March 14, 2019

FDA to Convene Advisory Committee Meeting After Preliminary Review Finds Signal of Increased Mortality With Paclitaxel-Eluting Devices

March 15, 2019—The FDA has announced that its preliminary review of the long-term follow-up data on paclitaxel-coated balloons and paclitaxel-eluting stents to treat peripheral artery disease (PAD) in the femoropopliteal artery has identified a potentially concerning signal of increased long-term mortality in study patients treated with paclitaxel-coated products compared to patients treated with uncoated devices. These concerns were initially raised by the findings of a systematic review and meta‐analysis of randomized controlled trials evaluating paclitaxel‐coated balloons and stents in PAD, concluding that there is an increased risk of death after application of these devices in this anatomy. Konstantinos Katsanos, MD, et al published the original study online in Journal of the American Heart Association.

Because of its finding, the FDA will convene an advisory committee meeting of the Circulatory System Devices Panel. Details concerning the timing and location of the advisory committee meeting will be announced in the coming weeks. The FDA letter to health care providers is available online here.

The agency is conducting an ongoing analysis of long-term follow-up data (up to 5 years in some studies) of the pivotal premarket randomized trials for paclitaxel-coated products indicated for PAD. The FDA stated that of the three trials with 5-year follow-up data, each showed higher mortality in patients treated with paclitaxel-coated products than patients treated with uncoated devices.

According to the FDA, among the 975 patients in these three trials, there was an approximately 50% increased risk of mortality in patients treated with paclitaxel-coated devices versus those treated with control devices (20.1% vs 13.4% crude risk of death at 5 years).

The FDA advised that these data should be interpreted with caution because:

  • There is large variability in the risk estimate of mortality due to the limited amount of long-term data.
  • These studies were not originally designed to be pooled, introducing greater uncertainty in the results.
  • The specific cause and mechanism of the increased mortality is unknown.

The FDA stated that alternative treatment options should generally be used for most patients while the agency further evaluates the increased long-term mortality signal and its impact on the overall benefit-risk profile of these devices.

The agency intends to conduct additional analyses to determine whether the benefits continue to outweigh the risks for approved paclitaxel-coated balloons and paclitaxel-eluting stents when used in accordance with their indications for use. The FDA will also evaluate whether these analyses impact the safety of patients treated with these devices for other indications, such as treatment of arteriovenous access stenosis or critical limb ischemia.

The planned meeting of the advisory committee will:

  • Facilitate a public, transparent, and unbiased discussion on the presence and magnitude of a long-term mortality signal
  • Discuss plausible reasons, including any potential biological mechanisms, for a long-term mortality signal
  • Re-examine the benefit-risk profile of this group of devices
  • Consider modifications to ongoing and future United States clinical trials evaluating devices containing paclitaxel, including added surveillance, updated informed consent, and enhanced adjudication for drug-related adverse events and deaths
  • Guide other regulatory actions, as needed

Additionally, the agency recommends that health care providers consider the following until more information is available:

  • 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 your patients. For most patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents should generally be used until additional analysis of the safety signal has been performed.
  • For some individual patients at particularly high risk for restenosis, clinicians may determine that the benefits of using a paclitaxel-coated product may outweigh the risks.
  • 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.

Finally, the FDA continues to recommend that health care providers 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 regulations. Health care 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 FDA's January 17, 2019 letter notifying health care providers about the potential for increased long-term mortality in these devices is available here. The FDA will keep the public informed as any new information or recommendations become available.

Since the publication of the JAHA meta-analysis in December 2018, numerous data sets have been presented and published, many conflicting with the findings of the meta-analysis. These include patient-level data reviews from industry-sponsored trials, as well as two analyses of the Medicare database. For more on the JAHA meta-analysis, please click here to see our interview with Dr. Katsanos.

For details regarding these data and all news related to the ongoing controversy regarding paclitaxel use in PAD, please visit our comprehensive continuing coverage page.


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