Paclitaxel-Coated Devices for PAD: The View from the Vascular Leaders Forum

By Sean Lyden, MD

In the months since Katsanos and colleagues published their meta-analysis late last year in the Journal of the American Heart Association (JAHA) suggesting a safety signal with paclitaxel-coated devices for treating peripheral artery disease (PAD) in the femoropopliteal artery, it’s been a challenge to keep up with the evolving related developments.

The latest came March 15, when the FDA issued a letter to healthcare providers recommending that “alternative treatment options should generally be used for most patients” while the agency further evaluates data on the question.

Another key development was the March 1-2 Vascular Leaders Forum convened on this topic by Vascular Interventional Advances (VIVA), a not-for-profit organization focused on vascular medicine and intervention. As current President of VIVA and a participant in this forum, I have written this post to review the issue through the lens of that expert forum and advise colleagues on what to look for next in the use and regulation of paclitaxel-eluting stents and paclitaxel-coated balloons for treating PAD (collectively “paclitaxel-coated devices” hereafter).

Background and the meta-analysis

Some 100 experts from across the globe were invited to the day-and-a-half Vascular Leaders Forum, including leaders of all pivotal clinical trials of approved paclitaxel-coated devices, regulatory officials from the FDA and Centers for Medicare & Medicaid Services, oncologists, vascular pathologists and others. The objective was to discuss all the relevant data to help understand the concern around paclitaxel-coated devices, particularly in view of the lack of any suggested plausible mechanism of harm, and to make recommendations on how to proceed.

After detailed sessions on PAD and mortality, the use of paclitaxel in other beds, and the basis for use of paclitaxel as a vascular antiproliferative agent, the forum turned to meta-analyses in general and the JAHA meta-analysis in particular, including a presentation on the latter by lead author Konstantinos Katsanos, MD, PhD, himself. Dr. Katsanos reviewed the methods and results of his group’s meta-analysis of 28 randomized controlled trials of paclitaxel-coated devices for PAD, including the finding of an increased rate of all-cause death at two years in claudicants receiving paclitaxel-coated devices with a potential dose-related signal.

Then came a review of potential limitations of the JAHA meta-analysis by William Gray, MD, of Lankenau Heart Institute, Boston, including:

• Use of summary-level data from publications rather than patient-level data
• Potential selection bias resulting from lack of complete follow-up
• Risk of a type I error from insufficient powering for mortality as an end point in any of the component studies
• Variation among the individual studies in device type, drug doses, excipients and other variables

Patient-level data from device trials

Next came a session of reviews of CEC-adjudicated trial data from the pivotal trials of individual paclitaxel-coated devices. Leaders of trials for each of six such devices reviewed patient-level data for the respective devices — specifically, the Zilver PTX and Eluvia drug-eluting stents and the Ranger SFA, Lutonix, IN.PACT and Stellarex drug-coated balloons. I presented the review of the Stellarex data. Notably, from all individual data sets with patient-level data, no increased mortality signal was found across any of the studies.

This session also included a presentation on the THUNDER trial of an additional paclitaxel-coated balloon (Cotavance) that was included in the JAHA meta-analysis. The presentation noted that patients who had received the drug-coated balloon had longer and more aggressive follow-up than did their angioplasty counterparts, which potentially biased the results.

Reactions and what to watch for next

The next session explored regulatory reactions around the world, including suspension of recruitment for two ongoing European studies, BASIL 3 and Swede PAD, while two ongoing American studies, BEST and TRANSCEND, are continuing.

The final session focused on the path ahead, highlighting two upcoming data releases that clinicians may look to for clarification of the controversy:

• VIVA Physicians is funding an independent patient-level data analysis of all five industry-sponsored trial programs for paclitaxel-coated devices.
• Another study is evaluating nearly 7,000 patients with claudication or critical limb ischemia —both with no prior peripheral vascular intervention — who were entered into the Vascular Quality Initiative (VQI) database between September 2016 and September 2017 for treatment with paclitaxel-coated versus non-drug-coated devices. Propensity matching was done to keep the data sets similar. No increase in mortality was found in matched cohorts with claudication or matched cohorts with critical limb ischemia. The data will be presented at the Society for Vascular Surgery’s 2019 Annual Meeting in June.

Additionally, Peter Schneider, MD, reviewed a newly published patient-level meta-analysis he had just co-authored (J Am Coll Cardiol. 2019 Jan 25 [Epub ahead of print]) evaluating data from four independently adjudicated prospective studies comparing paclitaxel-coated balloons versus angioplasty in 1,980 patients with femoropopliteal artery disease. The analysis found no correlation between any level of paclitaxel exposure and mortality through five years.

Perceptions at the forum

The forum concluded with a panel discussion and audience polling. The latter revealed the following:

• About two-thirds of attendees felt they would be more conservative in recommending drug-coated devices for patients with claudication.
• Most clinicians had no knowledge of any mortality events among patients they had treated with paclitaxel-coated devices.
• Most attendees said their hospitals had not yet had discussions about any changes in the use of these devices.
• Most attendees did not feel restrictions on the use of these devices were warranted at this time.
• There was broad consensus that merging patient-level data from all manufacturers of these devices would help address concerns and that enrollment in current trials should not be stopped.

Don’t assume awareness

One final takeaway from the forum is worth noting: Many physicians and affected patients may still not be aware of this controversy. Even if they are, they may not be aware of the many nuances raised on both sides of the issue. The question is further clouded by the lack of any proposed causality for potential harm from paclitaxel coating in this setting.

So while we await more definitive data, it is our duty to explain the controversy in its fullness to our patients and colleagues, as well as to continue diligent monitoring of patients treated with paclitaxel-coated devices to date.

Dr. Lyden is Chair of Vascular Surgery at Cleveland Clinic.