BMS were developed to mitigate elastic recoil and negative remodeling, but they remain prone to NIH. DES were developed to prevent NIH, and these devices (especially first-generation DES) can be accompanied by delayed reendothelialization, which has been associated with stent thrombosis. Even in the contemporary era of percutaneous coronary intervention using drug-eluting stents, ISR remains a common problem, occurring in 5% to 20% of cases, depending on several patient and lesion characteristics. The cumulative rates of DES failure have created a major clinical problem so that > 10% of all PCIs done in the United States are to treat ISR, and the number of ISR interventions appears to be increasing year over year

1. A N A L G O R I T H M I C A P P R O A C H T O D I A G N O S I S A N D T R E A T M E N T
Coronary In-Stent Restenosis (ISR)
Dr. Najeeb Ullah Sofi
LPS Institute of Cardiology

2. WHY ?
 Restenosis, the arterial wall healing response to mechanical injury, has plagued cardiologists since
the introduction of balloon angioplasty by Gruntzig.
 BMS were developed to mitigate elastic recoil and negative remodeling, but they remain prone to
NIH. DES were developed to prevent NIH, and these devices (especially first-generation DES) can be
accompanied by delayed reendothelialization, which has been associated with stent thrombosis.
 Even in the contemporary era of percutaneous coronary intervention using drug-eluting stents, ISR
remains a common problem, occurring in 5% to 20% of cases, depending on several patient and
lesion characteristics.
 The cumulative rates of DES failure have created a major clinical problem so that > 10% of all PCIs
done in the United States are to treat ISR, and the number of ISR interventions appears to be
increasing year over year .

3.  Second-generation DES have failure rates
at 1 year that average 5.7% and 8.7% in
non-diabetic and diabetic patients,
respectively.
 Worse yet, DES TLF rates do not plateau at
1 year, and all modern DES trials show a
gradual increase in MACE over time, such
that 5-year TLF rates are in the 9% to 12%
range in generally noncomplex lesions
 In real world use, modern DES fare even
less well with 5-year TLF rates that
exceed 15%

4. Normal versus Pathologic Response to Arterial Injury
 The initial consequences of balloon angioplasty
or coronary stenting are
1. de-endothelialization,
2. mechanical disruption of atherosclerotic
plaque, often with
3. dissection into the tunica media and
occasionally adventitia, and stretch of the entire
artery.
 In the majority of patients, the healing
response includes both stabilization of the
SMC structures and reendothelialization of
the artery without significant reduction in
vessel diameter.

5.  In contrast, restenosis is a pathophysiologic
response to injury, which leads to narrowing
of the vessel segment, due to:
1. Negative vascular remodeling
2. Neointimal proliferation

6. Coronary angiography and schematic model illustrating a segmental approach to
analyze and report the effects of drug-eluting stents on coronary arteries.
1. In-stent, which better describes the
antiproliferative effect of the biological
agent
2. In-lesion indicates potential paradoxical
effects of low drug concentrations at
traumatized stent edges (“edge
effect”)
3. In-segment, which is the ultimate
determinant of angiographic success from
a patient’s perspective.

7. ANGIOGRAPHIC RESTENOSIS & CLASSIFICATION
Diameter stenosis > 50%
Type I : focal <10 mm in length
 IA articulation or gap
 IB margin
 IC focal body
 ID multifocal
Type 2 : diffuse >10 mm intrastent
Type 3 : proliferative >10 mm extending
beyond stent margins
Type 4 : total occlusion: restenotic lesions with
TIMI flow grade of 0

8. Clinical Restenosis: Assessed Objectively as Requirement for Ischemia-Driven Repeat
Revascularization
1. Diameter stenosis > 50% and one of
the following:
 Positive H/O Rec angina presumably related to target
vessel
 Objective signs of ischemia at rest (ECG ) or during
exercise test (or equivalent) presumably related to
target vessel
 Abnormal results of any invasive functional diagnostic
test (FFR< .8)
 IVUS minimum CSA < 4 mm2(<6.0 mm2 for LMCA) -
correlate with abnormal FFR and need for subsequent
TLR
2. TLR with stenosis > 70% even in
absence of ischemic signs or symptoms
 Restenosis may cause no symptoms in up
to 50% of patients, even when silent
ischemia is demonstrable.
 The other end of the clinical spectrum,
restenosis may present itself in the form of
an acute coronary syndrome ACS in up to
one-third of patients, which challenges
the notion that restenosis is benign.
 Restenosis is of particular concern
following left main PCI because of the
potential risk of sudden cardiac death
associated with early “silent” restenosis.

