the future of sfa treatment

THE FUTURE OF SFA TREATMENT: NEW TECHNOLOGIES
Guest Editor: M. Bosiers
REVIEWS
J CARDIOVASC SURG 2010;51:115-9
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Are drug-eluting stents the future of SFA treatment?
M. BOSIERS 1, K. DELOOSE 1, K. KEIRSE 2, J. VERBIST 2, P. PEETERS 2
Drug-eluting stent (DES) technology was developed to
prevent early thrombosis and late luminal loss to potentially improve long-term patency rates. Although favorable DES results have recently become available with
the Zilver® PTX™ and STRIDES studies, the high price of
DES is a major drawback for this technology to become
the golden standard for peripheral endovascular therapy in de novo femoro-popliteal (FP) lesions.
Nevertheless, DES has the potential to make the difference and to establish itself as an important treatment
option in patients presenting with TASC C&D FP lesions
who are at high-risk for surgery and for the treatment
of in-stent restenosis, where until now, no valuable
treatment option has proven to be beneficial.
KEY WORDS: Stents - Coronary restenosis - Femoral artery.
eointimal hyperplasia is the most decisive factor
on results post-stenting in superficial femoral
artery (SFA). Stents themselves contribute to intimal
hyperplasia in ways which are becoming more predictable and potentially remediable in the near future.
The applications of a drug coating on a stent surface,
inhibits the inflammatory response and smooth muscle cell proliferation in the vessel wall during a certain
period and delays the process of intimal hyperplasia.
Thus, drug-eluting stent (DES) technology was developed to prevent early thrombosis and late luminal
loss to potentially improve long-term patency rates.
Because DES with active stent coatings have shown to
be beneficial in the treatment of coronary artery disease,1-3 the applicability of these drug coatings for
the treatment of femoro-popliteal (FP) lesions has
also been tested.
Corresponding author: M. Bosiers, MD, Department of Vascular Surgery,
AZ St-Blasius, Kroonveldlaan 50, 9200 Dendermonde, Belgium. E-mail:
[email protected]
Vol. 51 - No. 1
1Department of Vascular Surgery
AZ St-Blasius, Dendermonde, Belgium
2Department of Cardiovascular & Thoracic Surgery
Imelda Hospital, Bonheiden, Belgium
The SIROCCO (SIROlimus Coated COrdis Selfexpandable Stent) study was the first randomized trial to publish results with DES. This trial failed to prove
DES superiority over bare metal stents (BMS) in the
SFA.4, 5 Afterwards, two other important randomized
studies were started to evaluate the outcome of DES
vs. BMS: the ZILVER® PTX™ IDE Study6/Global
Registry and the STRIDES (The SFA Treatment with
Drug Eluting Stents) study.7 Preliminary results from
the ZILVER® PTX™ trial indicate improved patency
rates with DES in the SFA. However, the final results
of the ZILVER® PTX™ still have to be awaited. This
article overviews the results with DES in the SFA that
are currently available, and comments on the economic considerations and the treatment indications for
DES.
SIROCCO
The SIROCCO trial 4, 5 was the first CRT to publish
its results on the use of DES, and is still the only one
that reported completed long-term DES outcome. This
double-blind controlled randomized trial (CRT) evaluated the efficacy of sirolimus-eluting self-expanding nitinol stents versus the same commercially available bare metal stents (SMART®, Cordis., Miami, FL,
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DRUG-ELUTING STENTS AND SFA TREATMENT
USA) for treatment of SFA lesions. The study was performed in 2 phases. When interim analysis of SIROCCO I revealed a high fracture rate, the maximum
lesion length was reduced from 20 cm to 14.5 cm.
