Vasa 2015; 44: 257 270 N. M. Malyar et al.

: Restenosis after EVR

2015 Hans Huber Publishers, Hogrefe AG, Bern DOI 10.1024/0301 1526/a000440

Review 257

Restenosis after endovascular revascularization

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in peripheral artery disease

Nasser M. Malyar, Holger Reinecke, and Eva Freisinger

Division of Vascular Medicine, Department of Cardiovascular Medicine, University Hospital Mnster, Germany

Summary: Endovascular revascularization (EVR) plays a
leading role in the therapy of peripheral artery disease. The
acute success rates of EVR in all anatomic territories and of all
TASC lesions are excellent (> 95%). However, the occurrence
of restenoses after EVR such as percutaneous transluminal
angioplasty and particularly after stenting, poses a substan-
tial limitation to the success of the procedure. Influenced by
patients comorbidities, the severity of arteriosclerotic disease,
lesion length and morphology as well as the techniques and
devices used for EVR, the long-term outcome of EVR dete-
riorates markedly from the aortoiliac to the infrapopliteal
segments of the lower limbs. The development of drug-coated
balloons and drug-eluting stents reduced the occurrence of
restenosis leading to considerably improved primary patency
rates in the femoropopliteal segments. This review aims to
provide an overview about the underlying mechanisms and
current relevance of the various options in the field of EVR
with regard to the rate of restenosis.

Key words: Restenosis, endovascular revascularization, peripheral artery disease, PTA, patency

Introduction of special catheter based devices such Definitions and

In the last decades, further develop-
ment of endovascular revasculariza-
tion (EVR) techniques and devices
lead to an increased application of
EVR and slowdown of surgical re-
vascularization procedures in the
therapy of peripheral artery disease
(PAD). In current guidelines prompt
revascularization is recommended
(1A) for critical limb ischemia (CLI)
to relieve symptoms and save limbs
from amputation. In claudicants
with limited walking capacity not
adequately responding to conser-
vative therapy revascularization
can be considered to reduce symp-
toms. Consensus is reached on an
endovascular-first-strategy of
Trans-Atlantic Inter-Society Con-
sensus (TASC II) A-C lesions in the
aortoiliac segment, in infrapopliteal
arterial occlusion, and at the stage
of CLI with reasonable chance for
successful reperfusion [1].
EVR comprises percutaneous trans-
luminal angioplasty (PTA) using the
technique of plain old balloon an-
gioplasty (POBA) and drug coated
balloons (DCB), vascular stenting
with bare metal (BMS) or drug- elut-
ing stents (DES), covered stents and
stent grafts as well as the application
as cutting balloons (CB), atherectomy
systems (Jetstream, SilverHawk,
TurboHawk, Diamondback 360Or-
bital Atherectomy System) and ex-
cimer laser systems (Turbo elite).
The choice of device is dependent
on several factors, such as location,
dimension and length of the athero-
sclerotic lesion, degree of vessel occlu-
sion, or extent of plaque calcification
that determine amongst others the
chance of successful revasculariza-
tion. The success of the revascular-
ization procedure is being measured
on the primary (PPR) and secondary
(maintained by repeat intervention)
patency rates (SPR) of the treated vas-
cular section, and adjunctive clinical
end-points (wound healing, increased
perfusion indices, avoidance of am-
putation) aside from the absence of
procedure related complications (e.g.
bleeding at puncture site). Therefore,
the occurrence of hemodynamically
significant, symptomatic restenosis
constitutes a major challenge of EVR
therapy in patients with PAD.
classifications of
restenosis
The defi nition of restenosis in the
peripheral arterial bed is mainly de-
rived from the equivalent phenom-
enon in coronary artery disease.
Clinically, restenosis is usually in-
dicated by an unsustained improve-
ment according to the AHA grading
system of limb status after EVR [2],
by deterioration of Rutherford cat-
egory or by the onset of recurrent
claudication based on standardized
treadmill-testing [3]. Angiographi-
cally, restenosis is defined as at least
50% reduced diameter of the arterial
lumen (binary restenosis) following
vascular intervention at a specific
follow up period [3]. A quantitative
parameter of restenosis is the so
called late lumen loss(LLL) which
defines the decrease of the minimal
lumen diameter at the re-evaluation
time compared to the initial result
at revascularization. However, de-
viating definitions include impaired
blood flow determined by duplex
ultrasound measurement of peak
systolic velocity and velocity ratio
(Fig. 1), as well as clinical endpoints
such as target lesion (TLR) and tar-
get vessel revascularization (TVR)