9. BMS DES
BMS ISR
 Unstable angina -26% to 53%
 MI - 3.5% to 20%
 Reported to occur in average of 5.5 months
after stent implantation
 Shorter interval for patients presenting with
MI than those presenting with recurrent
angina
DES ISR
 Unstable angina-16% to 66%
 MI - 1% to 20%
 Mean time from PCI to ISR detection
approximately 12 months
PRESENTATION

10. Patterns of Restenosis
 After Palmaz-Schatz stent implantation, of those who experienced ISR,
1. focal restenosis occurred most frequently (42%),
2. diffuse ISR was seen in 21%,
3. proliferative ISR in 30%, and
4. total occlusion in 7%.
 Restenosis after bifurcation PCI frequently occurs focally at the ostium of the
side branch.
 The pattern of restenosis also influences the durability of repeat PCI. Mehran et
al showed that, TLR rates in the pre DES era for BMS restenosis ranged from
19.1% for focal lesions, compared to 50% for proliferative lesions, and
83.4% for total occlusions.

11.  Technique-related failures (geographic
miss, stent fracture, edge dissections) may
account for a proportion of focal ISR and are
observed at the stent edges or gaps between
stents in noncomplex cases.
 On the other hand, complex biological
factors may be more likely to contribute to
diffuse patterns of ISR, which is seen in
more challenging clinical scenarios such as
patients with bypass graft disease or diabetes
mellitus.
 The characteristics of DES restenosis may
vary depending on the device.
 For example, restenosis after sirolimus-
eluting stents (SES) were mostly
(>90%) focal and often located at the
stent edges, while diffuse intimal
proliferation or total occlusion
accounted for approximately half of the
restenosis cases after first-generation
polymer-coated paclitaxel-eluting
stents.

13.  NIH, in response to BMS, tends to
occur within the first 9 months.
 In contrast, restenosis after DES is
delayed, and neointimal tissue can
continue to accrue out to at least 5
years.
 Neoatherosclerosis has been reported to
occur earlier after DES than after BMS, but
is also highly prevalent in BMS, especially
in the setting of very late stent thrombosis
 Heterogenous appearance to the NIH
within DES, compared to a smooth
homogenous pattern typically observed
after BMS.
 Comparative studies also suggest DES
NIH is relatively hypocellular and
proteoglycan rich, compared to BMS
where there is an abundance of SMCs

14. In-Stent Restenosis Causes and Implications for Treatment

15. HYPERSENSITIVITY
BMS and first-generation DES
 Stent platform is 316L stainless steel
 Allergic reactions to nickel and molybdenum
released from 316L SS
 Potential triggering mechanisms for ISR
Novel DES
 Platform material used is cobalt chromium
 Lower nickel content than 316L stainless
steel
 DES consist of 3 components
 Stent platform, antirestenotic drug and
polymer carrying drug
 Hypersensitivity reactions can be caused by
any one
DES with biodegradable polymers and
improved metal alloys
 Expected to have fewer hypersensitivity
problems

16. Prevention of Restenosis–Drug-Eluting Stent Evolution and Redesigns
 The development of cobalt chromium and
platinum alloys for BMS and DES platforms
led to substantial reductions in strut
thickness with preserved radial strength.
 Randomized trials support the notion that
stent characteristics, particularly strut size,
affects the risk of restenosis.
 ISAR-STEREO trial showed that a thin
strut (50 μm) RX multilink design resulted in
marked reduction in binary restenosis and
TVR (12.3% vs. 21.9%) compared to the
thick strut (140 μm) BX velocity.
 Platinimum chromium alloys may
offer greater radial strength,
conformability, trackability, and
radiopacity compared to cobalt
chromium in bench testing, and
appear to be noninferior to cobalt
chromium stents in vivo.

