IN STENT RESTENOSIS

IN-STENT
RESTENOSIS
IN DES ERA
PRESENTOR : DR. PINKESH PARMAR
MODERATOR : DR. HASIT JOSHI SIR
DR. POOJA VYAS MAM
DR. JIT SIR
DR. JAYESH SIR

CONTENTS
Introduction
Definition
Incidence
Classification
Predictors of ISR
Etiopathogenesis
Presentation
Assessment
Treatment
Current guidelines
Future directions
Conclusions

INTRODUCTION
Percutaneous coronary intervention (PCI) with stenting is
currently the most widely performed procedure for the treatment
of symptomatic coronary disease.
In large trials, drug-eluting stents (DES) have led to a significant
reduction in in-stent restenosis (ISR) rates, one of the major
limitations of bare-metal stents (BMS).
Due to these favorable findings, DES was rapidly and widely
adopted enabling more complex coronary interventions.
Nevertheless, ISR remains a serious concern as late stent
complications.

DEFINITION
Restenosis is a pathologic response to injury that leads
to narrowing of the vessel segment as a result of
negative vascular remodeling and neointimal
proliferation of vascular smooth muscle cells.
Angiographically IRS is a binary event defined as
recurrent diameter stenosis at the stent segment more
than 50% of the vessel diameter as determined by
coronary angiography
The angiographic definition remains the main definition
since it allows determination of ISR severity and
morphological pattern.

CLINICAL DEFINITION
oPresence of greater than 50% diameter in-stent stenosis
and one of the following:
•Clinical symptoms of recurrent angina.
•Objective signs of ischemia (ECG changes).
•Positive coronary hemodynamic assessment with
fractional flow reserve (FFR) less than 0.80.
•Intravascular ultrasonography (IVUS) minimum
crosssectional area less than 4 mm2 (6 mm2 for LM).
oor restenosis with ≥ 70% reduction in lumen diameter
even in the absence of clinical symptoms or signs.

DEFINITIONS
Late loss (LL) is a continuous angiographic measure of
lumen deterioration. LL is conventionally calculated by
subtracting the MLD value at follow-up (FU) from
postprocedural MLD.
Target-lesion revascularization (TLR), defined as any
repeat percutaneous intervention of the treated coronary
segment or bypass surgery of the target vessel
Target-vessel revascularization (TVR) expands the
definition of TLR to include repeat percutaneous
intervention of the target vessel irrespective of the
location of the stenosis within the treated segment.

INCIDENCE
In general, rates of ISR range from 3% to 20% with drug-
eluting stents and 16% and 44% with BMS.
This occurs mostly between 3 to 20 mo after stent
placement
Beyond 1 year, rate of BMS restenosis is negligible and
most stenting events are related to disease progression
in vessel segments other than the stented lesion.
Restenosis rate of DES increased in the recent years due
to expanded use to include high-risk patients with
complex coronary lesions.

CLASSIFICATION
This classification system predicts the need for repeat
revascularization after intervention (19%, 35%, 50%, and
98%, respectively)
This classification schema, based on prognostic
predictors of repeat revascularization for BMSs, is less
relevant to DESs.
These historical criteria provide no insight into the
mechanism of stent failure and do not dictate applicable
treatment.

PREDICTORS OF ISR
• Patient characteristics.
• Lesion characteristics.
• Procedural characteristics.

PATIENT CHARACTERISTICS
Age & female gender
Diabetes mellitus
Chronic kidney disease (including hemodialysis)
Acute coronary syndrome
Non smoking status
Metal allergy
Local hypersensitivity reactions with immunologic and
inflammatory response to the drug or the polymer
Resistance to antiproliferative drugs.
Mutations of the gene polymorphism that encode mTOR -
resistance to sirolimus (rapamycin)

LESION CHARACTERISTICS
Lesion length
Smaller diameter
Ostial/bifurcation lesion
Initial plaque burden and residual plaque after
implantation
In contrast with BMS, DES tends to have a more focal
pattern of ISR, (except in diabetics), where the ISR tends
to be more confined to the stent edges.
Focal ISR (Mehran pattern I) has been associated with a
lower rate of ISR recurrence than nonfocal ISR.

PROCEDURAL
CHARACTERISTICS
Stent under/oversizing
Incomplete lesion coverage
Stent under expansion, and malapposition
Barotrauma outside stented segment
Stent gap
Stent fracture

PROCEDURAL
CHARACTERISTICS
Mechanical properties of stents that may lead to recoil
because of :
•Loss of radial force
•Stent fractures,
•and altering increase in shear stress are all associated
with higher rates of ISR.
For every 10 mm of excess stent length beyond lesion
has been independently associated with increased post-
procedural percent diameter stenosis by 4% and
increased TLR at 9 mo.