Consequently, the number of stents allowed for
implantation was decreased from 3 to 2, in order to
avoid stent fractures. Angiography was performed
before and after stent placement and repeated after six
months. The primary end point was in-stent mean
lumen diameter at six months as determined by quantitative angiography. All analyses were performed on
an intention to treat basis. In total, 93 patients with
stenotic or occlusive disease of the SFA were included, with an average lesion length of 8.3 cm. The
sirolimus-eluting SMART® stent was implanted in 47
and the bare SMART® nitinol stent in 46 patients. After
24 months, re-stenosis rates on duplex ultrasound
were 22.9% versus 21.1% for DES and BMS, respectively, which did not imply a significant difference. 6%
of the patients in the sirolimus group received a target lesion revascularization (TLR), whereas 13% had
a TLR in the BMS group. In both groups at 24 months,
no amputations were performed as a result of complications from stenting. In their conclusion, the
SIROCCO investigators stated that the study provided
objective evidence supporting the safety and efficacy
of drug-eluting and bare metal self-expanding nitinol
SMART® stents in patients with chronic limb ischemia
and TASC C SFA lesions. The lack of a statistically significant different between both study arms, was
ascribed to an unexpectedly low re-stenosis rate in the
BMS cohort
lar Therapies (ISET) meeting in Miami (http://www.
iset.org/), Michael Dake 6 presented an interim report
for the IDE-trial based on the first 60 patients enrolled
in the trial. In this subset, 28 patients were randomized
to the ZILVER® PTX™ arm and 32 to the PTA control
arm. After six months, the investigators reported a
92% Freedom for Target Lesion Revascularization rate
(TLR, being defined as clinically driven re-intervention
for >50% diameter stenosis (DS) within the treated
segment), in the Zilver® PTX™ group, compared to the
52% Freedom from TLR rate in the PTA control group.
Complete results of the Zilver® PTX™ study will be
available for the public by mid-February 2010.
At the 2009 meeting of the Cardiovascular and
Interventional Radiological Society of Europe (CIRSE)
meeting in Lisbon, Portugal (http://www.cirse.org/),
Marc Sapoval 7 presented the latest interim results of
the ZILVER® PTX™ drug-eluting stent in long SFA
lesions on behalf of the ZILVER® PTX™ investigators.
He presented data based on 12-month data for 719
patients, comparing the results from patients with
lesions shorter than 15cm (TASC A&B femoro-popliteal
lesions) to the outcome in patients with lesions of
15cm or longer (TASC C&D femoro-popliteal lesions).
In the cohort of 541 (75.3%) patients with 627 TASC
A&B femoro-popliteal lesions, an average of 1.4 stents
were used in lesions with an average degree of stenosis of 81 (±17)% and an average length of 6.1 (±3.9)cm.
Freedom from TLR after 12 months was 92% (574/627),
with a stent fracture rate of 0.9%. In the group of 178
(24.7%) patients with 182 TASC C&D FP popliteal
lesions, an average of 3.7 stents were used in lesions
with an average degree of stenosis of 96% (±9)% and
with an average lesion length of 22.9 (±4.8)%. In this
subgroup, 12-month Freedom from TLR was 79%
(143/182), with a 2.6% fracture rate.
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ZILVER
The ZILVER® PTX™ Paclitaxel-eluting stent study
from Cook Inc. (Bloomington, IN, USA) is a largescale safety and efficacy trial with the ZILVER® PTX™
stent in above-knee FP lesions. It consists of two components, enrolling a total of 1 034 patients treated
with the paclitaxel-coated ZILVER® PTX™ stent. First,
there is a randomized investigational device exemption (IDE) study in lesions up to 14 cm (TASC A&B FP
lesions) comparing 240 ZILVER® PTX™ patients with
240 patients who received PTA and bail-out ZILVER®
BMS implantation. The second part is a Global Registry
in 794 patients with lesions up to 28cm (TASC A, B, C
&D FP lesions) who receive a ZILVER® PTX™ stent.
At the 2007 International Symposium on Endovascu-
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STRIDES
At the CIRSE 2009 in Lisbon, Portugal, Johannes
Lammer 8 presented the one-year results of the
STRIDES trial (SFA Treatment with Drug-Eluting Stents
Study), sponsored by Abbott Vascular Inc. (Santa
Clara, CA, USA). This European prospective non-randomized controlled trial aims to evaluate the safety and
performance of the DYNALINK-E® Everolimus-Eluting
Peripheral Stent System in above-knee (AK) FP de
novo or restenotic lesions. Primary endpoint was ISR
after 6 months. Patency, survival and amputation-free
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TABLE I.—Hypothetical cost calculation for TASC A&B FP lesions: non-DES vs. DES.