17.  Bioresorbable stents are also under development to function as a temporary stent structure that biodegrades once the
need for redial strength and mechanical support is gone.
 The best studied device of this type—the Absorb Bioresorbable Vascular Scaffold (BVS, Abbott Laboratories, Abbott Park,
IL)—is comprised of a backbone of poly-L-lactide, which has a strut thickness of 150 um, but degrades to water and
carbon dioxide within 3 years.
 Based upon 1 year results from the ABSORB III trial,the first BVS was approved by the U.S. Food and Drug
Administration (FDA) in 2016. However, due to increased rates of adverse events between years 1 and 3, this device was
subject to a class 1 device recall by the FDA and pulled from the worldwide market in 2017.

18. Polymer and Elution Kinetics
 Early preclinical studies with DES showed
that the prevention of restenosis requires
an extended period of drug delivery.
 Thus, various polymers and elution
systems have now been developed not
only to attach the drug to the stent during
processing, sterilization, and storage, but
also to allow controlled drug delivery upon
stent implantation.
 The polymer design used in the Cypher
DES consisted of three layers. The steel
struts were coated with a primer layer of
Parylene C. Sirolimus was contained in a
middle layer of 67% polyethylene-co-vinyl
acetate (PEVA) and 33% poly(n-butyl
methacrylate) (PBMA) dissolved in the
organic solvent Tetrahydrofuran (THF).
This system leads to controlled elution of
sirolimus over 30 to 60 days

19.  The Xience V/Promus stent was designed to capitalize on the biocompatibility of fluorinated
surfaces. Several reports suggest that fluoropassive coatings offer improved long-term
biocompatibility.
 The stent is first coated with a primer layer consisting of PBMA. The polymer is a single-phase
layer of 7.8 μm consisting of an 83%/17% mixture of the semi-crystalline poly(vinylidene fluoride-
co-hexafluoropropylene) and everolimus.
 The elution of everolimus occurs over the course of 4 months, with 25% released within the first
day and an additional 50% over the first month. In a rabbit model, the Xience V stent design
resulted in improved endothelialization compared to first-generation DES

20. Clinical Outcomes with Newer Generation Drug-Eluting Stent
 Trials of newer-generation DES have shown both improved efficacy in terms of TLR and
improved safety with reduced stent thrombosis rates compared to first-generation DES designs.
 SPIRIT IV trial compared the Xience V everolimus eluting stent (X-EES) to the first-generation
paclitaxel-eluting stent (PES) in 3687 patients with stable coronary artery disease (CAD). TLF
rates at 1 year were significantly lower with X-EES (4.2% vs. 6.8%; relative risk [RR] = 0.62.
 The results held at 2 years, and EES was still associated with superior outcomes for TLF (6.9%
vs. 9.9%, P = .003) and MI (2.5% vs. 3.9%, P = .02). Stent thrombosis rates at 2 years were still
considerably lower for the newer-generation stent (0.4% vs. 1.2%, P = .008).

21.  Whereas trials of first-generation DES versus BMS convincingly demonstrated that local cell
cycle inhibition could lead to a dramatic reduction in restenosis rates, the trials of newer
generation DES versus first-generation DES establish that very late stent thrombosis risk is not a
“necessary evil” of DES.
 Newer-generation DES achieved additional reductions in restenosis while also lowering stent
thrombosis rates, which suggests that a better balance between reendothelialization and NIH
prevention was possible. In fact, contemporary DES now have very late stent thrombosis rates
similar to BMS.

22. Diagnosis of In-Stent Restenosis: Obligate Intravascular Imaging
 In treating patients with ISR, diagnosing the
cause of stent failure is critical to determining
the most appropriate treatment.
 It is essential to understand the mechanism
of stent failure because the mechanism of
failure will directly impact the therapeutic
decisions and devices needed to manage the
ISR segment .
 Angiography inadequately assesses ISR
because of limited resolution and inherent
deficiency in quantifying vessel size, stent
size, stent expansion, number of stent layers,
in-stent calcific neoatheroslcerosis, and extra-
stent calcific disease.
 In contrast to angiography, IVUS and OCT
provide detailed assessment of the native
artery and stented segment and readily
identify the precise mechanism(s) of stent
failure .
 The US and European PCI guidelines both
support the use of intravascular imaging in
the diagnosis and treatment of stent failure
 Importantly, randomized studies clearly show
that when treating denovo non-ISR stenoses,
intravascular imaging reduces target
lesion failure and ISR by 50%,

