JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 80, NO.

4, 2022

ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Coronary In-Stent Restenosis

JACC State-of-the-Art Review

Gennaro Giustino, MD,a Antonio Colombo, MD,b Anton Camaj, MD, MS,a Keisuke Yasumura, MD,a
Roxana Mehran, MD,a Gregg W. Stone, MD,a Annapoorna Kini, MD,a Samin K. Sharma, MDa

ABSTRACT

The introduction and subsequent iterations of drug-eluting stent technologies have substantially improved the efficacy
and safety of percutaneous coronary interventions. However, the incidence of in-stent restenosis (ISR) and the resultant
need for repeated revascularization still occur at a rate of 1%-2% per year. Given that millions of drug-eluting stents are
implanted each year around the globe, ISR can be considered as a pathologic entity of public health significance. The
mechanisms of ISR are multifactorial. Since the first description of the angiographic patterns of ISR, the advent of
intracoronary imaging has further elucidated the mechanisms and patterns of ISR. The armamentarium and treatment
strategies of ISR have also evolved over time. Currently, an individualized approach using intracoronary imaging to
characterize the underlying substrate of ISR is recommended. In this paper, we comprehensively reviewed the incidence,
mechanisms, and imaging characterization of ISR and propose a contemporary treatment algorithm.
(J Am Coll Cardiol 2022;80:348–372) © 2022 by the American College of Cardiology Foundation.

P ercutaneous coronary interventions (PCI) have

evolved significantly over the past 4 decades
(Figure 1).1 Bare-metal stents (BMS) overcame
the limitations of PCI with plain balloon angioplasty
(BA) by reducing the high rates of abrupt vessel
closure, coronary dissections, vessel recoil, and
1,2
constrictive remodeling. However, implantation of
a metallic stent in coronary arteries causes vascular
injury and triggers fibroblast proliferation and the
development of neointimal hyperplasia (NIH), the
main substrate of in-stent restenosis (ISR).3 Drug-
eluting stents (DES) constituted a technologic break-
through in the percutaneous treatment of coronary
artery disease (CAD). 2 Compared with BMS, by
combining the metallic stent platform with a polymer
releasing an antiproliferative drug, DES significantly
improved the efficacy of PCI by suppressing the for-
mation of NIH and reducing the risk of ISR. This
improvement in the efficacy of PCI was counterbal-
anced by a greater risk of late stent-related throm-
botic events beyond 1 year with early-generation
DES platforms.2 Iterations in DES technologies have
now led to current-generation DES that have demon-
strated excellent long-term thrombotic safety profiles
obviating the need of prolonged dual antiplatelet
therapy (DAPT) and have reduced even further the
incidence of ISR.4,5 However, despite the substantial
improvements in DES technologies, ISR and the
need for target lesion revascularization (TLR) still
occur at a rate of 1%-2% per year with contemporary
DES platforms (Figure 1).5 Given that millions of DES
are implanted annually around the world, ISR can

Listen to this manuscript’s

audio summary by
Editor-in-Chief
Dr Valentin Fuster on
www.jacc.org/journal/jacc.
From aThe Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York,
USA; and the bIRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
William F. Fearon, MD, served as Guest Associate Editor for this paper. Javed Butler, MD, MPH, MBA, served as Guest Editor-in-
Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received April 13, 2022; revised manuscript received May 16, 2022, accepted May 23, 2022.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2022.05.017

