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Drug-Coated Balloons and Stents for Endovascular Treatment of PAD
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This past October, the FDA Circulatory System Devices Panel of the Medical Devices Advisory Committee voted unanimously to approve a paclitaxel-eluting stent for endovascular treatment of de novo or restenotic lesions in above-the-knee femoral arteries in patients with symptomatic peripheral arterial disease.
The self-expanding nitinol stent (Zilver PTX; Cook Medical) is polymer-free and coated on its outer surface with paclitaxel (dose density of 3 mcg/mm2). This device would be the first-ever paclitaxel-eluting stent available in the United States for the treatment of symptomatic PAD.
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| Subhash Banerjee |
Percutaneous transluminal balloon angioplasty (PTA) for revascularization of the superficial femoral artery (SFA) has an initial technical success rate of more than 95%. However, restenosis occurs in 50% to 60% of the treated segments after 6 to 12 months. Implantation of nitinol self-expanding stents in infrainguinal arterial segments has improved intermediate and long-term patency compared with PTA, but the benefit has been limited by 30% to 40% restenosis and 5% to 15% stent fracture rates. Stent outcomes for complex lesions and specific patient subsets with diabetes mellitus have been particularly marginal. Attempts to improve long-term patency of peripheral stents have had a mixed success. The presentation in the Figure illustrates a typical case of complex SFA disease treated with stent implants and 6 month in-stent restenosis in a patient with diabetes mellitus.
COBRA
Our group recently reported the findings from the Cryoplasty or Conventional Balloon Post-dilation of Nitinol Stents for Revascularization of Peripheral Arterial Segments (COBRA) trial at the 23rd Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium in November.
In this prospective, multicenter, randomized clinical trial, 121 patients with diabetes mellitus were enrolled between August 2008 and December 2010 at four clinical sites within the United States. Inclusion criteria included insulin or non-insulin dependent diabetic patients, severe lifestyle-limiting claudication (Rutherford category >3), chronic critical limb ischemia with rest pain (RB stage 4) or ischemic ulcers (RB stage 5), and SFA lesions requiring a nitinol self-expanding stent at least 5 mm in diameter and at least 60 mm in length.
Seventy-four patients with 90 SFA lesions were randomly assigned to cryoplasty (n=45 lesions) or conventional balloon angioplasty (CBA; n=45 lesions). Mean age of the patients was 64 years, and 88% were men. Mean HbA1c was 7.4 g/dL. The baseline ankle-brachial index in the cryoplasty group was 0.59, and 0.62 in the CBA group. The primary endpoint was 12-month SFA binary in-stent restenosis, defined as at least a 2.5 times increase in peak systolic velocity by duplex ultrasound.
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Images: Subhash Banerjee, MD; reprinted with permission. |
The rate of occurrence was 55.8% for the conventional balloon group and 29.3% for the cryoplasty group. Based on this finding, we concluded that, in patients with diabetes mellitus presenting with lifestyle-limiting claudication, post-dilation of nitinol self-expanding stents in the SFA using cryoplasty significantly reduced 12-month in-stent restenosis compared with conventional balloon post-dilation. This study captured the potential biological impact of cryotherapy on smooth muscle proliferation, together with the scaffolding provided by stent implants in a complex lesion subset (mean lesion length 180 mm; approximately 50% chronic total occlusions). Cooling to –10·C was achieved by inflating the PolarCath balloon (Boston Scientific) with nitrous oxide instead of saline and contrast. This system induces smooth muscle cell apoptosis, minimizes necrosis (–5·C to –15·C), reduces restenosis and is easy to perform. Stent fracture rates were not systematically evaluated as part of this trial. More importantly, the results of the COBRA study also indicate the potential impact of stent post-dilation strategies on endovascular treatment of symptomatic PAD.
THUNDER
Drug-eluting balloons appear to be very promising for the lower extremities. The German THUNDER (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries) randomized trial studied the effect of paclitaxel on restenosis following angioplasty of stenotic or occluded femoropopliteal arteries using paclitaxel-coated angioplasty balloons compared with conventional PTA in 154 patients.
At 6 months, the paclitaxel-coated balloon group had significantly less restenosis and lower 6-, 12- and 24-month target lesion revascularization rates. The primary endpoint of mean late lumen loss was evaluated in 83 patients who underwent angiographic follow-up and was significantly lower in the group treated with paclitaxel-coated balloons vs. the control group (0.4 vs. 1.7; P<.001). Rate of TLR at 12 months was 10% in the paclitaxel-coated balloon group compared with 48% in the control group (P<.001). Even at 24 months, the rate of additional revascularization remained significantly less for the paclitaxel balloon group (P<.001). The 5-year results of the drug-coated balloon also demonstrated superior long-term results compared with uncoated balloons.
SIROCCO I and II
Compared with coronary drug-eluting stent applications, evidence on drug-eluting devices for the peripheral vascular system is less robust. In the SIROCCO (Sirolimus-Coated Cordis Self-expandable Stent) I study, 36 patients were randomly assigned to either a sirolimus-eluting stent (SMART, Cordis; n=18) or a bare self-expanding stent (SMART; n=18). The in-stent mean percent diameter stenosis was 22.6% in the sirolimus-eluting stent group vs. 30.9% in the uncoated stent group (P=.294).
