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.
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.
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.
Left superficial femoral artery (SFA) intervention in a patient with
lifestyle-limiting claudication and in-stent restenosis at 6 months follow-up.
Panel A: Arrow indicates proximally occluded left SFA. Panel B: Distal
reconstitution of the left SFA occlusion (arrow). Panel C: A blunt
microdissection catheter (CrossBoss, BridgePoint Medical) over a 0.014
guidewire is advanced through the proximal cap of the occluded SFA. Panel D:
The catheter is able to advance through the occluded segment into the distal
true lumen. Panel E: Pre-dilation of the occluded SFA segment. Panel F: Nitinol
self-expanding stent delivery and deployment. Panel G: Final angiographic
result. Panel H: Left SFA in-stent restenosis at 6 months follow-up.
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.
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.
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;
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
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
- 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.
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.
Dake MD. Circ Cardiovasc Interv.
Duda SH. Circulation.
Duda SH. J Endovasc Ther.
Reddy BK. Presented at: The Society for Cardiac
Angiography and Interventions Annual Scientific Sessions. May 6-9, 2009; Las
Scheinert D. EuroIntervention.
Siablis D. J Endovasc Ther.
Tepe G. J Am Coll Cardiol.
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
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.