258 Review
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Figure 1: Duplex-ultrasound image of a high grade stenosis in the distal
part of a native SFA. The ow pattern becomes turbulent within the
stenotic segment with an increase in peak velocity to 5 m/sec.
and the freedom thereof at a pre-
defined time course [3].
There is no specific classification sys-
tem for the morphology of native-
vessel restenoses covering the entire
peripheral bed from the iliac to the
distal crural arteries. For the femo-
ropopliteal in-stent restenosis (ISR),
Tosaka et. al. [4] developed an angio-
graphic classification of 3 types: class
I indicates shorter lesions (< 50 mm)
of focal character within the stent
body including the stent edges, class
II indicates diff use lesions of > 50 mm
(Fig. 2) and class III represents total
occlusion of the stent. In analogy to
the restenosis in the coronary vascu-
lature, ISR can also be classified as
type I-IV: type I denotes focal lesion,
type II diff use ISR , type III diff use
proliferative beyond the margins of
the stents and type IV total occlusion
with no-flow [5].
The incidence of peripheral resteno-
ses ranges from 5 % to 70 %, depend-
N. M. Malyar et al.: Restenosis after EVR
ing on the localization and complex-
ity of the treated lesion as well as on
endogenous and procedural factors
[6, 7].
Pathophysiology
According to the current knowledge,
the injury of the treated arterial seg-
ment set by angioplasty and/or stent
implantation leads to multiple in-
travascular changes at cellular and
paracrine levels [8]. These include in
early stages elastic recoil of the arte-
rial wall, as well as platelet activation
and thrombus formation [9]. These
conditions may further be affected
by extracellular matrix activation
and release of pro-inflammatory cy-
tokines, followed by migration and
proliferation of smooth muscle cells.
This, at later stages, has been shown
to be associated with neointimal tis-
sue proliferation and impaired arte-
Vasa 2015; 44: 257 270
2015 Hans Huber Publishers, Hogrefe AG, Bern
Figure 2: Representative angio-
graphic (A) and duplex-ultra-
sound images (B) of a segmental,
high-grade in-stent restenosis 9
months after implantation of ni-
tinol stents in a total occluded
SFA. Panel (C) demonstrates the
acute results after treatment
with two drug-coated balloons.
rial remodeling [10]. However, the
underlying pathomechanisms for
the development of restenosis are
still incompletely understood and
matter of intense research.
Risk factors
Endogenous risk factors
for restenosis
The co-prevalence of diabetes mel-
litus in PAD patients is known to
be associated with an impaired out-
come, including increased amputa-
tion rates and mortality. However,
the vast majority of prospective
clinical studies using nitinol stents
do not show a correlation between
diabetes mellitus and increased re-
stenosis rates in PAD [11]. Higher
 Vasa 2015; 44: 257 270
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levels of C-reactive protein and se-
rum amyloid A during and shortly
after EVR have been shown to be as-
sociated with higher restenosis rates
[12], suggesting restenosis to be trig-
gered by an increased inflammatory
reaction in these patients. Moreover,
few genetic variants (e.g. CYP2C19
loss of function alleles) have been
identified to be associated with
greater risk for in-stent restenosis
following EVR [13].
Lesion related risk factors
for restenosis
With regard to the complexity of a
lesion, the lesion length is an impor-
tant determinant of restenosis [14]. A
small diameter of the vessel and the
presence of a total occlusion before
EVR are predictors of restenosis. The
overall plaque burden with risk for
residual uncovered arteriosclerotic
plaques as well as a plaque com-
position with high content of col-
lagen and smooth muscle cells also
increases the risk of restenosis [15].
Severe calcification of the athero-
sclerotic lesions is not only a major
limiting factor for the acute success
rates of EVR, it is also an indepen-
dent predictor of decreased long
term vessel patency after EVR [16].
Further, mechanical exposure, such
as torsion, flexion, compression, or
bending varies with regard to the
affected arterial segment. Thereby
affected, shear stress and flow pa-
rameters vary depending on physio-
logical, pathological, anatomical and
functional conditions. Neointimal
hyperplasia has been shown to be ac-
celerated at sites of low shear stress,
which is predominantly at the tran-
sition zone of implanted stents [17].
Intervention related risk factors
and predictors of restenosis
Apart from the abovementioned
endogenous and lesion related fac-
tors leading to restenosis there are
several intervention related factors
N. M. Malyar et al.: Restenosis after EVR
which have been shown to initiate
and accelerate vascular restenosis.
Decreased blood flow has been
shown to increase the rate of re-
stenosis whereas high blood flow is
not associated with increased rate
of restenosis compared to normal
flow [18].
Acute elastic recoil is a common
phenomenon that can occur fol-
lowing angioplasty in any vascular
bed, most frequently after infrapop-
liteal angioplasty [19]. If not treated
adequately, elastic recoil within
the first minutes after angioplasty
leads to short and long term lumen
loss and subsequent vascular reste-
nosis in the later course. Vascular
scaffolds such as nitinol stents are
frequently used to overcome the
phenomenon of early recoil forces
and to treat flow limiting dissections
at the site of angioplasty. However,
stent implantation itself initiates a
local inflammatory process called
neointimal proliferation resulting
in poor long term outcome in terms
of vessel patency.
Neointimal proliferation is a local
response to injury of the vessel wall
set by angioplasty and/or stenting.
An inflammatory process, resulting
in migration of smooth muscle cells
from the media into the intima is
initiated and fi nally promotes the
plaque formation [9].
Stent fracture: The trend towards
primary EVR treatment even of
long and totally occluded lesions
(TASC C and D) necessitates the
implantation of long and multiple
stents. In contrast to the coronary
arteries where stent fracture (SF)
is a rare event, it remains a major
issue of concern in the peripheral
arteries (Fig. 4). SF has been shown
to be associated with increased rate
of stent failure and higher rates of
ISR and re-occlusions requiring re-
intervention [20]. Due to the unique
anatomy and peculiar flow pattern,
the superficial femoral artery (SFA)
Review 259
and particularly the popliteal artery
(PA) are exposed to distinct bio-
mechanical forces because of the
bending and foreshortening during
flexion of the knee and hip joint and
therefore prone to SF (Fig. 3). The
increased risk of SF, misalignment
as well as non-uniform stent strut
distribution and subsequent ISR
impair the outcome in these arte-
rial segments [21]. In femoropoliteal
segments, SF rates up to 35 % have
been reported resulting in vessel
obstruction rates between 55 % and
88 % depending on the severity of
the SF [20]. With the advances from
rigid first generation stents to now
available highly flexible stents that
are designed for exposure to higher
mechanical forces, the risk of SF
could be minimized: SF rates of 0 %
have been demonstrated for the SFA
[22] and for the popliteal segments
[23]. Stent graft s also have been
shown to have almost 0 % fracture
rate [24].
Prophylaxis and
treatment of restenosis
Medical approaches to
prevent restenosis
In general, there is limited evidence
that antiplatelet, anticoagulant and
vasoactive drugs reduce restenosis
or re-occlusion at six months follow-
ing EVR in patients with PAD, as
it has intensively been investigated
in a recent meta-analysis by Robert-
son et. al. [25]. The authors show that
neither a higher dose of acetylsali-
cylic acid (ASA;300 1000 mg com-
pared to low-dose ASA 50 300 mg)
nor a combined therapy with dipyri-
damole (DIP) was effective to sig-
nificantly improve patency follow-
ing EVR. Also, the reported trials on
ASA/DIP vs. vitamin K antagonists
(VKA) and ticlopidin vs. VKA did
not reach statistical relevance.
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Cilostazol (Pletal) is a selective

