Peripheral arterial disease (PAD) is a morbid condition defined by progressive atherosclerosis of the arteries of the lower extremities. Even hemodynamically important PAD can have no symptoms or can be manifest as typical intermittent claudication to ischemic rest or even tissue loss with ulceration and/or gangrene. PAD is further associated with increased risk of cardiovascular mortality often by way of myocardial infarction (MI) or cerebrovascular accident due to the polyvascular nature of PAD.¹

Despite optimal medical therapy, lifestyle modification and structured exercise programs, a significant proportion of patients with symptomatic PAD will go on to worsening functional capacity and quality of life with lifestyle- or limb-threatening symptoms which necessitate revascularization.

Over the past two decades, the proportion of patients receiving open surgical revascularization for PAD has been exceeded by those receiving endovascular revascularization procedures. With the rise in endovascular interventions for PAD has come a rapid growth in the armamentarium of interventional tools including standard percutaneous transluminal angioplasty (PTA), bare metal stents (BMS), atherectomy devices, drug-coated balloon (DCB) angioplasty, drug-eluting stents (DES), and intravascular lithotripsy, with many more devices in various stages of development and investigation. Early endovascular technologies including PTA and BMS were acutely successful but were plagued by high rates of early restenosis.^2-6

Local vascular delivery of drugs developed to inhibit intimal hyperplasia and restenosis were subsequently adapted from coronary DES to prevent restenosis and reduce clinically-driven target lesion revascularization.

While sirolimus and its analogs have dominated the coronary market, paclitaxel, a potent antimitotic drug that binds irreversibly to microtubules preventing cell division, has become the dominant drug for endovascular interventional therapies including both DCB and DES.⁷

As a highly lipophilic molecule facilitating rapid uptake into the treated tissue, along with its prolonged duration of antiproliferative effects, paclitaxel was found to empirically be a superior choice for peripheral vascular applications as an initial antirestenotic agent.⁸

With several early randomized controlled trials (RCTs) demonstrating superior primary patency rates and target lesion failure rates of paclitaxel-coated devices (PCD) compared with non–drug-eluting control devices in patients undergoing femoropopliteal intervention,^9-12 DES and later DCB angioplasty became the de facto standard of care therapy for most femoropopliteal interventions for the majority of the past decade.¹³

A Meta-Analysis, Updated FDA Guidance, More Questions

However, a meta-analysis published in 2018 brought this momentum to a screeching halt. Katsanos, et al., in their summary-level meta-analysis of 28 RCTs including 4,663 patients, comparing PCDs (DCB and DES) with non-PCDs in femoropopliteal intervention, demonstrated a concerning signal for an increase in all-cause mortality at two and five years of follow-up (hazard ratio [HR], 1.68, 95% CI, 1.27-2.68 at two years; HR, 1.93, 95% CI, 1.27-2.93 at five years), as well as a potential dose-dependent increase in the risk of mortality over time.¹⁴

The Katsanos analysis was criticized by many for methodological flaws, including the use of summary-level data rather than patient-level data, heterogeneous patient populations across trials with disparate comorbidity burdens and severity of disease, high rates of loss to follow-up (more patients lost to follow-up than mortalities observed), insufficient levels of vital status ascertainment, and no clear causal mechanism for their finding, all of which may have confounded their findings.

Following the meta-analysis, the U.S. Food and Drug Administration (FDA) convened a Medical Device Advisory Panel in 2019 to review the safety of PCDs in PAD intervention, and sponsors halted several ongoing large RCTs, including the SWEDEPAD and the BASIL-3 trials.

Based on the internal meta-analysis conducted by the FDA, including three trials with 1,090 patients, as well as one run by the Vascular InterVentional Advances (VIVA) physician group pooling patient-level data from several large RCTs in the space, both of which found a signal for late mortality with PCDs ranging from a 38-57% increase at five years, the Advisory panel issued guidance that PCDs should only be used for femoropopliteal interventions in patients with the highest risk of restenosis.^15,16

The FDA noted in their August 2019 guidance¹⁶ that the conclusions of their and the VIVA group's meta-analyses should be interpreted cautiously due to the small sample size, low number of events with wide confidence intervals, pooling of heterogeneous data, and lack of a causal mechanism for the observed mortality signal. While the FDA sought more definitive proof or lack thereof for this mortality signal, the use of PCDs in peripheral interventions all but disappeared for a time.