JACC VOL. 80, NO. 4, 2022
JULY 26, 2022:348–372
HIGHLIGHTS
! ISR is encountered frequently, due to
stent-related, procedure-related, and
biological factors.
! Intracoronary imaging is necessary to
characterize the mechanisms of ISR and
guide management.
! The available treatment options should
be selected based on the underlying
substrate, burden of disease, and clinical
risk profile.
be considered a pathologic entity of public health sig-
nificance. In fact, PCI for ISR constituted around 10%
of all PCIs performed in the United States over the
past decade and has been shown to be associated
with higher risk of major adverse cardiac events
compared with PCI of de novo lesions.6,7
The knowledge base of the mechanisms and char-
acterization of ISR has evolved over time. Since the
original angiographic classifications for ISR, the
advent of advanced intracoronary imaging has
further elucidated the mechanisms and underlying
substrate of ISR.8-10 The available therapeutic arma-
mentarium to treat ISR has also evolved and been
refined over time.8-11 Currently, the management of
ISR should be tailored and individualized based on
the underlying ISR substrate and clinical risk profile
of each patient. 11 In the present paper, we compre-
hensively review historical and contemporary data on
the incidence, mechanisms, histopathology, and
characterization of ISR and propose an individualized
substrate-based treatment approach for ISR with the
most contemporary therapeutic options.
INCIDENCE AND CLINICAL PRESENTATION OF ISR
The incidence of ISR has significantly declined in the
past 2 decades with advancements in coronary stent
technology, implantation techniques, and pharma-
cotherapies (Figures 1 and 2).1,2 ISR of BMS tends to
peak within the first year after implantation;
conversely, current-generation DES are associated
with an ongoing risk of ischemia-driven TLR of
around 2% per year.5 In a patient-level pooled anal-
ysis of randomized controlled trials (RCTs) the 1-year
rates of ischemia-driven TLR were 14.7%, 4.9%, and
2.5% with BMS, early-generation DES, and new-
generation DES, respectively. Conversely, from 1 to
5 years, the respective cumulative rates of ischemia-
driven TLR were 6.1%, 5.9%, and 4.4%.5 Rates of
TLR across RCTs of specific early- and new-
Giustino et al 349
Coronary In-Stent Restenosis
generation DES platforms are summarized in ABBREVIATIONS
Figure 2 and Supplemental Table 1. Currently, AND ACRONYMS
the proportion of patients undergoing PCI for
BA = balloon angioplasty
BMS-ISR is declining, consistent with the
BMS = bare metal stent
increased use of DES. 6 In a large contempo-
CABG = coronary artery bypass
rary report from the U.S. CathPCI registry,
grafting
approximately 50% of PCIs for ISR from 2009
CAD = coronary artery disease
to 2017 were performed >2 years after the
DAPT = dual antiplatelet
original stent implantation, and patients who
therapy
had DES-ISR were more likely to present after
DCB = drug-coated balloon
the first year compared with patients with
DES = drug-eluting stent
BMS-ISR.6
EES = everolimus-eluting stent
The pathophysiologic consequence of ISR
ELCA = excimer laser
is the development of obstructive CAD with
atherectomy
reduction of myocardial perfusion and
ISR = in-stent restenosis
development of ischemic symptoms. Though
IVBT = intravascular
originally considered to be a benign clinical
brachytherapy
entity presenting with anginal symptoms, ISR
IVL = intravascular lithotripsy
often presents as an acute coronary syn-
IVUS = intravascular
drome.6,12,13 In a large study from the U.S. ultrasound
CathPCI registry, among 542,112 patients who
NIH = neointimal hyperplasia
underwent ISR-PCI, most presented with
OCT = optical computed
unstable symptoms and around 25% pre- tomography
sented with an acute myocardial infarction.6 PCI = percutaneous coronary
Of note, an acute coronary syndrome at pre- intervention
sentation has been shown to be an indepen- RA = rotational atherectomy
dent predictor of major adverse cardiac RCT = randomized controlled
events and recurrent ISR at follow-up. 12,13 trial
Despite advances in the therapeutic stra- ST = stent thrombosis
tegies to treat ISR, the incidence of recurrent TLR = target lesion
ISR is still substantial. 14,15 For example, in a revascularization
large multicenter registry of >48,000 de novo lesions
treated in a 15-year period (2002-2016) the rates of
recurrence of ISR after a first, second, and third
reintervention were 8.3%, 17.1%, and 22.8%, respec-
tively.14 Of note, multiple metallic stent layers are
associated with a progressively higher risk of recur-
rent ISR, after treatment with DES or drug-coated
balloons (DCBs), particularly in the presence of 3-
layer ISR. 15,16
PATHOLOGIC MECHANISMS OF ISR
Different mechanisms account for the development,
severity, and patterns of ISR (Figure 3), including
biological or patient-related factors, anatomic factors,
procedural factors, and stent factors.
PATIENT-RELATED OR BIOLOGICAL FACTORS. Clin-
ical predictors of ISR include diabetes mellitus,
chronic kidney disease, older age, female sex, and
higher body mass index, among others. 8-10 In partic-
ular, in patients with diabetes mellitus, the metabolic
alterations that occur as a result of hyperglycemia or
hyperinsulinemia can accelerate the formation of
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Coronary In-Stent Restenosis JULY 26, 2022:348–372