phosphodiesterase-III-inhibitor
that leads to improved endothelial
function, platelet inhibition and anti-
proliferative effect via increased con-
centration of intracellular 3`-5`cyclic
adenosinemonophosphate (cAMP).
The Sufficient Treatment of Peripher-
al Intervention by Cilostazol (STOP-
IC) study [26] demonstrated a mark-
edly reduced angiographic restenosis
rate of 20 % in the cilostazol + acetyl-
salicylic acid (ASA) group (100 mg
cilostazol + 100 mg ASA) compared
to 49 % in the control (ASA only)
at 12 months for femoropopliteal
Figure 3: Schematic illustration of the diverse biomechanic forces affect- lesions as well as a favorable clini-
ing the ow dynamics and morphology of the femoropopliteal segments. cal outcome in terms of event-free
survival rate driven by the lower
rate of TLR in the cilostazol group.
These findings are further substan-
tiated by a multicenter study [27]
consisting of 861 patients who re-
ceived dual antiplatelet medication
(ASA+clopidogrel) following EVR
of de-novo femoropoliteal lesions
with self-expandable nitinol stents.
The additional treatment with cilo-
stazol resulted in a reduced binary
re-stenosis rate of 31.2 % compared
to 42.9 % in the control at 5-years
(p = 0.02) and revealed cilostazol to
be a negative predictor of restenosis
after risk factor adjustment. Hence,
cilostazol is given a class IIb, Level
A recommendation by the European
Society of Cardiology [28] and a class
I, Level A recommendation by the
ACC/AHA guidelines for medical
treatment of lifestyle-limiting clau-
dication [29]. The limitation of the
generalizability of those data is that
the abovementioned studies were
exclusively carried out in Asian
population, mainly in Japan. No data
from RCTs regarding the effect of
Cilostazol on restenosis in PAD are
Figure 4: Angiographic (A-C) and duplex-ultrasound images (D-E) of a available in Caucasian populations.
short stenosis resulting from a stent fracture (arrows) in the left popliteal Last but not least, it must be men-
artery. Panel C and E demonstrate the corresponding images after treat- tioned that the European Medicine
ment with a highly exible stent-in-stent-implantation. Agency has recently issued safety
concerns regarding use of cilostazol
 Vasa 2015; 44: 257 270
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in patients with acute coronary syn-
dromes or coronary interventions
within the last 6 months due to in-
creased rates of cardiovascular and
hemorrhagic events. The indication
also should be restricted in patients
with heart failure and the dose of
cilostazol should be reduced in pa-
tients treated concomitantly with
inhibitors of CYP3A4 and CYP2C19.
Impact of distinct EVR
strategies on restenosis
Apart from the previously men-
tioned patient-dependent factors,
the occurrence of peripheral reste-
nosis differs markedly between the
several EVR techniques and devices,
which should be summarized briefly.
Drug-coated balloon
The technology of drug-coated bal-
loons (DCB) is appealing since it
directly provides anti-proliferative
substances into the arterial wall
without the disadvantages of a per-
manent scaffold such as stimulus
for neointimal proliferation, SF as-
sociated complications and limita-
tion of future bypass anastomosis.
Although animal studies indicate
that as much as 70 % to 80 % of the
drug dose might be lost in the blood-
stream, the remaining dose and du-
ration of drug exposure seem to be
sufficient to prevent neointimal pro-
liferation [30].
Current literature provides evidence
that DCB technology effectively
prevents restenosis and indicates
superiority compared to POBA, in
particular in the femoropopliteal
segments. The efficacy of a paclitax-
el-coated balloon was tested in the
multicenter, randomized controlled
Thunder trial [31] in 154 patients.
Patients treated with DCB had sig-
nificant lower rates of late lumen loss
(LLL) resulting in significantly lower
rates of target lesion revasculariza-
N. M. Malyar et al.: Restenosis after EVR
tion (TLR) after 6 and 12 months
compared to the control group (drug
dilution and POBA). Moreover, in
case of high-grade non-flow-limit-
ing dissection the adjunctive use of
DCB was associated with significant
lower rates of restenosis and TLR at
6 month follow-up [32].
Initial experiences with DCB in the
infrapopliteal segments were prom-
ising: In a prospective, single-arm
study Schmidt et. al. [33] showed a
restenosis rate of 27.4 % at 3 month
after treatment with DCB which was
significantly lower than the 69 %
restenosis rate at 3 months after
POBA in another study by the same
group [7]. This encouraging observa-
tion was supported by an RCT [34]
which demonstrated superiority of
the DCB (RR at 12 months 27 % vs.
74.3 % and TLR rate at 12 months
17.5 % vs. 41 %, P < 0.05). However, a
subsequent large-scale, multicenter
RCT for treatment of infrapopliteal
lesions in a CLI population failed its
primary efficacy endpoint of DCB
superiority compared to POBA;
Moreover, the secondary endpoints
such as major amputation, death,
and amputation-free survival even
trended against the DCB treatment
arm [35]. The reasons, why a DCB
with the same drug coating technol-
ogy (IN.PACT Admiral, Medtronic
Inc., Santa Rosa, CA, USA) demon-
strated its effectiveness in the femo-
ropoliteal region [36] but failed in
the infrapopliteal segments [35]
is unclear. Until dedicated stud-
ies shade more light on this issues,
speculations about the underlying
mechanisms comprise differences
in pathophysiology, composition of
plaques, the degree of lesion calcifi-
cation and other currently unknown
patients-, lesions- and procedures-
related factors impairing the effec-
tiveness of DCB in the infrapopliteal
lesions.
A direct comparison of the exist-
ing literature is impossible, since
Review 261
the applied substances, dosage and
coating technology of antiprolifera-
tive agents and therefore its biologi-
cal and clinical effectiveness differ
markedly. Further, the paucity of ad-
equately powered studies and differ-
ing methods and endpoints further
complicate a direct comparison of
the literature and current data need
to be substantiated in future trials.
Drug-eluting stents
DES are metallic scaffolds coated
with an antiproliferative substance
(drug). After implantation the drug
is slowly and continuously released
in proportion to the degradation of
the polymer matrix from the stent
struts, penetrating the vessel wall
and thereby exerting its antiprolif-
erative and anti-restenotic effect.
Initial studies using polymer-based
DES (sirolimus-coated) in the femo-
ropopliteal segments failed the effi-
cacy end points [37]. At 24 months,
the restenosis rate in the DES group
was 22.9 % vs. 21.1 % in the BMS
group (p = n.s.). The failure of show-
ing superiority of DES was attributed
to the unexpectedly low ISR rate in
the BMS group with an initial aver-
age lesion length of 8.3 cm. The ef-
ficacy of an everolimus-coated DES
in femoropoliteal segments (mean
lesion length 9 4 cm) was demon-
strated in a prospective, nonran-
domized, single arm trial [38] with a
PPR of 94 2.3 % and 68 4.6 % after
6 and 12 months, respectively. The
effectiveness of a polymere-free DES
(ZilveriPTX) was demonstrated
by Dake et. al. [39] in a prospective,
multicenter, randomized trial as-
signing patients with femoropoliteal
lesions to DES or POBA. Those with
PTA-failure were then provisionally
assigned to either DES or BMS im-
plantation. The PPR after 12 months
was 83.1 % for the DES and 32.8 %
for the POBA group (P < 0.001) and
for the provisional stenting 89.9 %
for the DES and 73.0 % for the BMS