23.  This is especially important in light of recent
intravascular imaging studies that
demonstrate that
1. suboptimal stent deployment is
common—occurring in 31% to 58% of
patients
2. that suboptimal stent deployment confers
an increased risk of adverse events.
 Emerging data from several registry studies has
recently demonstrated that use of intravascular
imaging during PCI not only reduces stent
failure and TLF, but is also associated with a
reduction in cardiovascular mortality.
 In utilizing intravascular imaging to diagnose
and treat ISR, the goal is to determine the:
1. reference segment size,
2. lesion length,
3. site of ISR (in-stent vs edge),
4. nature of ISR (diffuse vs. focal),
5. predominance of neotinima vs. neoatherosclerosis,
6. number of stent layers,
7. prior stent expansion and apposition,
8. presence/absence of stent fracture, and
9. presence/absence of intra- and/or extra stent
calcium.

24.  In treating ISR, it is critical to identify the
presence of stent under expansion and
multilayer ISR with intravascular imaging.
 In a series of “recalcitrant” ISR cases
where patients with two layers of DES were
treated with a third DES layer, IVUS
demonstrated that two layer DES under
expansion was common (average
expansion, 64.5%) and severe calcification
behind the stents was seen in all cases of
under expanded multilayer DES ISR
 After reintervention in this ISR patient
series, most stents remained under
expanded (mean stent expansion, 67%).
 Emerging data suggest that in cases where
intravascular imaging identifies an arc of
calcium > 270 degrees or greater than 0.67
mm in thickness, atherectomy vessel
preparation should be considered to
optimize lesion and stent expansion.

25.  In clinical trials, OCT outperformed IVUS
for the detection of small degrees of NIH
and was more sensitive in detecting stent
malapposition, tissue protrusion, and edge
dissections.
 In addition, OCT-based single stent-strut-
level analysis provides clear assessment of
stent-strut coverage and apposition, which
are important clinical parameters that have
been linked to DES-induced delayed
arterial healing and the risk of stent
thrombosis.

26. An Algorithmic Approach to the Treatment of Coronary In-Stent Restenosis
 In the US, a relatively modest number of
treatment options are approved for ISR
lesions by the US FDA, including
1. the currently obsolete first-generation TAXUS
paclitaxel-eluting stent,
2. balloon angioplasty alone,
3. scoring-balloon angioplasty,
4. intravascular brachytherapy, and
5. excimer laser coronary atherectomy (ELCA).
 Currently, DES implantation in ISR
lesions, which holds a Class I level of
evidence A indication in the European 2018
ESC/EACTS Guidelines on myocardial
revascularization, has not been
incorporated in the AHA/ ACC/SCAI
guidelines.
 Hence, the most widely used treatment
option for ISR in the US is balloon
angioplasty, often followed by the off-
label implantation of another DES.

27.  Recurrent ISR can be a common problem
in these subjects, and adding layer upon
layer of stent struts in the restenotic lesion
is not an attractive treatment option.
Therefore, identification of the mechanism
causing restenosis using intracoronary
imaging, and optimization of the treatment
of the restenotic lesion, are of paramount
importance.

29. iLASER Algorithm
 This algorithm includes the :
1. assessment of the pattern of ISR
2. use of intravascular imaging to determine the mechanism of ISR
3. optimal lesion preparation using scoring balloons and/or ELCA,
4. repeat DES implantation if deemed necessary or DCB angioplasty if
available.

30.  An algorithmic approach to vessel
preparation and treatment that is focused
on
1. Debulking the ISR tissue to facilitate
expansion and maximize final stent area,
2. Aggressively treating stent under-expansion
if present, and
3. Treating severe inflow and outflow disease
 Multiple studies demonstrate that
suboptimal minimal stent area (MSA) is the
major predictor of stent failure, and an
IVUS optimized MSA of > 5.0 mm2 or
OCT optimized MSA of > 4.5 mm2 is
often defined as the minimum goal for
image optimized PCI.