Vascular Community Examines More Robust Data

The vascular community quickly took up the charge to determine whether this signal really was present across a wide range of both clinical trial and real-world data sources. Using administrative data from the Medicare dataset, Secemsky and colleagues demonstrated no difference in mortality between patients treated with and without PCDs in over 60,000 patients, stratified by device type (DES vs. DCB vs. DCB+DES) or clinical severity (claudication vs. chronic limb-threatening ischemia [CLTI]) as well as no dose-response relationship.^17,18

Additional analyses using various administrative databases encompassing more than 150,000 additional patients in the U.S. and Germany again demonstrated no evidence of increased late mortality with PCDs.^19-22 A study of the Veteran's Health Administration data, an administrative database with access to patient-level data, found no increase in late mortality comparing PCDs with non-PCDs in endovascular intervention, despite a higher risk cohort in the PCD arm of the study.²³

Several analyses of long-term follow-up of pivotal clinical trials were performed, importantly including a subgroup analysis of the VOYAGER PAD trial examining the effect on long-term mortality of PCDs in the 4,379 patients undergoing endovascular intervention, as well as the unplanned interim analysis of the SWEDEPAD data to look for evidence of a late mortality signal.

In the VOYAGER PAD analysis, which had 99.6% vital status ascertainment, there was no difference in adjusted all-cause mortality at 42 months of follow-up.²⁴ The SWEDEPAD interim analysis across 2,289 patients with median follow-up of 2.49 years again revealed no difference in all-cause mortality between PCD- and non–PCD-treated patients, regardless of PAD severity.²⁵

Most recently, Secemsky and colleagues reported an update from the SAFE-PAD trial, with results of a longitudinal Medicare claims-based cohort study that evaluated long-term mortality in patients treated with PCDs.²⁶

In 168,553 patients undergoing endovascular PAD intervention between April 1, 2015 and December 31, 2018, of which 70,584 patients were treated with PCDs, over a median follow-up of 3.52 years (>30,000 with five years of follow-up), there was no difference in all-cause mortality between groups across myriad prespecified subgroups encompassing treatment setting, high vs. low risk, claudication vs. CLTI, or device type.

FDA Safety Advisory Withdrawn For PCDs in PAD

All of this taken together in combination with an unpublished meta-analysis of more complete long-term data from seminal RCTs demonstrating no difference in late mortality have prompted the FDA to withdraw their safety advisory on paclitaxel-coated devices for the treatment of PAD in a letter to providers dated July 11, 2023.²⁷

This landmark reversal rests on the shoulders of countless researchers who saw that the signal observed in the work of Katsanos, et al., did not match up with their real-world experience of patient care and prior research findings.

Furthermore, it has demonstrated to the vascular research community that short-term follow-up and soft clinical endpoints are not adequate to fully understand the clinical impact of a given intervention.

While there has been a steady resurgence of PCDs in femoropopliteal intervention as these studies have come out, removal of the FDAs safety advisory will hopefully encourage further use of devices that have proven clinically useful and provide superior patency and limb salvage compared with most other forms of endovascular intervention we have had at our disposal today.

This article was authored by Robert S. Zilinyi, MD, Cardiovascular Disease Fellow at New York-Presbyterian Hospital, Columbia University Irving Medical Center and Columbia University Vagelos College of Physicians and Surgeons; and Sahil A. Parikh, MD, FACC, associate professor of medicine, Columbia University Vagelos College of Physicians and Surgeons and director of Endovascular Services, Columbia University Irving Medical Center, Center for Interventional Cardiovascular Care, all in New York.

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