F I G U R E 1 Technologic Iterations in Drug-Eluting Stent Technologies, Pharmacology, and PCI Techniques

A FDA-approval of the first FDA approval of FDA approval of the

BMS (Palmaz-Shatz stent) biodegradable polymer Absorb BVS
Synergy everolimus-
First coronary BA First treatment of eluting stent FDA approval of the
by Andreas AMI with a BMS ultra-thin bioresorbable
Gruentzig polymer Orsiro
Introduction of the Concerns about very late stent- sirolimus-eluting DES
concept of optimal stent thrombosis with 1st-generation
deployment using IVUS DES and need for prolonged Bioresorbable
Recognition of by Colombo et al DAPT (ESC Firestorm) scaffolds
negative remodeling abandoned due
as mechanism of Introduction of DAPT to high rates of
restenosis post-BA to reduce risk of ST ST and ISR

Balloon Angioplasty Era BMS Era 1st-Generation DES Era 2nd-Generation DES Era Last-Generation DES Era
1977s − 1990s 1990s − 2000s 2000s − 2010s 2010s − 2015s 2015s − 2020s

Development and Introduction of potent Neoatherosclerosis Adoption of

introduction of P2Y12-receptor identified as abbreviated
athero-ablation devices inhibitors mechanism of periods of DAPT
very-late DES failure
Angiographic and IVUS FDA approval of the SES Introduction of aspirin-
characterization of ISR Cypher and the PES Taxus free antithrombotic
regimens post-PCI

RA, ELCA, IVBT FDA approval of the The polymer-free

tested in BMS-ISR everolimus-eluting Xience Biolimus-eluting
and zotarolimus-eluting Biofreedom stent
Endeavor DES superior to BMS in

B HBR patients

60
Revascularization at 1 Year, %
Rates of Target Lesion

50

40 ≈40%

30

20 ≈20%
10
≈10%
≈4% ≈3%
0
1977 − 1990s 1990s − 2000s 2000s − 2010s 2010s − 2015s 2015s − 2020s

(A) Evolution in DES technologies, PCI techniques and pharmacotherapies over the last 4 decades, (B) paralleled by a substantial reduction in the rates TLR. (C) Rates of
ischemia-driven target lesion revascularization and target lesion failure with bare-metal stents (blue line), early-generation (red line) and new-generation drug-
eluting stents (gray line); reproduced with permission from Madhavan et al.5 BA ¼ balloon angioplasty; BMS ¼ bare-metal stent; BVS ¼ bioresorbable vascular scaffold;
DAPT ¼ dual antiplatelet therapy; DES ¼ drug-eluting stent; ELCA ¼ excimer laser atherectomy; FDA ¼ Food and Drug Administration; ISR ¼ in-stent restenosis;
IVBT ¼ intravascular brachytherapy; IVUS ¼ intravascular ultrasound; PCI ¼ percutaneous coronary intervention; PES ¼ paclitaxel-eluting stent; RA ¼ rotational
atherectomy; SES ¼ sirolimus-eluting stent; ST ¼ stent thrombosis; TLR ¼ target lesion revascularization.

Continued on the next page

NIH.8 Biological factors for ISR include drug resis-
tance and hypersensitivity. Drug resistance can be
primary (in genetically predisposed individuals) or
secondary, following exposure to the
proliferative drug. 8 Hypersensitivity and inflamma-
tory reactions promote the formation of NIH and can
be triggered by the metallic stent platform and the
DES polymer. 8 Implantation of a stent within a coro-
nary artery induces a local barotrauma with endo-
thelial denudation and subsequent activation of an
anti- inflammatory foreign body reaction. Persistence of
local inflammation after 90 days is associated with a
subsequent high risk of delayed endothelialization,
ISR, and late or very late stent thrombosis (ST).8 Older
JACC VOL. 80, NO. 4, 2022 Giustino et al 351
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

