FDA panel sees link between paclitaxel devices, patient death risk

Disregarding comments from the medical device industry, a panel of vascular doctors and other medical experts told the U.S. Food and Drug Administration on Wednesday that they believe there's legitimate statistical evidence showing that treating blocked arteries in the legs with the drug paclitaxel is associated with higher rates of death years later in U.S. patients.

But beyond that, the FDA's Circulatory System Devices Panel struggled to find anything else meaningful to say about the risks documented in wide-ranging studies about the devices, which treat blocked arteries above the knee by mechanically reopening the vessel and then leaving behind paclitaxel to prevent re-closure.

Medtronic, Boston Scientific and other manufacturers of leg stents and medical balloons say there's no elevated "mortality signal" in their own data, yet the FDA saw an elevated risks when all the studies were pooled together, as initially reported last December in the Journal of the American Heart Association.

During the second day of the meeting, scheduled for Thursday in Maryland, the panel is expected to advise the FDA what it thinks should be done, including whether new studies should be run and if changes should be made in how the devices are marketed. Any such decisions could have financial implications for Medtronic and Boston Scientific, and major health effects for patients being treated for severe peripheral artery disease.

Devices with paclitaxel for the legs have been studied extensively in clinical trials since the first one, Cook Medical's Zilver PTX peripheral stent, was approved by the FDA in 2012. Several others have made it onto the U.S. market with their own large studies, including Medtronic's In.Pact Admiral drug-coated balloon (DCB) and the Lutonix DCB, which was designed in Minnesota and is now sold by New Jersey-based BD. Collectively the devices comprise hundreds of millions of dollars in annual sales, and they help to prevent thousands of patients from having leg-artery bypass surgery or even amputation.

Yet the 14-member panel said Wednesday that the studies collectively did such a poor job of tracking deaths over three to five years that the experts couldn't answer many of the FDA's other questions, such as whether the enhanced mortality rate applied to some or all of the devices.

Adding to the uncertainty, panel members noted that the companies seemed to present different data than the FDA did, even though the FDA got its data from the companies themselves.

"We are being subjected to a forest of dueling numbers," said FDA panelist Dr. John Hirshfield Jr., a vascular-disease physician from Philadelphia.

Observers noted a large proportion of patients whose early results were reflected in the studies, but not their later data.

"In many trials, there were more people with missing data (you don't know what happened to them) than there were patients who died," said Dr. C. Michael Gibson, a Harvard medical researcher and physician who is not a member of the FDA panel. "I, like many others, found it hard to reach a definitive conclusion."

The much-discussed "mortality signal" in the studies is a "hazard ratio" comparing how long patients lived after getting paclitaxel to treat their peripheral artery disease vs. patients with the same disease who were chosen at random to get treatment without the drug.

The December JAHA article initially pegged the five-year hazard ratio at 1.9. (A result of 1 would have meant the risks were equal, while a result of 2 would have meant twice as many paclitaxel patients died.) That figure was subsequently lowered to 1.64, following a reassessment of the data by the JAHA authors. Research by an outside group hired by the not-for-profit doctors group VIVA Physicians placed the ratio at 1.38.

Joe Carlson • 612-673-4779