The subsequent SIROCCO II study involved 57 patients who were randomly assigned either to the nitinol bare stent (n=28) or the sirolimus-eluting stent (n=29). Differences in the 6-month primary endpoint of angiographic in-stent mean percent diameter stenosis did not reach statistical significance.
Zilver PTX
The Zilver PTX prospective, multicenter, randomized trial, which compared bare-metal vs. paclitaxel-eluting nitinol stents for SFA disease, had two randomization protocols. Patients were initially randomly assigned to either PTA or the Zilver PTX paclitaxel-eluting peripheral stent. Those who had at least 30% residual stenosis or a pressure gradient greater than 5 mm Hg following 2 to 3 minutes of PTA balloon inflation, otherwise defined as suboptimal PTA, were again randomly assigned to a provisional bare-metal Zilver stent or the Zilver PTX.
After 1 year, 83.1% of those who were treated with Zilver PTX were patent, compared with 32.8% in PTA-treated patients (P<.01). Zilver PTX still performed much better than optimal PTA, 83.1% compared with 65.3% (P<.01). In the provisional stenting group, the 12-month patency rate was 89.9% in patients treated with the Zilver PTX compared with 73% for patients treated with the BMS (P=.01). The patency rate for Zilver PTX-treated patients was also significantly better than the optimal PTA and provisional bare-stent groups combined (“standard-of-care” group; P<.01).
The 12-month patency rate for this combined group was 67%. Stent fractures were rare, only 0.9% at 12 months. It is important to point out that the average lesion length was 66 mm and nearly 50% were diabetic. Despite these impressive results of the Zilver PTX study at 12 months, potential for a late catch-up for restenosis remains. My personal belief is that the risk for delayed spike in restenosis is small, given the lack of a pro-inflammatory polymer coating on the stent.
Consideration of Lesion Length
Another aspect of peripheral drug-coated stents that is worth a mention is its application for short and intermediate length femoropopliteal atherosclerotic disease. The average lesion length in Zilver PTX was 66 mm and in SIROCCO II it was 81 mm. Therefore, for relatively short and uncomplicated lesions, bare nitinol stents may provide equivalent results to drug coated. In fact, the restenosis rates with the bare-metal comparator in SIROCCO II were much lower than expected. It may not be inconceivable to expect the application of non-stent based therapies (atherectomy, PTA with drug-coated balloons, bare nitinol self-expanding stents with adjunctive cryotherapy, and drug-eluting nitinol stents) to be based on lesion severity and patient profile. This speculation, however, needs to be tested for each lesion subset and patient profile.
Forthcoming Data
Currently, there are several ongoing studies evaluating the role of drug-coated peripheral stents in different locations and patient presentations that will help to further define the role of DES in PAD. They include:
- The STRIDES study, which will evaluate the use of a self-expanding stent system (Abbott Vascular) that is specifically designed to withstand normal leg movement, combined with the anti-proliferative drug everolimus, as a longer-term treatment alternative for patients with SFA disease.
- The Netherlands-based PADI trial, a prospective, multicenter, randomized, controlled, double-arm study investigating the safety and efficacy of primary paclitaxel-eluting stent implantation vs. primary PTA (Taxus Liberté, Boston Scientific) in infrapopliteal lesions in critical limb ischemia.
- The ACHILLES trial, a randomized, multicenter trial that aims to randomize 200 patients from 17 European centers to compare the patency rates following balloon angioplasty and Cypher stent (Cordis) implantation in symptomatic focal infrapopliteal stenosis or occlusions up to 9 cm.
- The YUKON trial, which will compare the sirolimus-coated Yukon Choice stent (Translumina) with the bare-stent platform in infrapopliteal lesions, with a maximum length of 45 mm.
- The randomized PICCOLO study, which will determine the angiographic outcome of paclitaxel-coated balloons vs. uncoated balloon angioplasty in treating below-the-knee lesions in 114 patients from five centers.
- The PACIFIER study, which will randomly assign patients with superficial femoral or popliteal artery disease to paclitaxel-coated or uncoated conventional balloon groups, and is due to recruit patients soon.
No matter which way the chips fall, we are certainly in for a much needed explosion in clinical trial data and evidence in the area of endovascular treatment of PAD.
References:
Banerjee S. Plenary Session XXI. Late-breaking clinical trials and first report investigations III. Presented at: Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.
Commeau P. Cathet Cardiovasc Interv. 2006;68:793-798.
Dake MD. Circ Cardiovasc Interv. 2011;4;495-504.
Duda SH. Circulation. 2002;106:1505-1509.
Duda SH. J Endovasc Ther. 2006;13:701-710.
Reddy BK. Presented at: The Society for Cardiac Angiography and Interventions Annual Scientific Sessions. May 6-9, 2009; Las Vegas.
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Subhash Banerjee, MD, FACC, FSCAI, is chief of the Division of Cardiology and co-director of the Cardiac Catheterization Laboratory, VA North Texas Health Care System, Dallas, and is associate professor of medicine at the University of Texas Southwestern Medical Center, Dallas. He is also a member of the Cardiology Today Intervention Editorial Board.
Disclosure:
Dr. Banerjee has received speaker honoraria form Boehringer Ingelheim, Gilead, Johnson & Johnson, Medtronic, Sanofi-Aventis and St. Jude Medical; research support from Boston Scientific and The Medicines Company; and has ownership and intellectual property with HygeiaTel and Mdcare Global LLC.