Abstract
Zilver® PTX® (Cook Medical, Bloomington, IN) is a self-expanding nitinol drug-eluting stent with a polymer-free paclitaxel coating on its outer surface. The stent aims to provide improved treatment for patients with symptomatic peripheral arterial disease in the above-the-knee femoropopliteal arteries. On October 13, 2011, the Food and Drug Administration’s (FDA) Circulatory System Devices Panel reviewed the Zilver PTX premarket approval application. This summary aims to describe the discussions and recommendations made during the meeting. Based on the Panel’s recommendations, it is anticipated that the device will be approved by the FDA.
1
Introduction
Peripheral arterial disease (PAD) affects 5–10 million individuals in the United States and up to 20% of patients > 70 years of age . PAD is associated with significant morbidity and mortality and is manifested by exertional pain (intermittent claudication) and critical limb ischemia, which can lead to amputation. Symptomatic patients are treated with risk-factor modification, antiplatelet therapy, and revascularization. Endovascular therapy is the most common revascularization technique for atherosclerotic femoropopliteal disease ; however, percutaneous transluminal balloon angioplasty (PTA) is associated with high procedural failures . Although endovascular stenting significantly decreases the complications of balloon angioplasty (e.g. early elastic recoil and flow limiting dissection), this treatment modality is still limited by high restenosis rates . Several small clinical studies have examined the use of drug-eluting stents for the treatment of femoropopliteal stenosis with evidence of favorable results .
Zilver® PTX® (Cook Medical, Bloomington, IN) is a self-expanding, nitinol drug-eluting stent with polymer-free paclitaxel coating on its outer surface. The stent aims to provide improved treatment for patients with symptomatic PAD in the above-the-knee femoropopliteal arteries. On October 13, 2011, the Food and Drug Administration’s (FDA) Circulatory System Devices Panel reviewed the Zilver PTX premarket approval application (PMA) .
The PMA application was primarily based on data from the pivotal randomized, controlled, multicenter clinical trial (RCT) comparing Zilver PTX with PTA and from a complementary multicenter registry Zilver PTX single-arm study (SAS) ( Fig. 1 ). Data from an outside-of-the-US registry were used as supporting data. Following is a summary of the discussions and recommendations made during the Circulatory System Devices Advisory Panel meeting, along with some important insights regarding the clinical use of the Zilver PTX stent in a post-approval era.
2
Methodological trial design
The trial design for the Zilver PTX pivotal trial was unique. In 2005, when the pivotal trial investigational device exemption received final FDA approval, no stent (with or without a drug eluting coating) was approved for femoropopliteal artery disease, therefore making the construct of a stent control group for the Zilver PTX difficult to define within the labeling confines. Additionally, the current standard of care at the time was not well defined with respect to the optimal percutaneous treatment modality for atherosclerosis in the arterial bed. For these reasons, the Sponsor and the FDA agreed upon a trial design that employed a randomized control group, defined as balloon PTA alone. The control group was designated as the primary randomization and was considered for the duration of the trial as the primary comparator group for the primary safety and efficacy end point evaluations.
To ensure the clinical relevance of these data at the time of trial completion, a secondary randomization of a priori was built into the pivotal trial design to allow for patients who experienced suboptimal PTA (defined as ≥ 30% diameter stenosis noted on arteriography or ≥ 5 mmHg mean trans-stenotic pressure gradient) to receive a stent when needed. For those patients who experienced a suboptimal PTA result, a second randomization between Zilver bare metal stent (BMS) and Zilver PTX was performed.
This hierarchal randomization structure allowed for several sets of analyses to be performed with regard to the primary end point analysis. The Sponsor and the FDA each presented a compilation of these analyses:
- 1.
Principal randomization alone:
- a.
Primary safety end point 1
1 Where suboptimal PTA is defined as acute PTA failure.
- b.
Primary efficacy end point 1
- a.
- 2.
Principal randomization and secondary randomization: Zilver PTX vs. the combination of optimal PTA + Zilver BMS + second randomization Zilver PTX — where the comparison regards treatment strategies as opposed to Zilver PTX compared to the standard of care.
- a.
Primary safety end point
- b.
Primary efficacy end point
- a.
The primary safety and efficacy analyses were powered on the principal randomization alone and, therefore, the combination analyses are secondary and post hoc in nature.
2
Methodological trial design
The trial design for the Zilver PTX pivotal trial was unique. In 2005, when the pivotal trial investigational device exemption received final FDA approval, no stent (with or without a drug eluting coating) was approved for femoropopliteal artery disease, therefore making the construct of a stent control group for the Zilver PTX difficult to define within the labeling confines. Additionally, the current standard of care at the time was not well defined with respect to the optimal percutaneous treatment modality for atherosclerosis in the arterial bed. For these reasons, the Sponsor and the FDA agreed upon a trial design that employed a randomized control group, defined as balloon PTA alone. The control group was designated as the primary randomization and was considered for the duration of the trial as the primary comparator group for the primary safety and efficacy end point evaluations.