F I G U R E 1 Continued

16
C
14.7%
14
Ischemia-Driver TLR (%)

12

10

6 6.1%
5.9%
4.9%
4 4.4%

2.5%
2
P < 0.0001 P < 0.0001
0
0 3 6 12 24 36 48 60
Time After Procedure (Months)
Number at risk:
BMS 3,449 3,317 3,145 2,768 2,615 2,316 1,851 663
Early-Generation DES 7,804 7,556 7,428 6,992 6,648 5,572 3,660 1,758
New-Generation DES 13,380 13,206 13,074 12,502 12,059 11,191 5,913 3,580

20

17.8%
Target Lesion Failure (%)

15

10 9.5%
8.1% 7.7%
7.7%

5 5.0%

P < 0.0001 P < 0.0001

0
0 3 6 12 24 36 48 60
Time After Procedure (Months)
Number at risk:
BMS 1,830 1,725 1,636 1,462 1,395 1,335 1,267 479
Early-Generation DES 4,591 4,384 4,296 4,108 3,916 3,465 2,850 1,470
New-Generation DES 13,157 12,792 12,653 12,287 11,819 10,928 5,679 3,446

studies in the BMS era showed a strong association deposition, greater persistent inflammatory reaction
between the extent of medial damage, inflammation and delayed re-endothelialization compared with
with leukocyte infiltration, and restenosis.17 Autopsy BMS, explaining the increased risk of late and very
studies with first-generation DES reported delay in late ST with first-generation DES. 18 Second-
arterial healing characterized by persistent fibrin generation DES have been shown to be associated
352 Giustino et al JACC VOL. 80, NO. 4, 2022

Coronary In-Stent Restenosis JULY 26, 2022:348–372

F I G U R E 2 Characteristics and Rates of TLR and ST With Metallic DES

Antiproliferative drug

Paclitaxel Sirolimus-analogues
Sirolimus Biolimus Zotarolimus Everolimus Zotarolimus Everolimus Sirolimus Zotarolimus Sirolimus Sirolimus Ridaforolimus Amphilimus Biolimus Sirolimus

Polymer material (µm)

22 13 10 6 8 6 4 7 6 10 15 7 N/A N/A 4-5

Platform material and strut thickness (µm)

132 140 120 91 81 91 74 60 91 64 80 87 80 112 60

Stent Taxus Cypher Biomatrix; Endeavor Xience; Resolute Synergy Orsiro Onyx Mistent Ultimaster Elunir Cre8 Bio- Supraflex
Name Nobori Promus Freedom

Material Stainless Stainless Stainless Co-Cr Co-Cr; Co-Cr Pt-Cr Co-Cr Co-Ni + Co-Cr Co-Cr Co-Cr Co-Cr Stainless Co-Cr
steel steel steel Pt-Cr Pt core steel

TLR Rate 4.4%- 0%- 2.1%-3% 4.5% 1.4%- 2%- 1%- 0.7%- 2.8% 2.2% 2.18% 3.2% 2.4% 1%-8% 3.5%
8.6% 10.3% 4.2% 10.4% 2.6% 2%

SR Rate 0.1%- 0.4%- 0%- 0.8% 0%- 0.1%- 0%- 1%- 1.3% 0.7% 0.9% 0.4% 1.4% 0.9%- 0.7%
3% 2% 0.8% 2.8% 1.4% 0.4% 3% 1.5%

Durable Polymer Biodegradable Polymer

Differences in platform material and thickness, polymer composition, and antiproliferative drug across DES types, as well the associated rates of TLR and ST at 1 year.
Co ¼ Cobalt; Cr ¼ Cromium; Pt ¼ Platinum; other abbreviations as in Figure 1.

