FDA Gives Go-ahead for More Trials of Paclitaxel Devices in PAD

Patrice Wendling

August 07, 2019

The US Food and Drug Administration (FDA) is giving the green light for clinical studies of paclitaxel-coated balloons and stents to continue after evidence of a late mortality signal in patients receiving the devices for peripheral artery disease (PAD) brought trials to a virtual halt worldwide.

In the August 7 updated letter to healthcare providers, however, the agency recommends that, "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."

The FDA made a similar, albeit less specific, recommendation in a March 15 updated letter, in which it said alternative treatment options "should generally be used for most patients" while it continued to evaluate the late mortality signal.

The safety signal was first identified in December 2018 in a meta-analysis, which reported a 68% relative risk increase in all-cause death with paclitaxel-coated balloons and stents beginning at 2 years, which increased to 93% at 5 years.

The signal persisted in the FDA's initial investigation and in a subsequent analysis of long-term follow-up data for paclitaxel-coated devices from pivotal premarket randomized trials, reported in June at its Circulatory System Devices Panel advisory committee.

Specifically, that analysis showed a 57% relative increase in all-cause mortality at 5 years in patients treated with paclitaxel-coated devices vs those treated with uncoated devices (95% CI, 1.16 - 2.13). A meta-analysis performed by Vascular InterVentional Advances (VIVA) Physicians of patient-level data provided by manufacturers reported similar findings, with a hazard ratio of 1.38 (95% CI, 1.06 - 1.80).

"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 including wide confidence intervals due to a 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," today's updated letter states. "The Panel determined, and the FDA concurs, that additional clinical study data are needed to fully evaluate the late mortality signal."

The agency said clinical studies of the devices should collect long-term safety and effectiveness data, including mortality, but that "these studies require appropriate informed consent and close safety monitoring to protect enrolled patients."

Two European trials, BASIL-3 and SWEDEPAD 1 and SWEDEPAD 2, suspended enrollment days after the publication of the meta-analysis but have subsequently resumed enrollment.

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

  • Continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents

  • Consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents when making treatment recommendations and as part of the informed-consent process

  • Discuss the risks and benefits of all available PAD treatment options with 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," the FDA said.

  • For some individual patients at particularly high risk for restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxel-coated product could outweigh the risk for late mortality

  • Explore patients' expectations, concerns, and treatment preferences when discussing treatment options

  • Ensure that 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.

Physicians are asked to report any adverse events or suspected adverse events experienced with these devices through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

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