31. 1. Identifying patients who may benefit from coronary artery bypass graft
surgery or intravascular brachytherapy
 The patients presenting with ISR may still develop it within an old BMS. The first step encompasses the
identification of clinical scenarios where patients may be better treated with non-percutaneous or non-
conventional methods such as coronary artery bypass graft surgery (CABG) or intravascular brachytherapy
(IVBT).
 For example in patients with recurrent ISR, rates of repeat revascularization have been reported to exceed
50% within two years. Furthermore, the angiographic pattern of ISR according to the classification holds
important prognostic implications

32.  In a study patients were predominantly treated with repeat BMS implantation, often after rotational
atherectomy (RA) or excimer laser coronary atherectomy (ELCA);
 1 year target lesion revascularization rates were
1. 19.1% for focal ISR (type 1),
2. 34.5% for proliferative ISR (type 2),
3. 50.0% for proliferative ISR (type 3), and
4. 83.4% for total occlusion ISR (type 4).
 This study reported significantly better outcomes after ISR if a patient was treated with CABG
as compared to PCI.
 Constantini et al reported 6-month target lesion revascularization rates after treatment of ISR with
IVBT in a cohort of 295 patients, the majority of whom had ≥ two prior interventions. This study
showed relatively favorable re-intervention rates in patients with type 3 and type 4 ISR of 30.2% and
8.3%, respectively.

33. 2. Identification of mechanical/technical issues using intracoronary imaging and
tailored treatment
 After performing intracoronary imaging (IVUS or OCT) in the ISR lesion, the presence or
absence of any mechanical/technical issues can be determined.

34. Calcified Non Calcified
 If stent underexpansion due to significant peri-
stent calcium (> 90˚) is diagnosed, ELCA is
recommend, followed by high-pressure scoring
balloon inflation.
 ELCA has been associated with calcium
modification, even in ISR lesions, and may
therefore be the preferred mode of atherectomy in this
case.
 If, even after ELCA, the (scoring- or cutting-)
balloon is unable to dilate completely, CABG
may be preferred, as this suggests that the
underlying problem of under-expansion is
insufficiently addressed.
 If stent underexpansion not due to
calcification is diagnosed, we recommend the
use of ELCA only if significant neointimal
hyperplasia was also found to be present on
IVUS imaging. If there was no or minimal
neointimal hyperplasia, high-pressure (scoring)
balloon inflation will be sufficient to dilate the
lesion.

35.  If ELCA and cutting-/scoring-balloon angioplasty are successful, the decision to treat with
additional DES implantation can be made based on the pattern of ISR.
1. As focal ISR has a relatively good prognosis, DES implantation would only be recommended
for bailout use, for example, in case of residual dissection.
2. For diffuse, proliferative, or occlusive ISR, which are associated with higher rates of ISR,
we recommend routine use of repeat DES implantation or DCB use

36.  If IVUS shows no mechanical/technical issues, and ISR is predominantly due to neointimal
hyperplasia, treatment is dependent on the pattern of ISR.
1. For focal ISR, aggressive lesion preparation, using a high-pressure or scoring/cutting balloon
followed by DES implantation only for bailout use will be sufficient.
2. On the other hand, for diffuse, proliferative, or occlusive ISR, we recommend atherectomy
followed by scoring/cutting balloon angioplasty for optimal lesion debulking, followed by repeat
DES implantation or DCB angioplasty, if available.

37.  If focal edge restenosis, stent gap, or stent fracture is identified, authors recommend lesion
debulking with ELCA only if significant neointimal hyperplasia is present.
 Authors always recommend conventional or high-pressure balloon predilation at the side of the
mechanical complication, followed by a short repeat DES implantation in case of focal ISR or a
long DES covering the entire lesion in case of diffuse, proliferative, or occlusive ISR.