with less fibrin deposition, less vascular inflamma-
tion, and faster and more uniform stent strut endo-
19
thelialization compared with first-generation DES.
PROCEDURAL FACTORS. Optimal stent implantation
is key to reducing the risk of both restenosis and
thrombosis after PCI. 8 Procedural factors influencing
the risk for ISR include stent underexpansion, stent
malapposition, and stent gap, among others. 20-26
Stent underexpansion results from poor expansion
during implantation.20 Stent underexpansion and
smaller postprocedural minimal stent cross-sectional
area are strongly associated with long-term DES
patency and risk of ISR and ST, particularly within 1
20
year after stent implantation. While undersizing or
poor lesion preparation during stent implantation are
the most common causes of stent underexpansion,
stent recoil can also occur and has been associated
21,22
with ISR. Unlike underexpansion, stent malap-
position refers to stent struts not apposed to the
vessel wall and leaving a space occupied by blood
between the struts and the arterial intima. Malap-
position can be detected with the use of intracoronary
imaging and usually occurs with undersized stents or
in arteries with significant tortuosity and fluctuations
of lumen diameter.23 In fact, malapposition and
underexpansion can coexist within the same
implanted stent. Whereas acute malapposition has
not been shown to be associated with higher risk of
stent-related adverse events, 25 late malapposition has
been associated with increased risk of DES failure,
including restenosis and thrombosis.26 Of note, late
malapposition has been shown in multiple studies to
occur more frequently with DES than with BMS,
possibly because of hypersensitivity to the polymer or
the antiproliferative drug, resulting in positive
vascular remodeling. 26
Stent gap can be defined as a discontinuous
coverage of a coronary lesions between 2 stents and
has been associated with higher risk of ISR and need
for repeated revascularization.24 A gap between 2 DES
leaves a zone of the coronary lesion not exposed to
the antiproliferative effects of the released drug and
the mechanical support of the metallic strut. PCI of
coronary bifurcations is also associated with higher
rates of restenosis and TLR compared with non-
bifurcation lesions, and the implemented stenting
JACC VOL. 80, NO. 4, 2022 Giustino et al 353
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

F I G U R E 3 Pathophysiology and Risk Factors for In-Stent Restenosis

Anatomical factors:
• Calcified lesions Percutaneous Coronary Intervention
• Bifurcation lesions
• Ostial lesions
• Small vessels Stent Implantation
• Long lesions
• PCI of ISR, CTO or SVG

Endothelial and vascular Injury

Clinical factors:
• Diabetes mellitus
• Chronic kidney diabetes Inflammation Fibroblast
• Older age proliferation
• Previous PCI / CABG
• Female sex
• Obesity Neointimal Hyperplasia
• Antiproliferative drug resistance

Stent-related and procedural

factors:
Excessive Neointimal
• Bare-metal stent Neo-
• Stent underexpansion Hyperplasia
atherosclerosis
• Polymer hypersensitivity
• Stent fracture
• Geographical lesion miss
• Stent gap or overlapping stents
• Smaller post-PCI MLA In-Stent Restenosis
• Thicker stents struts
• Smaller stent diameter
• Longer stent

The implantation of a coronary stent cause arterial tissue injury that induces vascular smooth-muscle cells proliferation and production of extracellular matrix resulting
in the formation of NIH, the main substrate of ISR. Neoatherosclerosis, an accelerated form atherosclerosis in which a neo-atheroma is formed within the neointima,
accounts for both ISR and ST in later phases after DES implantation. CABG ¼ coronary artery bypass graft; CTO ¼ chronic total occlusion; MLA ¼ minimal luminal area;
NIH ¼ neointimal hyperplasia; SVG ¼ saphenous vein graft; other abbreviations as in Figures 1 and 2.

technique can substantially influence clinical out-
comes. Most noncomplex bifurcation lesions can be
treated with the use of a 1-stent
approach. 27 Conversely, in true left main bifurcation
lesions (Medina 1,1,1 or 0,1,1), PCI using 2 stents with
a double-kissing crush technique resulted in larger
side-branch luminal diameter and lower rates of TLR
compared with a provisional approach.28 When per-
forming bifurcation stenting with a 2-stent technique,
the implementation of poststenting optimization
strategies, such as the proximal optimization tech-
nique (POT) or final kissing balloon dilatation, is
essential to improve final stent geometry and vessel
wall apposition, as well as long-term stent patency. 27
ANATOMIC FACTORS. Anatomic factors determining
ISR include vessel size, lesion characteristics, and
local shear stress. Vessel size is a strong predictor of
ISR after both BMS and DES implantation. 29,30 Po-
tential mechanisms underlying the poor outcomes
provisional associated with small vessel stenting include a
smaller postprocedural minimal luminal area, higher
degree of vessel injury and recoil, and higher metallic
density. 29-32 However, it remains controversial
whether higher degrees of arterial injury induced by
higher balloon-to-artery ratio result in higher degrees
of NIH formation. 33 High thrombus burden reduces
the antiproliferative drug penetration and distribu-
tion, and late thrombus resolution predisposes to
incomplete stent apposition. 34 Severe coronary artery
calcifications are strongly associated with higher rates
of TLR and ST. 35 Heavily calcified lesions may result
in suboptimal stent expansion and wall apposition.
Therefore, optimal lesion preparation with the use of
atheroablative devices is important to ensure optimal
stent apposition and long-term patency.
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Coronary In-Stent Restenosis JULY 26, 2022:348–372