PROCEDURAL
CHARACTERISTICS
Stent fracture, on the other hand, can trigger focal ISR or
thrombosis which can result in a reduction in drug
delivery at the breakage point of the stent.
Stent fracture occurs more frequently in the RCA,
overlapping stents, longer stents, SESs (because of the
ridged closed cell structure), and excessively tortuous
angulated vessels

PROCEDURAL
CHARACTERISTICS
Malapposition , also known as incomplete stent
apposition (ISA), is defined as :
The absence of contact between stent struts and the
vessel wall not overlying a side branch.
Malapposition seems to be related to procedural
technique due to under-sizing the stent, use of low
deployment pressures, and severely calcified lesions,
which do not allow for homogenous stent expansion.
Oversized stents can also lead to extensive trauma to the
vessel wall and increased proliferative reaction.

PROCEDURAL
CHARACTERISTICS
Geographic miss occurs when the stent does not fully
cover the injured or diseased segment of the artery (axial
miss) or the ratio of balloon to artery size is less than 0.9
or greater than 1.3 (longitudinal miss).
Geographic miss is associated with increased risk of TLR
and MI at 1 yr.
DESs decrease neointimal growth. As a result, geographic
miss or strut fracture may be larger factors of ISR in DESs
compared with BMSs.

ETIOPATHOGENESIS
Neoatherosclerosis is associated with a higher
proportion of in-stent atherosclerotic plaque, which
could explain unstable symptoms and myocardial
infarction presentation of patients with ISR years after
PCI.
The incidence of neoatherosclerosis was significantly
greater in DES compared with BMS (31% vs 16).
Younger age, longer implant durations, SES usage, PES
usage and underlying unstable plaques, are independent
risk factors for neoatherosclerosis.

CLINICAL PRESENTATION
Due to the gradual and slow progression of ISR
compared with stent thrombosis, majority of ISR
presents as progressive recurrent angina.
The time for symptoms to develop due to DES-ISR is 3 to
12 mo after stent placement.
BMS stent on the other hand develop ISR symptoms
sooner with reported average period of 6 mo post-PCI.
BMS-ISR presented as MI in 3.5%-20% of patients.
DES-ISR is similar to that of BMS with approximately
16%-66% of patients presenting with unstable angina
and 1%-20% with MI.

ANATOMICAL ASSESSMENT
Routine angiographic surveillance is not recommended.
Noninvasive assessment of recurrence of restenosis
(symptomatic status and ischemia tests) seems an
appropriate approach.
This recommendation is based on a series of previous
observations:
(1) routine angiographic follow-up may have increased
morbidity and mortality, albeit such an increase would be
slight;
(2) asymptomatic patients with nonfunctional
angiographic restenosis experience a benign course; and
(3) the so-called occulostenotic reflex leads to a higher
rate of repeat revascularization with no clear clinical

ANATOMICAL ASSESSMENT
Clinical and research assessment of restenosis has also
been markedly improved by both IVUS and OCT, which
enable high-fidelity measurement of restenotic area,
neointimal volume, and MLD in addition to enabling
three-dimensional rendering of restenotic segments.

IVUS
The stent and procedures characteristics can be readily
assessed as contributing mechanism of ISR using IVUS.
IVUS delineate external elastic lamina behind the stent
struts very well, which provides valuable insights on
vessel sizing for optimization of stent expansion.
IVUS does help detect the presence of neointimal
hyperplasia obstructing the stent, stent underexpansion,
stent fracture, or edge restenosis. In addition, it can
provide insights into optimal vessel sizing for choosing
the appropriate stent size .

IVUS
IVUS does help detect the presence of neointimal
hyperplasia obstructing the stent, stent
underexpansion, stent fracture, or edge restenosis.
In addition, it can provide insights into optimal vessel
sizing for choosing the appropriate stent size .
However, IVUS has limited axial resolution (150 μm),
which makes neointimal interface hard to define.

OCT
OCT provides better axial resolution (15 μm), allowing
better resolution of the vessel lumen, neointimal tissue,
and stent struts distribution.
The morphology of ISR can be identified using OCT
which could show macrophage infiltration, necrotic core,
in-stent calcification and neoatherosclerotic plaque
rupture.
The weakness of the OCT resides in the poor tissue
penetration, which cause poor visualization of the
residual plaque that is beyond the stent.