To ensure the clinical relevance of these data at the time of trial completion, a secondary randomization of a priori was built into the pivotal trial design to allow for patients who experienced suboptimal PTA (defined as ≥ 30% diameter stenosis noted on arteriography or ≥ 5 mmHg mean trans-stenotic pressure gradient) to receive a stent when needed. For those patients who experienced a suboptimal PTA result, a second randomization between Zilver bare metal stent (BMS) and Zilver PTX was performed.
This hierarchal randomization structure allowed for several sets of analyses to be performed with regard to the primary end point analysis. The Sponsor and the FDA each presented a compilation of these analyses:
- 1.
Principal randomization alone:
- a.
Primary safety end point 1
1 Where suboptimal PTA is defined as acute PTA failure.
- b.
Primary efficacy end point 1
- a.
- 2.
Principal randomization and secondary randomization: Zilver PTX vs. the combination of optimal PTA + Zilver BMS + second randomization Zilver PTX — where the comparison regards treatment strategies as opposed to Zilver PTX compared to the standard of care.
- a.
Primary safety end point
- b.
Primary efficacy end point
- a.
The primary safety and efficacy analyses were powered on the principal randomization alone and, therefore, the combination analyses are secondary and post hoc in nature.
3
Proposed indication for use
The proposed indication of use stated: “The Zilver PTX drug-eluting stent is indicated for improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in vascular disease of the above-the-knee femoropopliteal arteries having reference vessel diameter from 4 mm to 9 mm and total lesion lengths up to 140 mm per limb and 280 mm per patient. To avoid involvement of the common femoral artery, the most proximal stent end should be placed at least 1 cm below the origin of the superficial femoral artery (SFA). To avoid involvement of the below-the-knee popliteal artery, the most distal stent end should be placed above the plane of the femoral epicondyles.”
Panel members approved the appropriateness of the above specifications but recommended one modification to the proposed indication for use: adding the word “native” before “vascular disease” in order to emphasize that there are not enough data with respect to the safety and efficacy of the Zilver PTX for treating in-stent restenosis or lesions in bypass grafts. Dr. Theodore Heise, the Sponsor’s representative, commented that in the SAS registry there were 130 lesions where Zilver PTX was used for in-stent restenosis. However, these data were not reviewed in advance by the FDA.
The discussion evolved on the differences between the RCT and SAS. The SAS registry included a broader patient population and more complex lesions. In the registry, however, there was no lesion length limitation, there was no limit to the number of stents implanted, and treatment of in-stent restenosis was not included in the exclusion criteria. This study did not include a control group and was performed outside of the US only. Although the SAS incorporated statistical hypothesis for success criteria, the FDA Investigational Device Exemption Committee did not review its protocol prior to study initiation and did not incorporate the study hypothesis and success criteria in their respective review of safety and efficacy. Dr. Bram Zuckerman, Division of Cardiovascular Devices FDA, stated that the FDA’s position is that the available data on the Zilver PTX device from the SAS are informative but observational in nature and that the FDA could possibly support device approval only for those patients enrolled in the RCT ( Table 1 ). Specifically, device length should be up to 140 mm per limb. Dr. Kenneth Najarian, interventional radiologist and Panel member, presumed that the Zilver PTX stent will probably be used “off-label” in vascular beds with high rates of restenosis, such as dialysis grafts.
| Inclusion Criteria |
|---|
| • Patients with up to 2 de novo or restenotic lesions of the above-the-knee femoropopliteal artery (1 per limb). |
| • Symptoms of peripheral arterial disease classified as Rutherford category ≥ 2. |
| • Resting ankle brachial index (ABI) < 0.9 (or an abnormal exercise ABI if rest ABI is normal). |
| • Lesion length ≤ 14 cm. |
| • Lesion diameter stenosis ≥ 50%. |
| • Reference vessel diameter 4 to 9 mm. |
| • At least 1 patent runoff vessel (< 50% diameter stenosis throughout its course). |
| Exclusion Criteria |
| • Untreated > 50% diameter stenosis of the inflow tract (or treated to a < 30% residual stenosis). |
| • Unsuccessful arterial interventional treatment of the legs within 30 days prior to the study procedure. |
| • Lesion pretreatment with adjunctive devices. |
| • Previous target vessel stenting. |
| • Bypass graft with an anastomosis in the target vessel. |
| • Lesions requiring atherectomy (or ablative devices), cutting balloons, cryoplasty balloons, or any other device to facilitate stent delivery. |
| • Untreated angiographically-evident thrombus in the target vessel. |
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