The Future is Going to Be Drug-Coated or Drug-Eluting. We Need Individual Patient Data to Move Forward.

Dr. Katsanos was the lead author of a December 2018 meta-analysis¹ that found patients receiving treatment with paclitaxel devices in the femoropopliteal arteries experienced higher late mortality. An FDA Advisory Committee Meeting was held June 19-20, 2019 to discuss the data in depth. The FDA indicated that paclitaxel-coated and -eluting devices should be used with caution in peripheral arterial disease, and that available data will continue to be reviewed.

What led you to perform the meta-analysis¹?

I, and my team, have been performing endovascular procedures in the lower limbs for more than 15 years. We have been watching this space very closely. We have performed several clinical investigations using drug-coated balloons and drug-eluting stents in a number of different vascular fields. For example, I was the lead investigator in the first drug-coated balloon study for arteriovenous fistulae. Being aware of and conscious of the data, we saw a few hints in the areas under our study and decided to look into it further, in a systematic way.

There has been both criticism and acceptance of the meta-analysis. What has been your reaction?

It comes down to science. Science is there to be disrupted and for new evidence to come in. We are happy to take any criticism being delivered in a scientific way. This was an unexpected finding for us as well, because paclitaxel use has actually been a very important development in the lower limbs to reduce restenosis and improve clinical outcomes for patients. There is no perfect study. Most, if not all, of the studies so far have been on intermittent claudication alone.

Is there anything you would have done differently had you known the outcome when you were preparing the meta-analysis?

No, I don’t think so. We had been working on this project for months. We were very judicious in our systematic review and the chosen statistical methods. We had tested a number of different models. We tried to be as careful as possible, precisely to avoid any misinterpretation and to avoid getting a false message across. The community may have reacted in an exaggerated way, but I think that was because it was actually a very unexpected finding.

Have you seen a difference in the reaction in the United States vs Europe?

I wouldn’t say so. I think the reaction has been mostly some form of denial, perhaps sometimes driven by a conflict of interest, for example. At the end of the day, we have to stick to the science. It is about data and it is about what the data tells us. There might be uncertainty — and there is always uncertainty in science — and other people have proposed the use of different statistical methods. But I think it is very clear, at the end of the day, that this signal has to be discussed and taken into account.

How has your practice changed?

My practice has changed considerably. I have stopped using drug-coated balloons and drug-eluting stents, with a few exceptions. I personally still favor, for example, a very low dose drug-eluting stent in high-risk patients such as those with critical limb ischemia. My team and I are practicing the use of paclitaxel in a very judicious way and in a very, very select group of patients.

Will we return to a focus on preparing the vessel for plain old balloon angioplasty (POBA)?

One side effect of the use of drug-coated devices was that in order to get good clinical outcomes with drug-coated devices, we learned how to better perform POBA. Over the last few years, we have learned how to prepare the vessel, dilate the vessel, and how to perform prolonged POBA. Are we going to go back to POBA, without any medication? Any pause in drug-coated device use is going to be temporary. We have the mechanical means of preparing and dilating the vessel to get a proper clinical outcome, but we also need the biological means, and this is where the drug plays a role, in reducing restenosis and allowing for improved long-term patency. Drug use itself is not going to change, but perhaps we will come up with different formulations of paclitaxel, or use different drugs such as sirolimus or everolimus. The future is going to be drug-coated or drug-eluting. That is, I think, undisputed. The question is, what kind of formulation and what kind of drug? It is not that simple.

Is the risk of mortality linked to the location of treatment with paclitaxel in the lower extremities?

This is a very complex question and we don’t have the data to actually answer it. Does it depend on the actual site of application? Are the lower limbs at higher risk compared to the coronary arteries? There are so many differences in terms of the drug doses, devices, and excipients, as well as different applications in the lower limbs and in the coronary arteries, that it is impossible to speculate, or draw any conclusions or inferences. What I can tell you is that we shouldn’t draw any parallels with oncologic applications and chemotherapy, because pharmacologically, it is a completely different scenario. In cancer, we use intravenous high dose chemotherapy that has been appropriately formulated with some kind of solvent, so the paclitaxel can be cleared by the human body. That is not the case with paclitaxel-coated devices, where the application of paclitaxel is in its very solid state (amorphous or crystalline, or a mixture thereof). It is pure paclitaxel, which has very prolonged tissue residency. In oncology, paclitaxel has a half-life of several hours, and with drug-coated devices, paclitaxel has a half-life of several weeks, if not months. Therefore, it is impossible to draw any conclusions from paclitaxel’s oncologic applications.

What should happen going forward?