Non-DES
100 index interventions (1.4 stents/procedure)
30 endovascular reinterventions (12M PP=70%)
TOTAL
=
=
100 * 1.4 * € 1 000.00
30 * € 1 000.00
=
=
€ 140 000,00
€ 30 000,00
€ 170 000,00
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DES
100 index interventions (1.5 stents/procedure)
15 endovascular reinterventions (12 M PP = 85%)
TOTAL
survival up to 5 years will be investigated. In total
104 patients were enrolled, of which 83% had intermittent claudication and 17% presented with critical
limb ischemia. The mean lesion length was 9.0±4.3 cm,
of which 91.4% were de novo lesions. Primary endpoint was reached in 14% of patients. After 12-months,
Freedom from TLR was reported to be 79.7% and 12month primary patency was 68.5%.
Economic considerations
Even though the preliminary results from the ZILVER® PTX™ Paclitaxel-eluting stent study look promising, the price of DES will have to drop significantly for
it to become a fully acceptable alternative to the other non-coated SFA stents that are currently available.
Next to the clinical value of DES, also the cost for
society and health care systems have to be considered.
In this respect, a hypothetical cost calculation based
on the data that is currently available learns us that
DES, despite the fact that it works in the SFA, is not
cost-effective.
For TASC A&B FP lesions, the results of the corresponding subgroup from the ZILVER® PTX™ Global
Registry are the most reliable data currently available
for our cost-calculation. The Freedom from TLR after
12 months that is reported for TASC A&B FP lesions
is 92%, which corresponds with a primary patency
rate of 85%.
The comparator for TASC A&B is PTA with stenting
of the non-DES SFA stents.[9] Several CRT evaluating
percutaneous transluminal angioplasty (PTA) versus
nitinol stenting in TASC A&B FP lesion configurations,
have shown favorable primary patency and stent fracture rates for stents implanted in this arterial bed. The
12-month binary re-stenosis rates of the stent-arms in
the FAST (lesion length 4.5cm)[10], Resilient (lesion
Vol. 51 - No. 1
=
=
100 * 1.4 * € 1 500.00
15 * € 1 500.00
=
=
€ 210 000,00
€ 22 500,00
€ 232 500,00
length 7.1cm), Astron (lesion length 8.4 cm) and
Absolute Vienna (lesion length 13.2 cm) trial were
31.7%, 20%, 34.4% and 36.7%, respectively, approximating a 12-month primary patency rate of 70%.
Considering that all index TASC A&B lesions can be
treated with on average 1.4 stents and that all re-interventions can be performed with endovascular therapy using one single stent, only the stent cost differs for
both endovascular treatments. Currently non-DES
stents are available for ? 1 000 and DES at ? 1 500.
Consequently, per 100 patients, treatment and 12month follow-up cost is ? 62 500 or 36.7% more expensive after one year to maintain patency, as shown in
Table I.
The TASC C&D subgroup from the ZILVER® PTX™
Global Registry reported a Freedom from TLR of 79%,
which corresponds with a 70% primary patency rate
after 12 months. On average, 3.7 stents were needed
in this patient cohort, and all re-interventions can theoretically be performed with placement of a single
stent. For the total procedural and in-hospital cost for
an endovascular intervention, we refer to the BASIL trial, which reported an inpatient hospital cost per day
of UK £ 421 (±? 600) and an average procedure cost
for a PTA-only of UK £ 1 159 (±? 1 500).12 With an average of 1.5 days of in-hospital stay for the endovascular group, a ? 900 hospitalisation cost and ? 1.500 procedural cost has to be added to the material cost for