HEMODYNAMIC ASSESSMENT
FFR has been validated for clinical decision making in
patients with ISR.
The clinical outcome of patients with ISR with deferred
interventions based on a FFR > 0.75 is excellent.
This diagnostic strategy is useful in controversial cases
with angiographically moderate or inconclusive ISR.

TREATMENT
Medical
Balloon angioplasty
Cutting/scoring balloon
Vascular brachytherapy
Debulking techniques
Drug Eluting Stents
Bioresorbable Vascular Scaffolds
Drug Coated Balloons

Plain Balloon PTCA
Cutting/Scoring Balloon
Drug-Coated Balloon Drug-Eluting Stent
Atherectomy
Vascular Brachytherapy
ISR: DEVICE
SELECTION

MEDICAL TREATMENT
There is little evidence to support medical treatments for
ISR.
Several attempts to manage ISR using medical therapy
failed to significantly reduce the recurrence rate and
were associated with adverse effects.
Among these were abciximab, oral sirolimus, oral
corticosteroids, and local delivery of paclitaxel, with
limited efficacy as a primary treatment approach.

BALLOON ANGIOPLASTY
POBA is one of the earliest treatments that has been used
in patients with ISR.
The immediate angiographic improvement following
POBA results from both axial and longitudinal tissue
extrusion as well as further stent expansion.
Results are particularly favorable in patients with a focal
pattern of ISR and when stent/native artery size
mismatch has been identified with intravascular imaging.

BALLOON ANGIOPLASTY
One of the limitation of POBA is that sub-acute tissue re-
intrusion back to the lumen tends to occur within
minutes of the last balloon inflation.
This explains the “early lumen loss” phenomenon
detected in POBA studies in ISR, a finding also associated
with subsequent recurrent restenosis.

BALLOON ANGIOPLASTY
Additionally, edge-related complications should be
carefully avoided during aggressive balloon dilations.
Balloon slippage outside the stent (“water-melon
seeding” phenomenon), which occurs more often in
severe and diffuse narrowing when balloons are
oversized, can lead to edge dissections and suboptimal
outcomes.
Progressive balloon upsizing as well as the use of short
low profile balloons can help avoid this phenomenon and
edge-related complications.

CUTTING AND SCORING
BALLOONS
Cutting balloon device deeply incises neointimal tissue
and may favor its subsequent extrusion.
The lateral blades of the device anchor the balloon within
the target lesion, preventing balloon slippage-related
complications.
Initial observational data suggested that cutting balloons
may have superior efficacy compared to POBA, a finding
which was associated with a lower rate of target lesion
revascularization (TLR) (12.5% vs. 40%) at follow-up.
However, in the largest randomized trial (Restenosis
Cutting Balloon Evaluation Trial [RESCUT]), cutting
balloon angioplasty comparing POBA failed to show an
improvement in angiographic restenosis or in the rate of
clinical events at late follow-up.

CUTTING AND SCORING
BALLOONS
Scoring balloons are based on the same principle as
cutting balloons but are especially attractive in patients
with ISR due to their superior flexibility and deliverability.
The Intracoronary Stenting and Angiographic Results:
Optimizing Treatment of Drug-Eluting Stent In-Stent
Restenosis 4 (ISAR-DESIRE IV trial) assessed the use of
scoring balloons prior to DCB treatment of DES-ISR.)
The results showed superior angiographic outcomes at 6
to 8 months in the scoring balloon arm, but failed to
show any significant difference in clinical outcomes.

VASCULAR BRACHYTHERAPY
Brachytherapy inhibits neointimal formation within the
stent, but not the stent edges, by delivering radiation to
the areas of ISR.
Brachytherapy effectively suppressed the proliferative
response and significantly reduced clinical and
angiographic restenosis rates.
Both beta and gamma radiation sources could achieve
major reductions in the angiographic restenosis rates.
Gamma emitters had profound tissue penetration,
whereas beta emitters had less tissue penetration.

Brachytherapy was one of the most promising treatment
options for patients with neointimal hyperplasia related
to BMS-ISR.
Randomized clinical trials in patients with ISR
demonstrated the superiority of brachytherapy
compared with conventional BA or atheroablative
techniques.
However, the advent of DES signaled the end of
brachytherapy.

The 2 large randomized clinical trials which compared
the efficacy of brachytherapy versus DES in patients with
BMS-ISR were Sirolimus-Eluting Stents versus Vascular
Brachytherapy for In-Stent Restenosis Within Bare-Metal
Stents (SISR) and Paclitaxel-Eluting Stents versus
Vascular Brachytherapy for In-Stent Restenosis Within
Bare-Metal Stents (TAXUS V ISR).
Both showed that DES were superior in decreasing
restenosis rates and the need for revascularization as
compared to brachytherapy at long-term follow-up.

