FDA Issues Updated Statement on the Use of Paclitaxel Devices to Treat PAD

August 7, 2019—The FDA has issued an updated statement (online here) on the increased mortality potentially associated with the use of paclitaxel-coated balloons and paclitaxel-eluting stents for the treatment of peripheral artery disease (PAD).

The update provides the latest information on the FDA analysis of long-term follow-up data from premarket trials and provides summary information from the June 19–20, 2019 public meeting of the Circulatory System Devices Panel of the FDA Medical Devices Advisory Committee that discussed and made recommendations on the potential late mortality signal after treatment with paclitaxel-eluting devices in the femoropopliteal artery. In addition, it includes recommendations to health care providers for assessing and treating patients with PAD using paclitaxel-coated devices.

According to the August 7 update, the FDA's analysis of long-term follow-up data from the pivotal premarket randomized trials for paclitaxel-coated devices presented at the panel identified a late mortality signal in study patients treated with paclitaxel-coated devices compared with patients treated with uncoated devices. Specifically, in the three randomized trials that enrolled a total of 1,090 patients, the crude mortality rate at 5 years was 19.8% (range, 15.9%—23.4%) in patients treated with paclitaxel-coated devices compared with 12.7% (range, 11.2%–14%) in patients treated with uncoated devices. The relative risk for increased mortality at 5 years was 1.57 (95% confidence interval, 1.16—2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices.

Additionally, the FDA noted that a meta-analysis performed by VIVA (Vascular InterVentional Advances) Physicians of patient-level data provided by manufacturers reported similar findings with a hazard ratio of 1.38 (95% confidence interval, 1.06—1.8).

Although the panel concluded that a late mortality signal associated with the use of paclitaxel-coated devices to treat femoropopliteal PAD was present, the panel and the FDA agreed that the magnitude of the signal should be interpreted with caution because of multiple limitations in the available data. Limitations of the data include wide confidence intervals caused by small sample size; pooling of studies of different paclitaxel-coated devices that were not intended to be combined; substantial amounts of missing study data; no clear evidence of a paclitaxel dose effect on mortality; and no identified pathophysiologic mechanism for the late deaths.

The FDA concurs with the panel's determination that additional clinical study data are needed to fully evaluate the late mortality signal. Additionally, the panel concluded that the benefits of paclitaxel-coated devices (eg, reduced reinterventions) should be considered in individual patients along with potential risks (eg, late mortality).

Regarding Clinical Studies of Paclitaxel-Coated Devices

• Because of the demonstrated short-term benefits of the devices, the limitations of the available data, and uncertainty regarding the long-term benefit-risk profile of paclitaxel-coated devices, the FDA believes clinical studies of these devices may continue and should collect long-term safety (including mortality) and effectiveness data. These studies require appropriate informed consent and close safety monitoring to protect enrolled patients.

Recommendations

Based on the FDA's review of available data and the advisory panel conclusions, the FDA recommends that health care providers consider the following:

• Continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents.
• When making treatment recommendations, and as part of the informed consent process, consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.
• Discuss the risks and benefits of all available PAD treatment options with patients. For many patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents provide a more favorable benefit-risk profile based on currently available information.
• For individual patients judged to be at particularly high risk for restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxel-coated device outweigh the risk of late mortality.
• In discussing treatment options, physicians should explore their patients' expectations, concerns, and treatment preferences.
• Ensure patients receive optimal medical therapy for PAD and other cardiovascular risk factors as well as guidance on healthy lifestyles including weight control, smoking cessation, and exercise.
• Report any adverse events or suspected adverse events experienced with the use of paclitaxel-coated balloons and paclitaxel-eluting stents.

FDA Actions

• The FDA continues to work with the manufacturers and investigators on additional clinical evidence development to assess the long-term safety of paclitaxel-coated devices. Analyses of additional randomized trials and registry datasets are being planned to provide further insights into the magnitude and potential causes of the late mortality risk.
• The FDA is working with manufacturers on labeling updates for paclitaxel-coated devices to include information about the late mortality signal.
• For ongoing trials of paclitaxel-coated devices, the FDA is working with study investigators to modify informed consent documents to include information about the late mortality signal.

Commenting on the FDA update to Endovascular Today, Peter A. Schneider, MD, from the University of California at San Francisco, stated, "It is clear that the ability to deliver drug as part of a revascularization procedure has been a major advance—probably the biggest advance in our field of the last 10–15 years. Saving a leg or helping someone improve their limited mobility can have a dramatic effect on a person's life. Really understanding all the risks associated with that process is essential to the shared decision-making that must be undertaken with patients. The FDA's focus on that is laudable. Their statement indicates that the situation is dynamic, that studies must continue, that we must keep patients informed, and continue to work together on this until we understand the reason for the safety signal that has been identified."

Endovascular Today's coverage of the FDA paclitaxel advisory meeting on June 19–20 is available online.

• Day 1: Panel Addresses Updated Data, Signal Presence, Class Effect, Missing Data, Subgroups, and Causes of Death
• Day 2: Panel Weighs the Future of Paclitaxel and Clinical Trials in PAD

All articles from Endovascular Today's continuing coverage of the paclitaxel safety data review are available online here.