Paclitaxel in PAD: What to Tell Patients While the Numbers Are Crunched

HOLLYWOOD, FL—December 6, 2018, will long loom large in the minds of endovascular experts as the moment when a meta-analysis offered up a startling conclusion: an increase in late death with paclitaxel balloons and stents that have been on the market for years.

Today, panelists and attendees gathered at the 2019 International Symposium on Endovascular Therapy (ISET) to talk through those findings, as well as the implications not only for patients but for clinicians. Only a minority of those present at the end of the Town Hall session, when polled, said they believe the signal of increased mortality is real, and most said they’d continue using the devices. Even so, the majority reported they feel a responsibility to tell patients about the ongoing uncertainty.

Recalling when he first heard the news, Michael R. Jaff, DO (Newton-Wellesley Hospital, MA), said in a presentation: “I’m standing outside a consultation room of a new referral for a second opinion, someone who’s already been seen [and] with a plan arranged.” The patient, a 68-year-old man with disabling claudication of the right leg, had been referred by his vascular surgeon for treatment with a Zilver PTX stent (Cook Medical) and was coming for a second opinion.

This strategy seems reasonable according to what had previously been published, Jaff said.

“So I’m about to walk into the room and introduce myself when my iPhone in my pocket buzzes. I pull it out just by chance, and I saw [the headline] and I stopped opening the door. . . . I did not anticipate this, and I really didn’t have an inkling that this mortality risk existed over the long term.”

What would you have done, Jaff asked, had you been in my shoes that day? Half answered that they would have proceeded as normal, but 28% said they were uncertain about whether to tell the patient not to get a paclitaxel-based vascular device until more data were published. Fully 78%, though, said they would mention the alert right then in the consultation.

Nearly all (93%) agreed they too hadn’t anticipated the mortality signal, but 7% said earlier data had hinted at the concerns. None had patients who’d died for unexpected reasons after treatment with a paclitaxel-based device.

Patient-level analyses presented last week at LINC 2019 provide some new clues to help move past the confusion, Jaff said. The effort to merge all existing data into an independent database also is a positive move, he added. “I think that’s going to be critical to regain our confidence in this [area].”

Ultimately, Jaff said, he was fully transparent when speaking with the patient that day about the fresh concerns and, since there was no need for an urgent decision, asked for time to review the evidence. The follow-up appointment is scheduled for next week.

Everyone is reviewing again all the experimental data, to look at the systemic exposure of these devices. Juan Granada

Talking to TCTMD after the Town Hall, Juan Granada, MD (Cardiovascular Research Foundation, New York, NY), described next steps. “Everyone is reviewing again all the experimental data, to look at the systemic exposure of these devices. I think that’s going to be number one.”

Also key is a collaborative effort, Granada said.  “VIVA has assembled a multidisciplinary working group to try to collect all the data from all the trials involved to date, and then what we have to do is essentially run the analysis again but in a way that we all believe, as a working group, is the proper way to do it.”

A crucial element here in further analyses is patient-level data, given that so many in this population have comorbidities that make direct comparisons between the various study arms difficult. “If we don’t really clean the noise to try to normalize the groups, it’s going to be really difficult to [understand]. There’s a lot of confounding, for example mixing the stents and balloons and all of these [vascular] conditions—we really need to clean the data,” said Granada.

The Impetus

Back in December, Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), and colleagues first outlined the worrisome findings in a paper published by the Journal of the American Heart Association.

In their pooled data set encompassing 28 of the most rigorous randomized controlled trials of these devices in femoropopliteal artery disease, all-cause deaths began to diverge after 1 year. By 2 years, patients who had received paclitaxel-coated devices had a 68% higher relative risk of dying than those treated with uncoated balloons. By 5 years, their relative risk had risen to 93%, with a number needed to harm of just 14.

During the ISET session, it was clear that even the experts are unsure how to manage this information when engaging with patients.

“I actually had a patient come to the office today with their family and had heard about this, and [they] asked me if I was ‘going to use that balloon that will kill their father,’” panelist Richard F. Neville, MD (Inova Health System, Falls Church, VA), said. “I’ve not seen a publication that I can recall in recent memory, despite many of the very advanced devices we all use, that’s created quite the controversy and the awareness that it has in patients. . . . It’s really been fascinating to see the response.”

I’ve not seen a publication that I can recall in recent memory, despite many of the very advanced devices we all use, that’s created quite the controversy and the awareness that it has in patients. Richard F. Neville

Panelist Andrew Holden, MBChB (Auckland Hospital, New Zealand), said that, despite the upheaval, it’s important to “acknowledge and congratulate Katsanos. I think it took some courage, and while there are some reasonable concerns about the methodology, at least it’s got us considering some very important findings.

“Overall, though, I think we’re all struggling because the finding is essentially an illogical finding, in that as we know the drug dose is much, much lower than systemic dose of paclitaxel [and] the duration is very limited. Given that very limited duration, why would mortality be no different at 1 year but different at 2 years? And there’s no mechanistic explanation,” he continued, adding, “We need to try to find an explanation.”

It may be, for instance, that patients who receive balloons are more likely to return for reintervention and thereby benefit from the closer follow-up that care involves, Holden suggested. Or, there could be an imbalance in cardiovascular risk factors between the treatment and control arms of the RCTs.

From a statistical standpoint, getting as many individual patients as possible into future analyses will help, several people said. On a related note, Barry T. Katzen, MD (Miami Cardiac & Vascular Institute, FL), pointed out that the US Food and Drug Administration, “which obviously houses a huge amount of data,” had been invited to participate in the ISET session but were unable due to the government shutdown earlier this month.

James F. Benenati, MD (Miami Cardiac & Vascular Institute), said that it’s interesting how most of those polled don’t believe the data, but one-third had already changed their practice in some fashion. “That tells me people are being pretty [cautious], and I don’t think that’s the worst thing,” he said.

For him personally, though, the meta-analysis isn’t convincing, so Benenati advised putting the concern in perspective when weighing treatment options with patients.

“If I want to have an honest consent with a patient right now,” he said, “I think what I have to tell that patient is: ‘There’s a pretty good amount of data saying these stents and balloons are safe. There’s one study that suggests and recommends further investigation, but I truly believe that the technology I’m going to use could save your leg, give you a lot better patency, and prevent you from coming back.’

“If that’s a patient with critical limb ischemia or profound claudication,” he continued, “I actually don’t think that patient is going to have too hard a time coming to a decision. But I think the consent in this really has to also point out the benefits of the drug elution as opposed to the suggestion [of late mortality risk] in one analysis.”