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group (P = 0.01). The superiority of
DES vs. POBA and of DES vs. BMS
were sustained at the 2-years follow-
up (PPR of 74.8 % vs. 26.5 % (p < 0.01)
for DES vs. POBA and 83.4 % vs.
64.1 % (p < 0.01) for DES vs. BMS).
[40]. The effectiveness of DES in ex-
clusively restenotic lesions was dem-
onstrated in a subgroup analysis of
the single arm Zilver PTX study [41]
with a PPR of 95.7 % and 78.8 % at
6 and 12 months and a freedom of
TLR of 96.2 %, 81 % and 60.8 % at
6, 12 and 24 months,, respectively.
Currently, Zilver PTX is the only
commercially available DES for the
treatment of femoropoliteal lesions.
As for DEB, unequal stent designs
and properties of DES such as drug
type, drug dose and drug delivery
profi le all might impact the effective-
ness of DES for treatment of reste-
nosis. So far, no randomized control
trial evaluating the head-to-head ef-
ficacy of a Paclitaxel-based DES vs.
bare metal stents in femoropopliteal
lesions has been performed. The on-
going BATTLE Trial (Clinicaltrials.
gov identifier: NCT02004951) will
also address this issue.
In infrapopliteal segments the ef-
fectiveness of DES has been dem-
onstrated in RCTs with superior
patency rates for DES vs. POBA
(ACHILLES-trial) [42] and for DES
vs. BMS (DESTINY, YUKON-BTK)
[43, 44]. The results of the above-
mentioned RCT are summarized in
Table III. Despite the higher patency
rates for DES in the infrapopliteal
lesions compared to POBA and BMS,
a beneficial effect regarding hard
clinical end points such as event-
free survival and amputation rates
were lacking. One possible reason
for the lack of such an effect might
have been the low number of patients
included in those trials, thereby pos-
sibly lacking statistical power and
limiting subgroup analysis. Howev-
er, meta-analyses [45] and the long
term results of the YUKON trial [46]
N. M. Malyar et al.: Restenosis after EVR
demonstrated not only higher pa-
tency rates but also reduced TLR and
amputation rates as well as higher
event-free survival rates for DES vs.
POBA and BMS. It must, however,
be emphasized that the lesions in
the abovementioned trials were fo-
cal and short, not representing the
real-world scenario of BTK-PAD,
particularly in patients with diabe-
tes and renal failure, in whom the
disease pattern is typically of highly
calcified, multivessel, long and dif-
fuse nature. Based on thee currently
available data there is sufficient evi-
dence for use of DES in infrapopli-
teal short lesions. Its effectiveness in
typical more complex infrapopliteal
lesions has to be proven.
Bioabsorbable stents
Theoretically, bioabsorbable stents
(BAS) offer the unique opportunity
of scaffolding to overcome the issue
of early elastic recoil without the ad-
verse effect of neointima prolifera-
tion typically initiated by a foreign
metallic body onto the vessel wall.
Their efficacy in the peripheral arte-
rial bed has been investigated in the
GAIA trial: [47] In 30 patients with
SFA lesions a poly-L-lactic acid bio-
degradable stent (Igaki-Tamai) was
implanted. The 12 month TLR and
binary restenosis rate were 57.1 %
and 67.9 %, respectively, and there-
fore comparable to those of POBA,
but inferior to DCB and newest gen-
eration nitinol stents. In the AMS
INSIGHT trial [48] 117 patients were
randomized to POBA or BAS in in-
frapopliteal lesions. The 6 month an-
giographic patency rate of the BAS
group were lower than of the POBA
group, indicating the need for fur-
ther development in the promising
BAS technology.
Atherectomy
For artherectomy, several devices
(e.g. Jetstream, Pathway PV, Sil-
verHawk, TurboHawk, Diamond-
Vasa 2015; 44: 257 270
2015 Hans Huber Publishers, Hogrefe AG, Bern
back 360 Peripheral Orbital Ather-
ectomy System, Excimer Laser) are
available to remove plaque material
by rotational, directional, or orbital
motion or by laser debulking.
In femoropopliteal segments ather-
ectomy devices have been shown to
be effective in native vessels and in
ISR, albeit with a limited long term
patency rates and without any evi-
dence for superior outcome in terms
of clinical end points. A recently
published RCT by Dippel et. al. [49]
evaluating the safety and efficacy
of an Excimer Laser atherectomy
(ELA) device (Turbo Elite Laser,
the Spectranetics Corp., Colorado
Springs, Colorado) for treatment of
complex and long femoropopliteal
ISR (> 30 % total occlusions, mean
lesion length 19.6 12 cm in the
atherectomy and 19.3 12 cm in
the POBA alone group) compared
to POBA was prematurely stopped
because of an early success of the pri-
mary safety and efficacy end points
in favor of atherectomy + POBA. The
acute success rate was significantly
higher (93.5 % vs. 82.7 %) and TLR
rate (5.3 % vs. 16.0 %) was lower in
the ELA + POBA vs. POBA group.
Atherectomy devices seem also to be
effective in the treatment of infrap-
opliteal lesions: The CALCIUM 360
Randomized Pilot Trial [50], using
an orbital atherectomy device (Dia-
mondback 360 Peripheral Orbital
Atherectomy, Cardiovascular Sys-
tems Inc., MN, USA) including CLI-
Patients with infrapopliteal, calcified
lesions demonstrated a lower rate of
bail-out stenting and significantly
lower rate of adverse events such as
TLR and major amputation in ather-
ectomy + POBA compared to POBA
alone. The DEFINITIVE LE trial [51]
is the largest trial evaluating the ef-
ficacy and safety of a directional
atherectomy device (SilverHawk) in
the infrainguinal lesions: This study
