More data is needed on devices that elute the drug paclitaxel to determine if they pose a higher mortality risk than non-eluting devices in treating peripheral artery disease, the FDA said ahead of an advisory panel meeting today.
A meta-analysis published in the Journal of the American Heart Assn. last December suggested that PAD patients treated with paclitaxel-coated balloons and stents could be at a higher risk for late death. Led by Dr. Konstantinos Katsanos, researchers looked at data from 28 trials to find a 68% relative risk increase in all-cause death with paclitaxel-coated devices after two years and a 93% relative risk increase after five years, compared to therapy with an uncoated device.
The study prompted the federal safety watchdog to schedule a meeting of its Circulatory System Devices Panel today and tomorrow in Gaithersburg, Md., to discuss the late-death signal and whether it represents a class effect among paclitaxel-eluting devices.
In pre-meeting materials released this week, the FDA said it reviewed the data using both the JAHA analysis parameters and data from the four pivotal randomized controlled trials used to back pre-market approval bids for paclitaxel-coated devices. The agency’s analysis of the JAHA study “reproduced the same results based on fixed and random effects models shown in the paper,” raising concerns about a possible late-term death risk.
The next step in the FDA analysis involved all available clinical studies conducted with the FDA-approved devices that were randomized, controlled trials or single-arm registries of at least 200 patients with at least two-year followup, the agency said. Four of those studies – the RCT for Cook Medical‘s Zilver PTX DES; the Levant 2 trial of the Lutonix DCB made by Becton Dickinson (NYSE:BDX); the In.Pact SFA I and II studies of the Medtronic (NYSE:MDT) In.Pact Admiral DCB; and the Illumenate study of the Royal Philips (NYSE:PHG) Stellarex DCB – compared drug-eluting devices with non-eluting devices. A fifth, the Imperial RCT comparing the Eluvia DES made by Boston Scientific (NYSE:BSX) with Cook’s Zilver PTX, was excluded from the analysis but the FDA provided mortality data for comparison purposes.
“At one year, the crude mortality rates were generally low in the paclitaxel-coated and control device groups. However, at two years, the observed mortality rates for the paclitaxel-coated device group were higher for the Zilver PTX, Levant 2 and In.Pact SFA I & II trials, while the Illumenate trial did not demonstrate this trend,” according to the agency. “Only the Zilver PTX RCT, Levant 2 and In.Pact SFA I & II studies had follow up to five years. For these studies, an increased mortality rate was noted at years three through five.”
The Illumenate trial was the only study not to show “a similar separation in all-cause mortality over time, with subjects treated with paclitaxel-coated devices having increased late mortality” in the other four trials, the FDA said.
“FDA analyses of available data from FDA-approved devices show an increase in late mortality (between two and five years) associated with paclitaxel-coated devices intended to treat femoropopliteal disease. However, causality for the late mortality rate increase could not be determined. Additional data may be needed to further assess the magnitude of the late mortality signal, determine any potential causes, identify patient sub-groups that may be at greater risk, and to update benefit-risk considerations of this device class,” according to the FDA.