"Dueling Numbers": FDA Panel Trying to Determine Safety of Paclitaxel-Coated Stents and Balloons


The U.S. Food and Drug Administration (FDA)’s Circulatory System Devices Panel is in the middle of two days of presentations and meetings regarding mortality rates associated with the use of paclitaxel-coated balloons (DCBs) and paclitaxel-eluting stents (DESs). The discussions are noting missing data and conflicting analysis.

Paclitaxel is a drug that has been used on coating stents and balloons since 2003 and has expanded over the last decade. The stents and balloons are used to treat peripheral arterial disease (PAD) in the femoropopliteal artery. The balloons and stents mechanically open the restricted or blocked vessels. Paclitaxel is released from the balloon or stent to prevent formation of scar tissue in the blood vessel.

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It was a December 2018 publication of a meta-analysis that launched the controversy. The research was led by Konstantinos Katsano of Patras University Hospital, Rion, Greece. The analysis looked at data from 28 randomized controlled trials, which found an increased risk of all-cause mortality starting at two years and running out to five years for patients treated for femoropopliteal artery disease using a paclitaxel-coated balloon or stent compared to a device without a coating.

The panel is chaired by Richard Lange of Texas Tech University Health Sciences Center, El Paso. The advisory committee’s job is to make formal recommendations to the agency on various topics, including potential regulatory actions concerning devices already on the market as well as those in clinical trials.

The current two-day meeting launched with FDA reviewers and statisticians is discussing the current data and their attempts to round it out by requesting mortality data and information on patients that were lost in follow-up studies.

“The agency said today that some of the manufacturers, in the interim, have provided missing data, such that the percentage of five-year mortality data still missing now ranges from 2.7% to 26% across the pivotal paclitaxel DCB studies, down from as high as 40% a few months ago,” reported tctMD/the heart beat.

However, an FDA cause-of-death analysis continues to show cardiovascular and non-cardiovascular-related deaths of all types excluding infections to be higher in the patient groups using paclitaxel DCB and DES compared to those receiving uncoated devices. They haven’t found any data among the groups that explain the numbers.

During the session, FDA representatives were not always able to answer questions from the committee because of either lack of data or not enough time to analyze new data they had received. FDA advisor John W. Hirshfeld Jr., of University of Pennsylvania Medical Center in Philadelphia, referred to it as “a forest of dueling numbers.”

“The problem is that the numbers presented by industry and the numbers presented by FDA are not the same,” Hirschfeld continued. “As a consequence of this, we have a conundrum in trying to decide what weight to place on each analysis that we see. What I would hope would be that there would be a way … to get a common agreement about what the real numbers are between the sponsors and the agency so that we know exactly what data we’re dealing with.”

Industry representatives also spoke and introduced data, arguing that their own data doesn’t show the same mortality signals seen in Katsanos’ meta-analysis. Katsano also spoke, reviewing some of the criticisms of his research study. He pointed out that the only device manufacturer to provide patient-level data for more research was Cook Medical. And using that data, which derived from the ZILVER PTX trial, Katsanos demonstrated a negative interaction between paclitaxel and other risk factors, showing that the risk of death was highest for patients with the fewest risk factors and lowest for patients with the highest number of risk factors. He concluded that patient risk-stratified analysis was worthwhile to guide medical decisions.

In the midst of the panel debate before questioning, they appeared to agree across the board that a mortality signal does exist. What isn’t as clear is whether it should matter to clinicians and patients.

“The lack of practical significance is especially important in light of the technology’s potential to improve quality of life versus surgery,” stated Todd E. Rasmussen, of Walter Reed National Military Medical Center in Bethesda, Md.

The panel discussions will continue today.

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