FDA Review Affirms Mortality Signal With Paclitaxel-Based Devices for PAD Ahead of Panel Meeting

Two weeks before a US Food and Drug Administration advisory committee convenes to discuss the issue at hand, the agency has released its executive summary review concluding that the data—such as it is—supports the mortality signal seen among patients with femoropopliteal artery disease treated with paclitaxel-based balloons and stents.

Causality, however, “for the late mortality rate increase could not be determined,” concludes the FDA review, which was published online last week. “Additional data may be needed to further assess the magnitude of the late mortality signal, determine any potential causes, identify patient subgroups that may be at greater risk, and to update benefit-risk considerations of this device class.”

The 2-day meeting of the Circulatory System Devices Panel, to be held on June 19 and 20, comes after months of presentations from industry and special sessions at annual meetings tackling the questions raised in a paper published last December. This pooled meta-analysis of 28 RCTs, which was led by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), showed an increased risk of all-cause mortality beginning at 2 years and continuing out to 5 years. The authors of the meta-analysis, and now the FDA, have been unable to explain the observed association between the devices and mortality risk.

During the upcoming panel meeting, the FDA committee will be tasked with reviewing the existing data from RCTs and registries. A major question surrounding the mortality signal debate has been the reliability of those data. In February, Medtronic revealed that some mortality data on patients treated in its IN.PACT Global study were not included in two publications. Not long after that, Circulation issued a correction for the Zilver PTX trial because all-cause mortality data for the study arms were “inadvertently reversed” by the authors in their original manuscript and were subsequently corrected, along with one additional mistake. The adjudication of the mortality data also has been at issue because many of the deaths in the RCTs were categorized as “other” or “unknown.”

The 83-page executive summary notes that the FDA’s analyses of available trial data were conducted prior to receiving updated information, adding that “the industry is attempting to gather missing mortality information from [lost to follow-up] study subjects for further analyses.” Some of these results presumably will be delivered during the 2-day session. Chaired by Richard Lange, MD (Texas Tech University Health Sciences Center El Paso, TX), the panel will be asked to comment on the impact of the data limitations in their overall conclusions and make recommendations for future studies and device labeling.

Whether the panel will vote to recommend more serious regulatory action is uncertain, but at a Town Hall meeting at CRT 2019 in March, a panel of clinicians, statisticians, researchers, and a patient advocate voted unanimously in favor of informing patients about the mortality signal so that they could factor it into their decision-making. At the time, this informal panel could not agree on whether current labeling for paclitaxel-based stents or balloons should be restricted, changed, or remain unchanged.

The FDA advisory committee is also expected to discuss the potential relationship between paclitaxel dose and mortality. While no consistent association has been detected, some researchers, including Katsanos, have speculated that mortality may be increased at higher doses. Speaking at LINC 2019, Katsanos contended that there is a fine line between the effective therapeutic dose of the drug and a toxic dose. Further complicating this issue is the fact that there is very little information from the trials regarding additional paclitaxel-based treatments that patients may have received after their index procedure to manage restenosis. Another important issue will be how to handle ongoing femoropopliteal disease trials and paclitaxel devices that are either on the market or in testing for non-PAD indications.

The FDA initially entered the fray in January, when it issued a Dear Doctor letter acknowledging that it was requesting and evaluating long-term follow-up data from individual device manufacturers. Its medical officers also publicly addressed the issue at the VIVA Vascular Leaders Forum and again at CRT 2019. In mid-March, the FDA updated its letter to healthcare providers and recommended that despite uncertainty as to how or why the devices could impact mortality, physicians should opt for alternatives for most patients, reserving the paclitaxel devices for those at high risk for restenosis. That recommendation was based on the agency’s own analysis of long-term follow-up data.

Among the three clinical trials that had 5-year follow-up available for review (IN.PACT SFA I and II, ZILVER PTX, and LEVANT 2), the FDA found that each showed higher mortality in patients treated with paclitaxel-coated products than in those treated with uncoated devices. The executive summary provides 5-year mortality risk ratio estimates for treated patients versus controls for the individual trials. They range from RR 1.64 (95% CI 0.99-2.71) in LEVANT 2 to RR 1.76 (95% CI 0.87-3.55) in IN.PACT SFA I and II, with the highest being RR 1.80 (95% CI 1.08-3.01) in ZILVER PTX.