enrolled 800 patients including
CLI (25 %) and claudicants (75 %),
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diabetics (52 %) and non-diabetics
(48 %). Procedural success rate (de-
fined as 30 % residual stenosis in
the target lesion after DA) was 89 %
and bail-out stenting rate was only
3.2 %. The 12 months PPR was 78 %
with no difference between diabetics
and non-diabetics. The major am-
putation rate in the CLI subset was
only 5 %, which is markedly lower
than in the historic CLI population
(25 %). Interestingly, the 12-months
PPR was higher in the infrapopli-
teal than in the femoropoplitela
segments, irrespective of the lesion
length. Despite the encouraging re-
sults of the DEFINITIVE LE trial,
the currently existing literature does
not provide sufficient evidence for
routine use of atherectomy, as stated
in a recent Cochrane review [52]. Fu-
ture adequate powered trials using
sophisticated atherectomy devices,
especially in combination with DEB/
DES, might define the role of ather-
ectomy for treatment and prevention
of restenosis in PAD.
Cutting balloon
CB consist of a conventional, low-
pressure balloon-catheter with
3 4 microsurgical blades attached
longitudinal or elliptical to the bal-
loon surface. Due to the high stiff-
ness of the devices, cutting balloons
are only available in short lengths
(10 20 mm). The design of CB
theoretically offers a more effective
dilatation of the stenotic segment
due to low balloon slippage and a
successful dilatation at controlled
and low-pressure inflation with
less recoil. Further, it should result
into a reduced rate of restenosis by
less trauma and therefore dimin-
ished inflammatory response to
the stimulus set by the angioplasty.
However, in an RCT evaluating
the efficacy of CB for treatment of
de-novo femoropoliteal short seg-
ments ( 5 cm) CB was not superior
to POBA regarding the acute success
N. M. Malyar et al.: Restenosis after EVR
rates and the clinical improvement
(ABI, walking distance) at 6 months
follow-up [53]. Moreover, the reste-
nosis rate was even higher in the
CB group compared to POBA (62 %
vs. 32 %, P = 0.048). For treatment
of ISR Dick et. al. [54] evaluated
the efficacy of a CB in 17 patients
compared to 22 patients undergo-
ing POBA. The rates of binary re-
stenosis were indifferent after 1, 3
and 6 months with similar need for
re-intervention at 6 months (41 %
for CB vs. 37 % for POBA); thereby
CB failed its primary efficacy end
point in ISR lesions. Likewise, the
clinical surrogates such as ABI
and walking distance did not dif-
fer between POBA and CB. Stud-
ies combining cutting balloon with
adjunctive techniques such as DCB
are lacking but might offer an addi-
tional option/strategy for restenosis
prevention and treatment.
Stentgrafts
Covered stents or stent grafts are
commonly used for treatment of
endovascular complications such as
vessel perforation, aneurysms and
pseudoaneurysms. Such devices can
also be used for treatment of diff use
atherosclerotic long lesions, since
they theoretically offer the advan-
tage of reducing the rate of ISR by
limiting the neointimal in-growth
within the stented region. However,
the disadvantages of covered stents
grafts are: thrombosis, covering of
side branches and collaterals thereby
possibly posing patients at higher
risk for acute or worse ischemia than
at initial presentation.
In the aortoiliac segments the
iCAST, an ePTFE-covered, balloon-
expandable, stainless steel stent
(Atrium Medical, Hudson, New
Hampshire) showed its superiority
compared to BMS in a case serie [55].
This observation was confirmed in
a randomized multicenter trial [56]
comparing covered vs. BMS stent-
Review 263
ing for treatment of TASC C and D
aortoiliac lesions.
The fi rst generation covered stent
grafts without a bioactive surface in
the femoropopliteal segments did
not show a benefit compared to BMS.
In the VIBRANT trial, a multicenter,
randomized trial, an early version of
the covered stent graft (non-heparin
bonded Viabahn) was compared to
BMS for the treatment of femoropop-
liteal long lesions. After 12 months,
there was no difference in terms of
patency rates between covered stents
and BMS (53 % vs. 58 %). The results
regarding primary and secondary
patency were still indifferent after
3 years [57]. In the subsequent VI-
PER trial [58], a single arm, multi-
center registry, the efficacy of a newer
generation Viabahn endoprosthesis
(heparin-bonded, bioactive surface)
was evaluated. The 12-months PPR
of 73 % was encouraging, suggesting
a beneficial impact of the bioactive
surface on long term patency.
Stent grafts perform particularly in
long lesions (> 20 cm) significantly
better than BMS as recently shown
in a single arm, multicenter trial
[59]: Implantation of the Viabahn
endoprosthesis in very complex
femoropopliteal lesions (> 20 cm of
length and > 90 % total occlusion)
demonstrated a 12-months primary
and secondary patency rates of 67 %
and 96.9 %, respectively.
Radiation
Intravascular brachytherapy (IVBT)
is the application of radiation di-
rectly to the site of vessel narrowing
aimed to inhibit the inflammatory
and proliferative resulting in reste-
nosis following EVR. Proof of con-
cept and efficacy studies showed uni-
formly a reduced stenosis rate and
lower TLR rate after use of IVBT for
treatment of PAD in femoropopliteal
lesions (P < 0.05) [60]. However, all
studies using IVBT for treatment of
restenosis either did not report or