We shouldn’t remain in denial anymore. We should acknowledge and act on the facts. The fact that paclitaxel is the only difference in the randomized studies makes it very likely that paclitaxel is also the cause of the problem. But this is not to say that we definitively know that paclitaxel causes the problem. Going forward, we must first attempt to better understand the phenomenon by using the current data at hand, and only then should we decide what to do next. It is quite unfortunate that the individual patient data are not available to all the investigators. Only one company, Cook Medical, has released the data and that is a limited data set, because some patient characteristics are missing. The rest of the companies have not released any individual, randomized patient data into the public domain, which is important to do, because there seems to be some sort of heterogeneity between the mortality risk and the baseline patient characteristics. We need to be able to explore this more thoroughly before we make any decisions about how to continue using paclitaxel. We need access to the data in order to be able to tease out this kind of information.

What about any changes to clinical trial design going forward?

We must insist on a randomized study design. Perhaps the sample size could be increased. Safety has to be taken more seriously, because we have been only analyzing, emphasizing, and paying attention to the clinical outcomes. It is clear we need 5-year, long-term follow-up in all of the studies. With paclitaxel, we cannot rely on one-year follow-up any more. Importantly, we need to look at functional outcomes. We have been discussing things like freedom from target lesion revascularization (TLR), which is one dimension of the clinical outcomes. At the end of the day, however, the patients want to live, they want to be able to walk on both legs, and they want to enjoy a good quality of life. Out of the 28 studies that we utilized in our meta-analysis — and this is a critical point — only 5 studies had investigated quality of life outcomes, but for no more than one year. Only one study looked at quality of life at two years. There was virtually no difference in the quality of life outcomes with drug-coated devices at one year. It then becomes very difficult and complex to communicate the appropriate message to patients about a potentially high-risk device. So we need more data on functional outcomes. Perhaps we need to again look into the endpoints. We need to improve the appropriateness and increase the breadth of clinical outcomes interrogated in the randomized studies.

You mentioned the majority of trials looked at intermittent claudication. What do we know about critical limb ischemia (CLI) and paclitaxel use in that population?

Approximately ninety percent of the patients in these randomized studies were suffering from intermittent claudication. The clinical problem was restenosis, which is why everyone wants to use paclitaxel, because there are no alternative means to inhibit restenosis. I personally think that had there been an alternative means (other than paclitaxel) to treat restenosis, we wouldn’t have had the kind of intense reaction we experienced. As doctors, we don’t want to go back to the Stone Age — and I do not expect us to be going back to the Stone Age, anyway. We are saying that we need to think about paclitaxel use in a very conscious, scientific way. If we were to do proper patient risk-stratified analysis from the individual patient data, we might be able to identify which of the individual patient subgroups are at risk and which are on the safe side. It might be the case — and I do not know, so I am hypothesizing — that paclitaxel does not affect the CLI population as much as it does the claudicant population. Unfortunately, there is no evidence to say that, either. This is why it is so imperative to make public the individual patient data. I have been stressing this time and again over the last several months. We need the individual patient data to be able to tease out the unique patient characteristics that may interact in a different way with this mortality signal.

Some interventionalists are limiting their paclitaxel use to patients with more complex lesions, Rutherford 4 and 5.

This is, again, just hypothetical, because there is no data whatsoever to drive this kind of decision. It is a gut instinct. Science is not black and white. Science is a continuum of interactions, of risk factors, of clinical outcomes, of numbers, etc. There is a wealth of data now sitting in the companies’ archives. They have been very expedient in collecting more data. We now have nearly 1500 randomized patients going out to 5 years follow-up; we have approximately 3500 randomized patients going out to 2 years. We need the individual patient data in an anonymized way, and then we can start looking into interactions and alternative hypotheses. Is the CLI population perhaps safe to treat with paclitaxel? I agree that perhaps it is a lot more important not to refuse treatment with paclitaxel in the CLI population, where it is a matter of avoiding a limb amputation, if indeed paclitaxel proves to be safe and effective in this patient population.

What advice do you have for the individual interventionalist?

We need to proceed with good medical practice, good scientific practice, and good statistical practice, and this will make a big difference. Physicians should carefully read all the evidence and frequently explore, judiciously and intellectually, all the numbers. We do not know what we do not know, as unfortunate as that may sound. We know there is something there. We don’t have the answers. Those numbers have been out there; we just happened to pull them together. Every physician needs to become more aware and responsible in regards to the published studies. There will be some direction and guidance by the FDA, and no more than that. In order to understand further, we need to be able to scrutinize all the individual patient data in more depth and explore alternative hypotheses, if any.

Disclosures reported with the publication of the meta-analysis can be found here.

Dr. Konstantinos Katsanos can be contacted at katsanos@med.upatras.gr.

REFERENCE

1. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018 Dec 18; 7(24): e011245.