quality Initiative, or another registry, and follow all these patients longitudinally to see what happens to them? And more importantly, if they die, how did they die? These are important questions that will need to be discussed and debated. For the short run, if you were to do a mortality trial in this space, we are looking at 10,000-20,000 patients, which would probably be very hard to accomplish any time soon.
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Cite this: Paclitaxel-Coated Devices on Pause for Patients With PAD - Medscape - Mar 05, 2020.