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did not improve any hard clinical
endpoints such as limb amputation
or all-cause mortality.
A recently conducted Cochrane Da-
tabase systematic review evaluated
the efficacy of IVBT for the treat-
ment of PAD [61]. The authors found
out that the cumulative patency was
significantly improved after IVBT
compared to POBA + stenting up
to 24 months, while the need for
re-intervention was only reduced
at 6 months, but not after 12 and
24 months. Studies reporting all
secondary end points and mea-
sures such as Quality of life, com-
plications, limb loss, cardiovascular
deaths, and death from all causes,
pain free walking distance and max-
imum walking distance on a tread-
mill were similar for the two arms of
the trials with no statistically signifi-
cant difference found between the
treatment groups. Data comparing
Figure 5: Target lesion revascularization (TLR, given in %) in relation to le-
sion length (cm) in randomized control trials of femoropopliteal stenting.
The data demonstrate a positive correlation of the stented lesion length
with the subsequent TLR at follow-up.
N. M. Malyar et al.: Restenosis after EVR
drug eluting technology (DCB, DES)
with IVBT are lacking.
In conclusion, IVBT is effective
in reducing the rate of restenosis,
however, data indicating its role in
preventing hard clinical end points
are lacking. Apart from this issue,
the application of IVBT is associated
with extensive personal and logistic
resources, thereby limiting its wide-
spread use.
Restenosis rates depending
on anatomical locations
From an anatomical point of view,
PAD of the lower extremities is di-
vided into aortoiliac, femoropoliteal
and infrapopliteal/BTK lesions. The
long term outcome of EVR is af-
fected not only by the technique of
endovascular intervention but has
also been shown to depend on the
Vasa 2015; 44: 257 270
2015 Hans Huber Publishers, Hogrefe AG, Bern
anatomical location and distribution
of the disease.
Aortoiliac lesions
Aortoiliac arterial occlusive disease
affects the larger elastic vessels above
the inguinal ligament. Conventional
balloon angioplasty, with or without
the use of self- (SES) or balloon-ex-
pandable stents (BES), has been com-
mon practice since many years with
excellent acute and long term results
similar to data obtained from sur-
gical bypass-interventions. In fact,
restenosis and re-occlusion rates in
the aortoiliac segments are at a very
low and acceptable level. Currently,
almost all aortoiliac lesions (TASC
A-D) are recommended to be treated
by endovascular approach [28], pref-
erentially by means of primary stent-
ing, although the evidence for this
approach is sparse. The only ran-
domized trial comparing primary
with provisional stent implantation
in the case of a persistent pressure
gradient after angioplasty alone did
not demonstrate any benefit of pri-
mary stenting [62].
In a contemporary, retrospective
analysis by Aihara et. al. [63] the
1- and 5-year PPR after stenting of
the aortoiliac bifurcation (n = 190)
were 87 % and 73 %, respectively. The
overall complication rate was 6.3 %,
SF, reocclusion and TLR rates were
1.1 %, 2.1 % and 11.6 %, respectively.
Another retrospective study evalu-
ating long term outcome after iliac
stenting showed a 10 years primary
and secondary patency of 68 % and
86 %, respectively [64]. Uniformly,
endovascular treatment of aortoiliac
TASC type A and B lesions result in
better long term outcome than TASC
C and D lesions. In the modern era
of EVR, new generation stents have
been shown excellent patency rates
of 98.3 % and 96.6 % at 1-year in the
MISAGO ILIAC study [6] (including
only TASC A and B lesions) as well
as with PPR > 90% as shown in the
 Vasa 2015; 44: 257 270 N. M. Malyar et al.: Restenosis after EVR
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Table I: Randomized control trials comparing the efcacy and outcome of DCB vs. POBA in SFA lesions

