August 28, 2019 — The U.S. Food and Drug Administration (FDA) released an updated MedWatch Alert this month on the safety of paclitaxel-coated devices used to treat peripheral artery disease (PAD) following its review of long-term follow-up clinical data. The agency said five-year results from three randomized trials showed an increased mortality rate in patients treated with these devices compared to those treated with uncoated devices. While these data provide reason for caution, the FDA noted that the devices still provide documented short-term benefits, and healthcare providers should consider all options for their PAD patients.
The safety of paclitaxel was first brought into question by a meta-analysis published in Journal of the American Heart Association in December 2018. That analysis showed a higher mortality rate at two years post-procedure and prompted the FDA to release its first warning letter on the subject. At that time the agency asserted that the benefits of paclitaxel-coated devices outweighed the possible risks when used as indicated.
FDA Panel Findings on Paclitaxel
Following the January warning letter, over the summer the FDA convened a public meeting of the Circulatory System Devices Panel of the Medical Devices Advisory Committee to discuss the safety of paclitaxel, assess long-term data and arrive at recommendations for providers. The trio of randomized trials reviewed by the panel enrolled a total of 1,090 patients, with data available out to five years.
Across the three trials, the FDA found the crude five-year mortality rate with paclitaxel-coated devices was 19.8 percent compared to 12.7 percent for patients treated with uncoated devices. Relative risk for increased five-year mortality was 1.57, which corresponded to a 57 percent relative increase in mortality. 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 percent confidence interval 1.06 - 1.80).
Despite the presence of this “late mortality signal,” the FDA believes clinical studies of these devices may continue and should collect long-term safety (including mortality) and effectiveness data.
The FDA update concluded with the following list of recommendations for healthcare providers:
- 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. Voluntary reports can be submitted through MedWatch, the FDA Safety Information and Adverse Event Reporting program. Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations. Healthcare personnel employed by facilities that are subject to the FDA's user facility reporting requirements should follow the reporting procedures established by their facilities. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.
The agency said it is continuing to work with device 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.
FDA and Device Manufacturers Collaborating
The FDA is also working with manufacturers to update labeling on paclitaxel-coated devices, as well as the informed consent documents for ongoing clinical trials, to include information about the late mortality signal.
“Philips appreciates the thoughtful discussions we have had with the FDA, our industry partners, and physician leaders to help clarify the benefits and possible risks of paclitaxel-coated therapies,” said Chris Landon, business leader, image guided therapy devices at Philips. “The safety of patients is our highest priority and we will continue to work with the FDA and our industry partners on further actions to assess the long-term safety and appropriately inform patients of the potential risk.”
Philips said it will continue to follow up on all its clinical trials including the ILLUMENATE Pivotal trial, the ILLUMENATE European Randomized Controlled Trial (EU RCT) and the ILLUMENATE SAVER registry. The company is also focused on continued enrollment in its ILLUMENATE Below the Knee (BTK) clinical trial.
For more information: www.fda.gov
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