AUSTIN, TX—The ongoing controversy about paclitaxel-eluting devices was featured in a debate at the Society of Interventional Radiology meeting in Austin, Texas. Luke R. Wilkins, MD, addressed the packed room from the standpoint of arguing for a pause, while Bret N. Wiechmann, MD, FSIR, took the opposite stance.
Dr Wilkins: Time for a Pause
Dr Wilkins began his presentation by summarizing and refuting the 3 main criticisms levied against the Katsanos study—that it was a meta-analysis that did not have patient-level data and used flawed statistical modeling, that there is no identifiable cause of death underlying the increased risk of mortality, and that currently available devices use small amounts of paclitaxel.
In fact, a meta-analysis is the highest level of evidence available, Dr Wilkins pointed out, and past meta-analyses have helped to advance the field. In the case of the Katasanos study, both fixed and random effects modeling as well as other methodologies were used to ensure that there was no significant bias.
Regarding the second criticism, Dr Wilkins acknowledged that it is true that the cause of death is currently unknown. “However, just because we don’t understand the effect or how the effect happens, doesn’t mean we can discount that,” he said. He mentioned the COX-2 trials from years ago and how a trial showed increased cardiovascular mortality, causing controversy. After further investigation, it was discovered that some patients were put into a pro-thrombotic state.
The small amount of paclitaxel has also been a source of criticism. To counter this, Dr Wilkins presented his calculations about the surface area of balloons and the actual amounts he ends up using in treatment, pointing out that while the amount is a fraction of that used in chemotherapy, he would still push back against the official amount estimates. Additionally, he noted that a 2016 JVIR article showed some downstream effects of drug-eluting devices and the vascular changes that occur in non-target tissues. “So there’s something that’s happening that we don’t fully understand,” he said.
Dr Wilkins recommended following the FDA’s updated recommendations and discussing the risks and benefits of all available PAD treatment options with patients. The FDA has recommended that alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents should generally be used until additional analysis of the safety signal has been performed.
Dr Wiechmann: Flaws in the Meta-Analysis, and More Data Review to Come
Bret N. Wiechmann, MD, FSIR next took the podium and acknowledged that his position was more difficult following the updated FDA letter. “The meta-analysis has piqued everyone’s interest, but no one is ignoring it,” he said. “But there is a lot of information that’s available to rebut some of these inferences before we ground the whole fleet of paclitaxel devices.”
He showed a slide illustrating that there is a dose-dependent curve with paclitaxel. Additionally, he pushed back on Dr. Wilkins’ assertion about the quality of the meta-analysis by pointing out that individual patient data sits at the top of the hierarchy of evidence, and that data is not included in the Katsanos study. “Patient-level data is more reliable, more precise, and more powerful. It’s replicable and it’s consistent,” he said. Most importantly, he said, patient-level data allows the creation of a time-to-event analysis, which industry is currently working to develop.
A granular analysis of the industry patient-level data was beyond the scope of the time allotted, but a broad overview shows no increase in mortality at the individual patient level. “These are not small studies,” Dr Wiechmann noted.
An important point, he said, is to evaluate the data on an as-treated level rather than an intention-to-treat analysis. In one study, patients were allowed to cross over, and approximately 40% of patients in the non-DES arm at some point received paclitaxel. When those patients were included in the as-treated analysis, the mortality difference disappeared. “It’s an important point that we can only gather from individual patient data that you can’t gather from a meta-analysis,” he said.
Regarding dose, patients with PAD are receiving amounts orders of magnitude lower than those received in systemic IV chemotherapy, and there is no difference in mortality in the chemotherapy patients. Finally, Dr Wiechmann noted that most studies in the meta-analysis were not powered for mortality, and that almost all studies, including those not involving paclitaxel, show increases in mortality in the experimental vs control arms.
He concluded by explaining that the pieces of the puzzle will be coming together over the next several months as data are reviewed in-depth. “It is not an issue that’s going to be going away anytime soon. Just as no one is ignoring the original meta-analysis, no one should ignore this data,” he said.