No Excess Mortality Risk Found in Paclitaxel-Coated Devices, Concludes FDA

July 11, 2023—The FDA has determined that the totality of available data and analyses does not support an excess mortality risk for paclitaxel-coated devices, according to the letter issued to health care providers informing them of updated information regarding paclitaxel-coated devices used to treat peripheral arterial disease (PAD).

The update applies to all paclitaxel-coated devices, models, lots, and unique device identifiers, and the agency will work with device manufacturers to update product labeling.

The FDA's current updated statement includes the following recommendations for health care providers:

• Discuss the risks and benefits of all available PAD treatment options, including paclitaxel-coated devices, with your patients.
• Continue routine monitoring of patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.
• 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 to the FDA. Instructions for reporting are available online here.

In December 2018, a systematic review and meta‐analysis of randomized controlled trials (RCTs) evaluating paclitaxel‐coated balloons and stents in the femoral and/or popliteal arteries concluded that it found an increased risk of death after the application of these devices in this anatomy. The findings were published by Katsanos et al in Journal of the American Heart Association.

According to the current FDA statement, additional data from pivotal RCTs has become available since the Circulatory System Devices Panel’s meeting and the FDA’s follow-up Letter to Health Care Providers in August 2019, during which time regulators have also worked with device manufacturers and external stakeholders to develop the protocol and analysis plan for new data generation.

The FDA noted that device manufacturers collaborated in an updated meta-analysis, which included additional studies, more complete vital status information, and longer-term follow-up compared to previous studies. Patient follow-up ranged from 2 to 5 years, with data from most studies available out to 5 years. FDA clinicians and statisticians reviewed the data and concluded that the updated RCT meta-analysis does not indicate that the use of paclitaxel-coated devices is associated with a late mortality risk.

Additional analyses of the risk for late mortality, including the SWEDEPAD trial interim analysis, the VOYAGER PAD study, the German BARMER Health Insurance study, the US Veterans Health Administration study, and the Medicare SAFE-PAD study were also reviewed. With mean or median follow-up ranging from 1.7 to 3.5 years, none found a risk for late mortality associated with paclitaxel-coated devices, advised the agency.

Longer-term follow-up in several of studies is ongoing, and the FDA will continue to monitor postmarket performance of this product class and post any new recommendations on its Paclitaxel-Coated Balloons and Stents for Peripheral Arterial Disease web page.

“This is a much-awaited, critical moment for the peripheral vascular space,” said Eric A. Secemsky, MD, in comments to Endovascular Today, stating that the advent of drug-coated balloons and stents was a true breakthrough in the field of peripheral intervention, which has been limited by aggressive early restenosis leading to the development and uptake of drug-delivery devices. “Since the paclitaxel controversy started at the end of 2018, these devices have been appropriately cautioned for patients while the data have been further evaluated. During this time, however, we have lacked an important tool to achieve the best outcomes for these patients, as the physicians who treat them have had restrictions placed by their institutions and medical-legal concerns, resulting in their not being able to perform procedures to the standard that they’ve been trained to meet.”

“This is great news for our patients, who will have access to beneficial paclitaxel technologies without any ambiguous safety concerns,” agreed William A. Gray, MD.

“In terms of what this means for patients, for more than 4 years, we have routinely avoided one of our most effective therapies for lower extremity arterial disease,” added Peter A. Schneider, MD. “Our ethos is to do no harm, and we did not want to cause unintended issues while treating a patient’s disease, so our algorithms have changed while this concern was explored. Now, with it resolved, we can return to using the best care we have.

“The FDA was not ambiguous in its language regarding what has been confirmed about the safety of these devices. Science must take center stage, and although it took time, the data have proven what we believed at the outset and confirmed that there was no connection between paclitaxel and early mortality.”

From a global standpoint, Dr. Secemsky noted that the FDA stands as a beacon of regulating medical devices, and he expects similar actions regarding these devices will occur around the world in countries that still have restrictions in place. “I think this action will allow the field to return to where we were before this controversy started, when we were able to speak about the science and evidence on how these devices outperform uncoated devices, identify patients who are most likely to benefit from these devices, and train on how best to use them,” he said.

Looking forward, Drs. Secemsky, Schneider, and Gray each commented on the lasting impact the research conducted to explore the paclitaxel controversy will have on clinical trials, the understanding of the patient population, and how the peripheral vascular space responds to and even prevents similar concerns in the future.

“From how we interpret and dissect evidence before we create chaos, how we prepare a safety response to a potential controversy, and how we as a community ensure that this doesn’t happen, we’ll all be better informed,” added Dr. Secemsky. “It’s also imperative that in a clinical trial, every patient needs to be on optimal medical therapy before they go to the procedure lab or operating room. Every patient needs to be consented for long-term follow-up too, not just until the study endpoint hits. We need to be thoughtful about any potential off-target harms that a device can cause, and how we collect information to ensure this will not happen. Part of this will also come in terms of better preparing ourselves on the postmarket side, where we have mechanisms in place—whether it’s observational data, registry data, or ongoing clinical trials—that will collect necessary information so that if potential concerns come up with breakthrough devices or newer, novel devices, we have data available to at least preliminarily understand whether signals of harm can be detected or not.”

Dr. Schneider agreed and reiterated the importance of the collaborative research done over the past 4 years to explore the safety of these devices, also emphasizing that best medical management must be administered and tracked throughout a patient’s care.

“We can go forward with terrific confidence that these are safe treatments, and that all of this work will inform our trials going forward,” said Dr. Schneider. “We have learned so much about mortality and life expectancy in this population, about our patients’ long-term outlook, and how we communicate about their options.”

“Throughout this whole process, the FDA has been extremely collaborative. They have looked for solutions, not fault. All of these groups working together have produced a result everyone can be enthusiastic about, and a better result for the patient.”

“This result is not possible without the commitment and collaboration of industry and the FDA to complete data sets and careful, rigorous analysis of outcomes,” concluded Dr. Gray. “Good science wins in the end.”

Dr. Secemsky is Director of Vascular Intervention at Beth Israel Deaconess Medical Center; Section Head, Interventional Cardiology and Vascular Research; Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology; and Assistant Professor of Medicine at Harvard Medical School in Boston, Massachusetts. Dr. Schneider is Professor of Surgery in the Division of Vascular & Endovascular Surgery at the University of California, San Francisco. Dr. Gray is System Chief of Cardiovascular Services at Main Line Health and President of Lankenau Heart Institute in Wynnewood, Pennsylvania.