Paclitaxel Townhall: The Concern About Mortality Risk

A recent meta-analysis by Katsanos and colleagues in the Journal of the American Heart Association has raised questions about whether paclitaxel-coated devices may increase the risk of patient mortality. ISET 2019 will begin with a Townhall session that will delve into the details of the study, draw on the collective experience of experts, and provide practitioners with a consensus moving forward. Barry T. Katzen, MD, the founder and Chief Medical Executive of Miami Cardiac & Vascular Institute, joined us to explain the controversy and the roadmap to addressing it.

Can you give some background on the use of paclitaxel-coated devices and explain the current controversy?

In the past decade it has been well demonstrated in scientific literature that paclitaxel in both balloons and stents has had a beneficial effect in improving patency in multiple trials compared with similar devices without paclitaxel. The delivery of this medication in low doses seems to reduce and prevent proliferative response and therefore prevent restenosis and prolong patency. The use of these devices has increased in recent years and has become a mainstay of peripheral vascular therapy.

However, a recent meta-analysis by Katsanos and colleagues seems to show that there may be an increased risk of mortality for patients who have received paclitaxel compared with patients who did not receive paclitaxel. There is some suggestion that this effect may be related to dose. As a result, that publication has generated concern among practitioners, manufacturers, and regulatory agencies because of the data about mortality.

At this point, the article has not led to a change in practice. A number of the manufacturers who conducted the trials included in the meta-analysis have reanalyzed their data, which did not seem to confirm the findings demonstrated in that study. Virtually every company has presented or will be presenting some sort of public statement regarding their specific data supporting safety paclitaxel in their devices.

How will ISET address different perspectives on the study results?

At this point in time, we are taking the question raised by this paper seriously, but I think most practitioners are wondering about the significance of the study results and their implications. It’s unusual for a single study to completely change clinical practice. Furthermore, this was a meta-analysis rather than a prospective randomized trial in which mortality was specifically examined as an endpoint. As a result of the significant statistical limitations of the meta-analysis, and other issues in the manuscript, it is likely most prudent to do further study on the question

We are left with essentially two possibilities—the findings could be accurate, or they might not be accurate as a result of the limitations of the statistical methodology involved. Some people believe the conclusion is too drastic to be made from a single paper and that more study should be done. Others say that informed consent and our use of paclitaxel should be changed based on this study.

The Town Hall Meeting at ISET will  address these questions from the practitioner’s point of view. Through both scientific presentations, panel discussions, and audience questions and answers, we will thoroughly examine the study, its strengths/weaknesses, and its implications as well as other data regarding questions raised. We also will use polling questions to get a sense of the audience’s overall opinion and to come to a consensus that practitioners can take away when they come home from ISET.

How will the ISET Townhall add to the field’s discussion regarding the JAHA study?

At ISET we’ll have the benefit of participation from faculty from all parts of the world, as well as an audience of practitioners. This unique combination means that we’ll have people who are incredibly knowledgeable in the field as well as people doing procedures every day. It’s an unusual opportunity to be able to bring practitioners into contact with the leading experts in the field to together make sense out of this study and develop a plan moving forward.

Can you preview some of the viewpoints audience members might hear?

I think everybody in the space is aware of the findings of the paper, but the question is how to interpret those findings. That would depend on the strength of the level of evidence of the paper. The problem is that the conclusions of the paper are in conflict with what we see clinically and what has been demonstrated in other studies.

If a trial is not designed for mortality analysis then looking at a single finding is a problem. I think fundamentally there may be a statistical method problem with the conclusions of the Katsanos paper, and this is what is challenging the field in interpreting its results. I think it will be interesting to hear about the strengths and weaknesses of the methodology from faculty who are scientific writers.

Who are some of the faculty invited for the Townhall?

Juan Granada, MD, who is CEO of the Cardiovascular Research Foundation, will speak on the pharmacology and mechanism of action of paclitaxel. He is a very well-known researcher in endovascular therapy and patient science and has a done a lot of the animal work in understanding paclitaxel.

His presentation will be followed by a talk by Jihad Mustafa, MD, who is a highly experienced interventionalist who has published extensively, and he is going to do a critical review of the study’s findings and offer comments on the strengths and limitations of the paper. Thomas Zeller, PhD, MD, is one of the leading interventionalists in Europe and will share the impact the study is having in Europe. They are having similar discussions to the ones we are having in the US, and there are quite a few clinical trials underway too.

Michael Jaff, DO, will present on the patient’s perspective. Dr. Jaff, a vascular medicine physician, is going to help us address what to tell our patients. He will simulate a conversation with a patient in terms of addressing these issues, and that conversation will be followed by a panel discussion that will encourage audience participation. We’ll conclude with some interactive polling questions to decide in the opinion of ISET attendees and faculty, is paclitaxel safe to treat PAD?

What else will be discussed?

In addition to the concern about paclitaxel, there have been new data coming out on the value of paclitaxel. The entire session will cover the use of drug-related therapy. Dr. Zeller will discuss how we determine whether to use a balloon or a stent with paclitaxel. Additionally, many patients are treated with bare metal stents, and Dr. DeRubertis will talk about drug delivery for in-stent restenosis.

What is your personal opinion regarding the Katsanos study and its clinical implications?

After reading the study myself, I currently feel comfortable continuing to use drug-coated delivery right now, especially if used where indicated, for patients who need it. I have concerns that need to be answered with further study, though I’m not concerned enough to stop using it at this time or to warn patients that there could be an increased risk of death from using this but also look forward to what we will learn from the Town Hall session.

What are some options clinicians might consider in communicating with patients regarding the meta-analysis?

One option is to say you feel the matter deserves further study but the increased risk of mortality has not been proven because of flaws or questions regarding the scientific methodology used, so you are comfortable continuing to treat patients as you are now. Another option is to make patients aware that you are aware of this study and that you’ve analyzed it and do not feel there is a significant increased risk of mortality for them and that you’re comfortable using paclitaxel. I personally feel that is the most appropriate position to take. However, people who are very concerned might want to change that position into informed consent where they actually inform patients that there is a paper showing an increased risk of mortality.  We are still in the mode of gathering and analyzing information to deliver the best possible care to our patients.