First DES for Above-the-Knee Vascular Disease on the Horizon

The first drug-eluting stent for the treatment of above-the-knee femoropopliteal artery disease is one step closer to availability in the United States following a unanimous (11-0) vote on October 13, 2011, by a US Food and Drug Administration (FDA) advisory panel.

“This is an important panel decision and I think it brings for the first time a biologic solution for restenosis of the peripheral vasculature,” said William A. Gray, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD. “Obviously, the combination of the 2 data sets from the trial and the registry were compelling enough for the FDA panel to recommend approval.”

Similarly, Hitinder S. Gurm, MD, of the University of Michigan Medical Center (Ann Arbor, MI), told TCTMD in an email communication that the advisory panel decision is a great step forward.

“We currently lack the perfect therapy for [superficial femoral artery] disease and this stent is clearly associated with robust primary patency up to 2 years,” he said. “This is much better than anything else out there. I envision that once this stent is released, it will become the preferred stent for [superficial femoral artery] disease.”

The panel decided in favor of the polymer-free paclitaxel-eluting Zilver PTX (Cook Medical, Bloomington, IN), a self-expanding nitinol stent. The device is indicated for improving luminal diameter in de novo or restenotic symptomatic lesions with reference vessel diameters of 4 to 9 mm and total lesion lengths up to 140 mm per limb and 280 mm per patient.

The Evidence

The primary evidence reviewed by the Circulatory System Devices Panel included a multinational trial that randomized 479 patients with symptomatic, above-the-knee femoropopliteal disease and Rutherford class ≥ 2 to treatment with the Zilver PTX stent (n = 241) or balloon angioplasty (n = 238).

At 12 months, the primary safety endpoint of survival free of amputation, TLR, or worsening Rutherford score (by 2 classes or to class 5 or 6) was met by 90.4% of patients who received the Zilver PTX stent vs. 82.6% who underwent angioplasty (P < 0.01). In addition, the primary efficacy endpoint of patency on duplex ultrasonography or angiography, when available, was reached by a greater proportion of patients receiving the Zilver PTX than those who underwent angioplasty or provisional implantation of a bare metal stent. In the 278 patients with 24-month follow-up data, patency rates also were higher among those treated with the Zilver PTX stent, whether they received the stent following the first or second round of randomization.

The panel also reviewed supporting data from the Zilver PTX Registry Study, a prospective, non-randomized, open-label, multicenter, single-arm study of patients in Europe, Asia, and North America with de novo or restenotic (including in-stent restenosis) lesions of the above-the-knee femoropopliteal artery.

The advisory panel recommended that revisions be added to the Indications for Use, including adding the word “native” to the vascular disease site, and agreed that a descriptive analysis of the dual antiplatelet therapy used in the pivotal study be included in the labeling.

Furthermore, the panel said the long-term follow-up data collected on the durability of the Zilver PTX results were promising, after seeing the sponsor’s (un-reviewed) 3-year data. They also concluded that although stent fracture rates were low, some uncertainty remains regarding the long-term clinical significance of fracture with the device.

In a press release, Cook Medical said it looks forward to a final decision on approval to market the device in the United States in the coming months. Zilver PTX received CE Mark approval in 2009 and is now available in 48 countries.

A Welcome New Option

Importantly, Dr. Gray said the data indicate no safety issues with the device. “Although there probably are not enough patients with enough follow-up time to know whether something like subacute thrombosis is going to be an issue,” he said, “it does at least appear at this early stage that that is not the case.”

Dr. Gray said clinicians who have patients with complex superficial femoral artery disease likely will welcome the availability of the device to their therapeutic options. He added that the Zilver trial participants had “straightforward” lesions, the average being relatively short between 5 and 6 cm. However, the unanswered question is how the device will perform in longer lesions.

“Hopefully the FDA will take the panel’s advice and approve the device,” Dr. Gray said. “Then CMS will need to weigh in in terms of payment.”

Dr. Gray also predicted that a post-approval registry will be a condition of approval. How this plays out remains to be seen since the panel admitted to mixed feelings on the study design. While some panelists felt that the original subjects from the pivotal Zilver study followed out to 5 years would be adequate to obtain clinical outcomes and stent thrombosis rates, others suggested that there should be a separate cohort study to capture stent thrombosis totaling 900 patients followed out to 5 years.

For the post-approval study, the panel agreed that a majority of the patients should be enrolled from the United States and also agreed that subjects from the global registry could be re-consented for longer-term follow-up to help power a post-approval study. They also suggested attempting to capture other outcomes in the post-approval study such as major bleeding, hemorrhage, GI bleeding, gender differences, and outcomes in diabetic patients.

 

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Source:
US Food and Drug Administration. Brief Summary of the Circulatory System Devices Panel Meeting. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/
MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM275925.pdf.  Published October 13, 2011. Accessed October 18, 2011.

 

 

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