3.7 DES stents.
For TASC C&D FP lesions, the results of the corresponding subgroup from the ZILVER® PTX™ Global
Registry have to be compared to those of bypass
surgery, which is currently the recommended treatment.9-11 In a meta-analysis on FP bypass grafts on
more than 6 000 cases by Pereira et al., for a subgroup of predominately claudicants, a 12-month primary patency was reported of 87.5±4.4% for AK
venous bypass surgery (VBS) and of 85.3±1.9% for
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TABLE II.—Hypothetical cost calculation for TASC C&D FP lesions: bypass vs. DES
Non-DES
100 index interventions + hospitalization cost
15 endovascular re-interventions (12M PP=85%)
TOTAL
=
=
100 * € 4 200
15 * € 1 000
=
=
€ 420 000
€ 15 000
€ 435 000
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DES
100 index interventions (3.7 stents/procedure)
100 hospitalisations + procedural costs
30 endovascular re-interventions (12M PP=70%)
TOTAL
prosthetic bypass surgery (PBS).12 Nowak et al. calculated the total procedural and hospitalization costs
for VBS and PBS, taking into account an average hospitalization time of 12.2±3.6 days for VBS and 14±8.35
days for PBS, they calculated an average total costs for
VBS of ? 4 368 and for PBS of ? 4 069.13 In our cost-calculation, we therefore consider a 12-month primary
patency of 85% and a total procedure and hospitalisation cost of ? 4 200.
Endovascular repair after bypass failure in 15% of
patients or after in-stent re-stenosis in the DES group
after one year can be done by means of single stent
placement. Thus, cost-calculation per 100 patients for
a 12-month follow-up period results in an extra total
cost for DES of ? 405 000 or 93.1% to maintain patency, as shown in Table II.
Indications for DES
Although DES technology will improve and could
potentially expand the possibilities of endovascular
therapy towards TASC C&D FP lesions, our cost calculation hints at the weak spot of this interesting new
technology: its price tag. Particularly in times of economic recession, and already steeply rising healthcare costs, ethical considerations have to be made
when implementing a high-cost treatment modality
that does not improve the clinical results after one
year. It is our opinion that DES will not be the treatment
of choice in de novo SFA lesions, due to the comparable results in TASC A&B lesions with non-DES stent
and in TASC C&D lesions with by-pass surgery.
However, DES might play an important role for
treatment of high-risk surgical patients, such as elderly people and diabetics, who present with TASC C or
D FP lesions. It is clear that this specific patient subset will benefit from a minimally invasive approach
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=
=
=
100 * 3.7 * € 1 500
100 * (€ 900 + 1 500)
30 * € 1 500
=
=
=
€ 555 000
€ 240 000
€ 45 000
€ 840 000
that can offer satisfying results. In this respect, a randomized trial in this patient subgroup is warranted
comparing DES implantation versus other endovascular
treatment modalities.
Thomas Zeller presented favorable results for a
subgroup of 106 patients from the ZILVER® PTX™
Global Registry who were treated for ISR at the Leipzig
Interventional Course 2009 in Leipzig.14 In this patient
subgroup an 116 lesions were treated with an average length of 12.4±8.6 cm and an average degree of stenosis of 87±14% was treated with an average of 2.3
stents. After 12-months, data was available for 98
patients. Freedom from TLR after one year was reported to be 78% and the stent fracture rate was 1.7%.
After subanalysis, freedom from TLR after 12-months
was 82% and 70% in lesions up to 14 cm and in lesions
longer than 14 cm, respectively. Twelve-month freedom of TLR rates were 81% for stenoses versus 69% for
occlusions. This means a remarkable improvement
compared to other results availble for similar patient
groups. Zeller et al.15 reported their results in 43
patients who were treated by directional atherectomy
for ISR in FP lesions with an average length of
13.3±11.1cm and an everage diameter stenosis of
88±9%. Here, the 12-month freedom from TLR was
53%. Results for PTA and cutting balloon were even
worse, with recurrence of re-stenosis after 6 months
reported to be as high as 73% and 65%, respectively.16
Based on these results, DES definitively has to potential to be of great value in the treatment of ISR.
Conclusions
Because neointimal hyperplasia remains the most
important reason for long-term failure, either after
endovascular therapy or surgery, drug-coating technologies will certainly play a decisive role in preven-
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tion and treatment of re-stenosis in the future.
Currently, the high price of DES is a major drawback
for this technology to become the golden standard
for peripheral endovascular therapy in de novo FP
lesions, despite the favorable clinical results obtained.
Nevertheless, DES has the potential to make the difference and to establish itself as an important treatment
option in patients presenting with TASC C&D FP
lesions who are at high-risk for surgery and for the
treatment of ISR, where until now, no valuable treatment option has proven to be beneficial.
10.
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