DEBULKING TECHNIQUES
Debulking techniques such as directional/rotational
atherectomy and excimer laser are a novel treatment for
ISR through their physical removal of neointimal tissue or
neoatherosclerotic plaque.
Early observational studies suggested that the use of
laser or rotational atherectomy, followed by a POBA
post-dilation, was superior to conventional POBA alone
in ISR.
Directional atherectomy was also assessed in early
studies, but this was soon abandoned because it was not
well suited for small or distal vessels, which are common
locations for ISR.

The value of rotational atherectomy in patients with
BMS-ISR was evaluated in 2 randomized trials.
In Randomized Trial of Rotational Atherectomy Versus
Balloon Angioplasty for Diffuse In-Stent Restenosis
(ROSTER), rotational atherectomy reduced the amount of
residual tissue within the stent and the rate of TLR at
follow-up, compared with POBA alone.
On the other hand, in the Angioplasty Versus Rotational
Atherectomy for Treatment of Diffuse In-Stent
Restenosis Trial (ARTIST), which compared rotational
atherectomy with POBA alone, lower restenosis rates, an
improved safety profile and superior clinical outcomes
were seen in the POBA group.

EXCIMER LASER
ANGIOPLASTY
Excimer laser angioplasty (ELA) produces
monochromatic light energy, which generates heat and
shock waves that disrupt plaque.
Tissue ablation mechanisms:
 Vaporization of tissue (Photothermal effect)
 Ejection of debris (Photoacoustic effect)
 Direct breakdown of molecules (Photochemical dissociation)
Infrequently used (high cost, lack of benefit over PCI
alone)
The excimer laser showed good results in some cases
but eventually proved to have poorer ablation capability
compared with rotational atherectomy.

Therefore, although debulking techniques are not
considered to be a routine treatment of ISR, they can be
considered as a pre-treatment option for undilatable ISR
lesions, especially those as a result of severely under-
expanded stents or calcified intrastent
neoatherosclerosis.

REPEAT STENTING WITH BMS
Early studies suggested that the problem of early tissue loss,
which was seen with POBA, was virtually eliminated with the
use of BMS, which gave credence to the possible superiority of
stenting over POBA in the treatment of ISR.
In the Restenosis Intra-stent Balloon Angioplasty Versus
Elective Stenting (RIBS I) trial, patients with BMS-ISR, were
randomized to receive either POBA or repeat BMS
implantation, with acute angiographic results being
significantly better after BMS placement due to a larger acute
gain.
However, at 6-month follow-up, significant late lumen loss in
the BMS group resulted in the final angiographic appearance
being similar in both groups.

REPEAT STENTING WITH DES
The Intracoronary Stenting or Angioplasty for Restenosis
Reduction-Drug-Eluting Stents for In-Stent Restenosis
(ISAR-DESIRE) trial was the first randomized study
assessing the value of DES in patients with BMS-ISR.
The rate of recurrent restenosis was significantly lower
with sirolimus- (14.3%) and paclitaxel-DES (21.7%)
compared with POBA alone (44.6%). Similar results were
also shown in a subsequent meta-analysis comparing
these 2 DES for BMS-ISR.

In the Restenosis Intrastent: Balloon Angioplasty Versus
Elective Sirolimus-Eluting Stenting (RIBS II) trial, which
compared sirolimus-DES versus POBA in patients with
BMS-ISR, patients with sirolimus-DES had a significantly
lower restenosis rate (11%) and superior long-term
clinical outcomes.
In addition, IVUS imaging confirmed the dramatic
reduction of neointimal proliferation seen after the use
of sirolimus-DES.
The 4-year long-term follow-up study demonstrated a
sustained clinical benefit from DES placement without
any significant increase in major adverse cardiac events
(MACE).

Unfortunately, the treatment of DES-ISR is more
challenging, and overall, the outcomes in patients
requiring treatment for DES-ISR are worse compared with
patients with BMS-ISR.
Investigators have proposed that DES-ISR that results
from a mechanical complication (such as stent under-
sizing, edge dissection or stent fracture) can be
successfully overcome by placing another DES.
However, debate regarding whether to use a DES eluting
the same or a similar type of drug (homo-DES approach)
versus a switch to a different type of drug (hetero-DES
approach) has continued.

