Mortality signal from paclitaxel-coated devices persists, but cause remains elusive
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SAN FRANCISCO — Analyses continue to show a long-term mortality risk associated with paclitaxel-coated devices in patients with peripheral artery disease, but investigators are no closer to determining a cause, according to members of a panel convened at TCT 2019.
As Healio previously reported, the long-term mortality risk was first detected in a summary-level meta-analysis published in December 2018. It was later confirmed by an FDA analysis. However, individual randomized trials and retrospective cohort studies have not demonstrated mortality signals and investigators have been unable to pinpoint a mechanistic explanation for the signal. The FDA has allowed the devices to remain on the market but is working with industry on amended labeling and more thorough trial follow-up and has advised clinicians to conduct a deep discussion of the risks and benefits of the devices with patients.
Konstantinos Katsanos, MD, PhD, MSc, EBIR, consultant interventional radiologist at Patras University Hospital in Rion, Greece, who led the summary-level meta-analysis that sparked the controversy, provided updated data from his group’s research. He noted his team has been denied access to patient-level data by industry.
He said the analysis now includes 19 trials covering 3,386 patients. At 2 years, there remains a 42% elevated risk for mortality in patients assigned paclitaxel-coated devices compared with controls (RR = 1.42; 95% CI, 1.05-1.92; risk difference, 2.2%; 95% CI, 0.7-3.6), he said.
At 5 years, among 1,429 patients from five trials, the paclitaxel group had a 64% elevated risk for mortality compared with controls (RR = 1.64; 95% CI, 1.22-2.2; risk difference, 6.3%; 95% CI, 2.8-9.9), Katsanos said.
A time-to-event analysis at 5 years showed the devices were associated with a 62% increased risk for death (absolute risk difference, 6.1%; number needed to harm, 16) and a 42% reduced risk for target lesion revascularization (absolute risk difference, –12.9%; number needed to treat, 8), he said, noting that a “highly significant nonlinear dose-response relationship” has been observed.
“This usage of paclitaxel is completely different from that in cancer patients, in the sense that paclitaxel is embedded into the arterial tissue, and the half-life is between weeks and months,” he said. “It has been shown to be maintained in the system for at least 90 days, at least in the major commercial products. It does not go away very quickly.”
Preliminary results of a meta-analysis of individual patient-level data also indicate a long-term mortality risk associated with paclitaxel-coated devices, but not to the same extent as the findings of Katsanos and his team, Krishna Rocha-Singh, MD, FACC, FAHA, chief scientific officer for the Prairie Heart Institute of Illinois at St. John’s Hospital in Springfield, Illinois, said during a presentation.
In the preliminary analysis of 2,185 patients from eight randomized trials including data available up to August, paclitaxel-coated devices were associated with a 27% increased risk for long-term mortality (HR = 1.27; 95% CI, 1.03-1.58), Rocha-Singh said, noting data are not yet available for 9% of patients assigned paclitaxel-based treatments and 10% of controls.
However, he said, there was “no consistent effect of increasing dose” on mortality, noting that while patients who received a high dose of paclitaxel had the greatest mortality risk, those who received a medium dose had less risk than those who received a high or low dose.
“The updated meta-analysis, which represents the most comprehensive analysis of available individual patient data to date, demonstrated a modest and consistent mortality signal in patients exposed to paclitaxel,” Rocha-Singh said. “However, it did not identify an explanation. Consideration of real-world evidence, although hindered by reliability, lack of follow-up, selection bias and internal controls, may offer insights into paclitaxel device use and mortality.”
Rebecca Ward, MPH, epidemiologist in the Office of Cardiovascular Devices at the FDA’s Center for Devices and Radiological Health, outlined how the FDA’s Medical Device Safety Action Plan has been implemented during the paclitaxel controversy.
The agency has issued three safety communications, the most recent of which, in August, provided final results from the agency’s internal analysis, summarized the results of a meeting of the FDA’s Circulatory System Devices Panel and offered various recommendations, she said.
“For ongoing trials of paclitaxel-eluting or -coated devices, the FDA is working with study investigators to modify informed consent documents to include information about the late mortality signal,” she said. “These devices remain on the market. The FDA is working with manufacturers on labeling updates for paclitaxel-eluting or -coated devices to include information about the late mortality signal.”
The issue will be further explored next week during a panel discussion at VIVA.19. – by Erik Swain
References:
Katsanos K.
Rocha-Singh K.
Ward R. FDA Town Hall Meeting Part 1. Session III: Safety Signal Detection and Response Case Example – Paclitaxel-Coated Devices for Femoropopliteal Disease. All presented at: TCT Scientific Symposium; Sept. 25-29, 2019; San Francisco.
Disclosures: Katsanos reports no relevant financial disclosures. Rocha-Singh reports he receives grant/research funding from Medtronic and VIVA Physicians, receives consultant fees/honoraria from Alucent Biomedical and Medtronic, holds equity in PQ Bypass, is the founder and owner of Convergence Consulting LLC and serves on the board of VIVA Physicians, a nonprofit organization. Ward is an employee of the FDA.