Trial Number of RR @ 6 mo LLL @ 6 mo TLR @ 6 mo TLR @ 12 mo

patients (%) (mm) (%) (%)
FEMPAC Werk et al., 2008
POBA 42 47 0.8 33 50
DCB 45 19* 0.3* 7* 13
THUNDER Tepe et al., 2008
POBA 54 44 1.7 37 48
DCB 48 17 0.4* 4 10
PACIFIER Werk et. al. 2012
POBA 47 31 0.6 22 28
DCB 44 10 0.1* 7.3 7
DEBATE SFA Liistro et. al. 2013
POBA (+ stent) 51 47.3* 1.7* n.a. 33.3
DCB (+ stent) 53 17 (12 mo) 0.9* (12 mo) n.a. 17
LEVANT I Scheinert et. al. 2014
POBA 36 51 1.1 21 33
DCB 39 28 0.5* 6 22
DEBELLUM Fanelli et. al. 2014
POBA 25 n.a. 1.8 24 35.3
DCB 25 n.a. 0.6 (12 mo) 6 12.2
Data are presented as absolute numbers or as percentage as indicated.
POBA, plain old balloon angioplasty; DCB, drug coated balloon; RR, restenosis rate; LLL, late lumen loss; TLR, target lesion
revascularization.

BRAVISSIMO trial [65] (including
type C and D lesions).
Femoropopliteal lesions
The superficial femoral artery (SFA)
and popliteal artery (PA) are dynam-
ic and active arteries characterized
by a complex anatomic geometry
and flow pattern, exposed to high
biomechanical stress. Particularly
the PA is subject to intensive forces
such as flexion, extension, torsion
and compression, mainly in proxim-
ity to joints (Fig. 3) which increases
the risk of stent fracture, misalign-
ment and subsequent restenosis.
Another problem is the often highly
fibrocalcific and longsome plaques
in the femoropopliteal segments,
leading to early recoil and flow lim-
iting dissections. Th is issue could
be addressed by stent implantation,
which has been shown to result in fa-
vorable short and midterm outcome
[66] compared to POBA. A recently
published report of the health tech-
nology assessment evaluating the
different technologies in the treat-
ment of femoropopliteal lesions as-
serted good evidence of a significant
benefit to reducing restenosis rates
for SES, stent-graft, EVBT and DCB
compared with POBA and for DES
compared with BMS. Other tech-
nologies such as balloon-expandable
stents, cutting balloons, cryoplasty,
external beam radiation therapy,
atherectomy and laser angioplasty
did not show any significant differ-
ences to POBA [67] .
The fi rst generation stents (e.g.
Palmaz stent, Wallstent) did not
have the properties of the newest
generation stents and were there-
fore more vulnerable to the above-
mentioned biomechanical forces.
Thus, it is not surprising that the
ISR and re-occlusion rates of the
fi rst generation stents were much
higher than observed in recent era
of self- expandable, flexible nitinol
stents with higher radial forces. The
TLR rates at 12 months following
femoropopliteal stenting in relation
to the average lesion length in se-
lected trials are illustrated in Figure
5. The 12 months clinically driven
TLR ranged between 10 % (MISAGO
2 [68], with a mean lesion length 6
cm) and 32 % (ProtgEverflex [69],
mean lesion length 24 cm). The su-
periority of self-expandable stents
(SES) compared to PTA was demon-
strated in ABSOLUTE trial [66]: The
1-year restenosis rates as obtained
per duplex-ultrasound were 37 % for
stenting and 63 % for PTA, further
maintaining this advantage over the
follow up of 2 years (46 % and 69 %).
However, the FAST trial-including
shorter lesions (mean length 45 mm)
failed to demonstrate the superiority
of stenting over PTA (1 year binary
restenosis rates of 32 % for stenting
and 39 % for PTA). The RESILIENT
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Table II: Randomized control trials comparing the efcacy of DCB with POBA at 12 months follow-up in infrapopli-
teal lesions
Trial Number of Lesion length PPR LLL RR TLR Maj. amputation
patients (cm) (%) (mm) (%) (%) (%)
IN.PACT DEEP
Zeller et. al. 2014
POBA 91 12.9 9.5 n.a. 0.6 0.8 35.5 13.1 3.6
DCB 165 10.2 9.1* n.a. 0.6 0.8 41 9.2 8.8
DEBATE-BTK
Liistro et. al. 2013
POBA 67 13.1 7.9 n.a. n.a. 74.3 41 1.5
DCB 65 12.9 8.3 n.a. n.a. 27* 17.5* 0
* P < 0.05
Randomized control trials comparing the efficacy regarding restenosis and outcome of DCB vs. POBA at 12 months follow-up.
DCB, drug-coated balloon, POBA, plain old balloon angioplasty; PPR, primary patency rate; LLL, late lumen loss; RE, restenosis rate, TLR,
target lesion revascularization;

trial [70], which included lesions of
moderate length (71 44 mm in the
stenting arm and 64 41 mm in the
PTA arm) demonstrated a signifi-
cant reduction of TLR for the self-
expandable Nitinol Lifestent and
significantly lower restenosis rates
at 1-year (12.7 % stent vs. 54.8 %
PTA, P < 0.001) and 3-years follow-
up (24.5 % vs. 58.2 %, P < 0.001). In
summary, the acute and midterm
patency in the femoropopliteal seg-
ment has substantially improved
with the use of newest generation
stents resulting in satisfying long
term outcome.
The concept of drug-coated balloon
(DCB) in the treatment of femo-
ropopliteal lesions has meanwhile
been extensively investigated with
clear and effective results compared
to POBA. An overview of the pub-
lished RCT comparing the efficacy
and outcome of DCB vs. POBA in
femoropopliteal lesions is given
in Table I. The superiority of DCB
(Admiral In.Pact) over POBA in
combination with subsequent stent-
ing was proved in the prospective,
single center DEBATE SFA trial [71]
in 104 patients (110 lesions) with
Rutherford III-V PAD. Restenosis
rate of DCB + stenting was 17 % at
12-months follow-up and therefore
significantly reduced compared
to POBA (47.3 % POBA+stenting;
P < 0.01; TLR: 17 % DCB+stenting
vs. 32.7 % POBA+stenting; P = 0.05).
The most recent prospective, mul-
ticentre, single-blinded, random-
ized trial evaluating the efficacy of
a DCB compared to POBA in 331
symptomatic PAD patients with
femoropoliteal lesions [36] showed

Table III: Randomized control trials comparing the efcacy of DES with BMS or POBA at 12 months follow-up in
infrapopliteal lesions