39. Tools and Techniques
DEB :
 The function of DES is to provide scaffolding to prevent
recoil and cover dissections and to deliver antiproliferative
drugs that inhibit neointimal formation.
 In treating ISR, the main purpose of a second stent
implant is to deliver antiproliferative drugs, and in many
cases, the additional layer of stent further crowds the
lumen with minimal benefit of additional scaffolding.
 In the complex multilayer ISR scenario, drug-
eluting balloons provide an attractive opportunity to
deliver antiproliferative drugs without adding
an additional layer of stent
 Angioplasty with a drug-coated balloon (DCB) has been
shown to be superior to plain balloon angioplasty in those
with BMS restenosis.
 A paclitaxel DCB had similar results to restenting with
a paclitaxel DES.
 The RIBS V study randomized patients with BMS ISR to
the newer-generation EES versus DCB. The EES was
associated with superior angiographic results, but the
DCB led to similarly low rates of TVR and MACE at 1
year.
 DCB use leads to improved rates of TVR compared to
balloon angioplasty and may be similar to repeat
stenting with a first-generation DES.
 Whether DCB is superior to newer-generation DES is
less clear based upon observational studies.

40. Intra coronary Brachytherapy
 The 1-year DEB treatment outcomes for two-
and three-layer stent treatment are however
suboptimal, with MACE rates of 16.1% and
43.1%, respectively
 The challenges in treating multilayer ISR has
led to a resurgence in coronary artery
brachytherapy therapy for ISR in several referral
centers.
 The coronary artery brachytherapy system
available in the US (Novoste Beta-Cath) utilizes
a strontium-90 source to deliver beta radiation to
the ISR stenosis to inhibit neointimal
proliferation without the need for placement of
an additional stent.
 Two recent series evaluated the efficacy of
coronary brachytherapy for recalcitrant
multilayer ISR where in the best case, multilayer
DES ISR brachytherapy TLR rates were 3.3% at
6 months, 12.1% at 1 year, 19.1% at 2 years,
and 20.7% at 3 years
 The Washington Radiation for In-Stent Stenosis
Trial (WRIST) study showed brachytherapy
results in improved early TVR rates (26% vs.
68%), but higher rates of TLR between 6
months and 5 years (21.5% vs. 6.1%).
 Brachytherapy is also associated with very late
stent thrombosis, which is probably due to
delayed endothelial healing

41. Laser Atherectomy
 There are three mechanisms by which the
laser operates to ablate fibrous tissue and
plaque.
1. The light pulse mechanism is that by which
the energy from the laser breaks carbon-
carbon bonds in the fibrous tissue, thus
ablating it.
2. The sonic wave mechanism is that by which
pulsed waves are generated by the laser
“cracking” hard materials and changing vessel
compliance. The sonic waves affect both
luminal and medial disease.
3. The third mechanism action is driven by the
vapor bubble at the distal tip of the catheter.
When this vapor bubble expands and bursts, it
addresses mixed lesion morphologies and
debulks for luminal gain. The small size of the
released particles generally does not obstruct
the distal circulation

42.  Lasers atherectomy is frequently used for the treatment of in-stent restenosis, particularly in the
setting of multiple layers of stent or a heavily fibrotic segment of disease.
 The catheter comes in various diameters, and there are different guidelines for selecting a size
for a given vessel. In our practice, the 0.9-mm laser is the most frequently used in the coronary
circulation. The size of the vapor bubble is approximately 2.5 times the diameter of the catheter.
The 0.9-mm laser is 6-Fr guide compatible and has a short monorail segment.

43. Same DES or different DES
 Drug resistance
 DES eluting a different drug might be more effective
ISAR-DESIRE trial
 RCT, 450 patients with SES ISR
 Treatment with same (homo-DES) or different DES
(hetero- DES [PES])
 Mean lesion lengths -12.7 and 12.5 mm respectively
 Focal pattern of restenosis (65% and 61%) respectively
 No significant differences in
1. in-stent late lumen loss at 8 months
2. 1-year clinical end points of TLR(17% vs 15%)
3. Death/MI (6.1% vs. 5.8%)
4. Stent thrombosis (0.4% in both groups).
 Focal ISR might not be due to drug resistance
 Diffuse ISR has a greater chance to be due to drug
resistance
 Alternate DES should focus solely on diffuse ISR
pattern

44. THANK YOU