In Intracoronary Stenting and Angiographic Results: Drug
Eluting Stents for In-Stent Restenosis 2 (ISAR-DESIRE 2)
trial of sirolimus-DES-ISR, the hetero-DES strategy using
a paclitaxel-DES failed to reduce restenosis or target
vessel revascularization rates compared to repeat
stenting with sirolimus-DES.
The Restenosis Intra-Stent: Balloon Angioplasty vs Drug-
Eluting Stent (RIBS III) trial also compared the DES-switch
approach to same-stent implantation.
Although there was no significant difference between the
hetero-DES and homo-DES approach, the study
suggested that the use of second-generation DES was
superior to first-generation DES, and intravascular
imaging for treatment guidance had improved
angiographic and clinical outcomes.

Despite these benefits of repeat stenting with DES in the
management of DES-ISR, current data suggests that 10–
20% of these patients will go on to develop recurrent ISR.

BIORESORBABLE VASCULAR
SCAFFOLDS
The main advantages are that the device eventually
disappears from the vessel wall, avoiding the presence of
multiple stent layers, and prevents early lumen loss
associated with tissue retraction seen in balloon
angioplasty
Some small studies have established that BVS placement
in the treatment of ISR is safe and feasible.
In 65 patients with ISR treated with BVS, clinical
outcomes at 1 year revealed a TLR rate of about 12%, and
all of these patients avoided having a permanent second
layer of stent struts.
Nevertheless, since no randomized trial evaluating the
effectiveness of BVS in management of ISR has yet been
performed, the routine use of this strategy cannot be

DRUG COATED BALLOONS
The development of DCB enabled deliver of anti-
proliferative drug to the area of ISR without leaving
behind an additional layer of stent strut.
Although the value of DCB in de novo lesions remains
controversial, the use of DCB has been to proven to be
very effective in patients with both BMS-ISR and DES-ISR
For that purpose, multiple randomized studies have
been done to evaluate the efficacy and durability of DCB
compared with DES in treating BMS or DES-ISR.

COMPARISON
Siontis et al. included 27 trials with a total of 5,923
patients at 6 months to 1 year follow-up.
The primary outcome of this analysis was percent
diameter stenosis at follow-up, and the secondary
endpoint included binary restenosis, rates of TLR,
myocardial infarction or death.
All modalities included POBA alone, debulking
techniques, brachytherapy, BMS, DES, and DCB.
Repeat stenting with everolimus-DES was found to be
statistically superior to all other modalities for both the
primary outcome as well as for binary restenosis rates
and TLR.
DCB appeared to be the second most preferable
treatment but did not achieve a significant difference
over sirolimus or paclitaxel-eluting stents.

COMPARISON
Giacoppo et al. included 24 trials with a total of 4,880
patients, and the primary outcomes were TLR rates and
angiographic late lumen loss.
Both DCB and DES were superior to other treatment
modalities based on the predefined clinical outcomes.
Angiographic outcomes favored DCB or DES over all
other modalities, however late lumen loss appeared to be
slightly lower in the DCB arm compared with DES.

CURRENT GUIDELINES
Current European guidelines recommend either DESs or
DCBs with consideration for intracoronary imaging to treat
ISR.
DCBs, however, are not approved for use in coronary
arteries at present in the United States.
ACC/AHA guidelines are from 2011 and recommend that
patients who develop clinical restenosis after DES
implantation may be considered for repeat percutaneous
coronary intervention with balloon angioplasty, BMSs, or
DESs containing the same drug or an alternative
antiproliferative drug if anatomic factors are appropriate
and the patient is able to comply with and tolerate
antiplatelet therapy (Class IIb, level of evidence C).
Additionally, the guidelines suggest that intravascular
ultrasound is reasonable to determine the mechanism of
stent restenosis (Class IIa, level of evidence C).

FUTURE DIRECTIONS
The feasibility of combined rotational atherectomy with
intravascular lithotripsy for ISR with calcified
neoatherosclerosis was reported recently.
In addition, the next generation of sirolimus-based DCBs
should be tested clinically for the treatment of DES-ISR.
Further research is needed, however, to assess long-
term benefits and ideal candidates for these novel
modalities.
Finally, the best way to address DES-ISR is to prevent it.
This can be mitigated with imaging-guided DES
placement and continued improvements in stent
technology.

CONCLUSIONS
ISR remains a challenging clinical problem with DESs.
ISR remains difficult to treat, and optimizing stent
implantation at the time of stent deployment with
imaging-guided techniques is perhaps the best strategy
to minimize ISR.
Lesion stratification according to Waksman ISR
Classification can guide treatment tailored to the specific
lesion characteristics.
Because of the various pathologies associated with ISR,
there is not a universal treatment for all ISR.
Lesions with ISR should universally undergo
intracoronary imaging assessment to determine the
cause.

IN STENT RESTENOSIS

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