Trial Number of Lesion length PPR (%) LLL (mm) RR (%) TLR (%)
patients (cm)
ACHILLES Scheinert et al. (2012)
POBA 101 2.8 2.2 58.1 0.4 41.9 16.5
SES 99 2.7 2.1 77.6* 0.5 22.4* 10
DESTINY Bosier et al. (2012)
BMS 66 1.9 1.0 54 1.4 47 34
EES 74 1.6 1.0 85* 0.8* 21* 9*
YUKON-BTK Rastan et al. (2011)
BMS 82 3.1 9 55.6 n.a. 44.4 13
SES 79 3.0 8 80.6* n.a. 19.4* 13.8
* P <0.05
BMS, bare metal stent, DES, drug-eluting stent, EES, everolimus-eluting stent; LLL, late lumen loss; POBA, plain old balloon angioplasty;
PPR, primary patency rate; SES, sirolimus-eluting stent; TLR, target lesion revascularization
 Vasa 2015; 44: 257 270
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a clear benefit for DCB vs. POBA in
terms of 12-month patency (82.2 %
vs. 52.4 %, P < 0.01) and of clinically
driven TLR rate (2.45 % vs. 20.6 %,
P < 0.01). Th is study confirmed the
findings of previous RCTs, i.e: In the
femoropopliteal segments, DCB are
very effective regarding binary re-
stenosis and clinically driven TLR
rates, even in long and complex
TASC II C and D lesions [72].
Infrapopliteal lesions
Infrapopliteal arterial occlusive dis-
ease is frequently present in diabetic
patients, particularly at the stage of
CLI with a high rate of restenosis
as the major drawback of EVR [73].
Despite consensus about the need
for urgent revascularization in the
setting of CLI, the optimal treatment
strategy remains a matter of debate.
Current opinion favors EVR due to
the lower risk for peri-interventional
complications in this high-risk sub-
set of PAD patients.
So far there are 2 RCT evaluating the
safety and efficacy of DCB in BTK
lesions (Tab. II): The DEBATE-BTK
trial [34], a randomized, open-label,
single-center study tested the effi-
cacy of a DCB vs. POBA in 132 ex-
clusively diabetic and CLI patients
(Rutherford class 4 or higher). Mean
length of the treated segments was
129 83 mm in the DCB group com-
pared to 131 79 mm in the PTA
group (P = n.s.). The study showed
positive 12 months results in terms
of binary restenosis (27 % vs. 74 %,
P < 0.01), TLR (18 % vs. 43 %, P < 0.01)
and target vessel occlusion (12 % vs.
55 %, P < 0.01).
The results of the In.PACT DEEP tri-
al [35], however, were disillusioning
showing no significant difference be-
tween DCB and POBA regarding the
coprimary end points LLL (0.6 mm
vs. 0.6 mm) and clinically driven
TLR (9.2 % vs. 13.1 %) at 12 months
follow-up. Moreover, there was a
trend towards increased rate of ma-
N. M. Malyar et al.: Restenosis after EVR
jor amputation in the DCB group
(8.8 % vs. 3.6 %, P = 0.08).
Despite good acute success rates the
short and midterm patency rates
are extraordinary poor. The 1-year
restenosis rates after POBA of long
lesions in BTK arteries are as high
as 70 % [7]. Nitinol SE Stent implan-
tation in the infrapopliteal region
did not perform better by showing
a 12-month binary restenosis rate
of up to 68.5 % [74]. In a system-
atic review and meta-analysis Yang
et. al. [75] investigated the outcome
of POBA vs. primary stenting in the
infrapopliteal lesions: The 1-year
PPR and TVR-free rate did not differ
between POBA and BMS (58 % and
73 % for POBA vs. 61 % and 74 % for
BMS, respectively). However, DES
implantation was associated with
reduced restenosis and revascular-
ization rates as illustrated in Table
III. Although these data may hint
to a promising opportunity by the
use of DES, the lesions included in
the RCTs summarized in Table III
do not represent the real-world BTK
lesions, which are usually extensive,
consisting of multiple stenotic and
occluded segments and therefore
limiting the applicability of DES.
Although the generally low- to mod-
erate level of evidence makes it dif-
ficult to give firm recommendations,
the available data indicates that PTA
with optional bailout stenting, pref-
erably with DES, should remain the
preferred strategy in treating CLI
patients with BTK arterial lesions.
Conclusions
Progress in the design and techniques
of dedicated devices alongside with
increasing experience in sophisticat-
ed endovascular procedures paved
the way for the ongoing shift from
surgical to the less invasive endovas-
cular approach for revascularization
in peripheral arterial disease. Regard-
Review 267
ing restenosis following EVR there is
a downward slope from proximal to
the distal lesions of the lower extremi-
ties: While EVR in the aortoiliac seg-
ments results in excellent acute and
acceptable long term patency, EVR in
the femoropopliteal, and particularly
in the infrapopliteal segments, is still
hampered by high rates of restenosis
which is the major drawback of this
technique and still an unmet chal-
lenge. Antiproliferative drug eluting
devices have been shown to reduce
the rate of restenosis in the femoro-
popliteal segments; their beneficiary
effect for treatment of lesions below
the knee, however, has not been
demonstrated yet. Basic and clinical
studies indicate a multifactorial gen-
esis of restenosis involving patients`
site, localization and procedure-re-
lated factors affecting the incidence
of restenosis. Therefore, dedicated
physiological and clinical studies are
needed to thoroughly understand the
pathophysiology of restenosis and to
explore its determinants eventually
serving as target for therapeutic in-
tervention to overcome the challenge
of restenosis.
Conflicts of interest
There are no conflicts of interest
existing.
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Correspondence address
Dr. Nasser Malyar, MD
Division of Vascular Medicine
Department of Cardiovascular
Medicine
University Hospital Mnster
Albert-Schweitzer-Campus 1,
Gebude A1
48149 Mnster
Germany
nasser.malyar@ukmuenster.de
Submitted: 17.11.2014
Accepted after revision: 30.12.2014
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