F I G U R E 4 Representative Images of Histopathology and OCT of Neointimal Hyperplasia and Neoatherosclerosis

Upper panel: (A) homogeneous neointimal pattern on OCT with fibrous connective tissue (blue); (B) neointimal hyperplasia with heteroge-
neous neointimal pattern on OCT and loose connective tissue (gray) and fibrin (pink); (C) obstructive neointimal hyperplasia with peri-strut
inflammation and layered neointimal pattern on OCT; reproduced with permission from Kim et al.115 Lower panel: ex-vivo imaging with
corresponding histologic section of neoatherosclerosis; (D) neoatherosclerosis on OCT with foamy macrophages accumulation (white arrows)
and a trailing shadow (white arrowheads); the yellow arrows point to highly backscattering region with attenuation indicating cholesterol
crystals in the necrotic core (NC); (E) histological section showing superficial foamy macrophages (G), confirmed by anti-CD68 immuno-
staining (I), and the necrotic core (F), (H) appearance on intravascular ultrasound imaging; reproduced with permission from Otsuka et al.36

STENT FACTORS. Stent-related factors influencing
ISR include stent type, drug distribution, drug type,
stent strut thickness, and stent fracture. There are
substantial differences in the time course, phenotypic
appearance, and underlying mechanism of ISR be-
10
tween BMS and DES. The time course of neointimal
accumulation differs considerably between the 2
types of stents. With BMS, lumen late loss tends to
peak 6-8 months after implantation and then de-
creases over time. Conversely, with DES, there is a
slower but ongoing neointimal accumulation through
5 years after implantation.10 BMS-ISR is more
frequently associated with diffuse or proliferative
patterns, whereas DES-ISR is more frequently asso-
ciated with focal or edge-related NIH.10 Finally, neo-
atherosclerosis as a mechanism of ISR is more
frequently found with DES, particularly beyond 1
year, and earlier in time compared with BMS.36 A
stent fracture is defined as complete or partial sepa-
ration of a stent that was contiguous after the original
stent implantation. DES fractures result in impaired
local drug delivery and loss of the metallic platform
support. Risk factors for stent fracture include
stenting of the right coronary artery, excessive vessel
tortuosity or angulation, and longer or overlapping
stents. 37 Conversely, stents with larger diameter or an
JACC VOL. 80, NO. 4, 2022 Giustino et al 355
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

T A B L E 1 Histopathologic Differences in ISR Among Stent Types

BMS Early-Generation DES New-Generation DES

Angiographic More frequently diffuse ISR.
characteristics
OCT characteristics Homogeneous tissue.
Neoatherosclerosis rare.
Histopathology Rich in smooth muscle cells.
Moderate proteoglycan content.
Peristrut inflammation less frequent.
Complete endothelialization by 3-6 mo.
Thrombus rare.
Neoatherosclerosis rare.
More frequently focal or stent-edge
ISR.
Homogeneous tissue.
Neoatherosclerosis more frequent than Neoatherosclerosis more frequent than
with BMS and has larger lipid
content than with new-generation
DES.
Poor in smooth muscle cells.
Rich in proteoglycan content.
Peristrut inflammation frequent.
Delayed endothelialization (>1 y).
Occasional thrombus present.
Accelerated neoatherosclerosis.
More frequently focal or stent-edge ISR.
Heterogeneous tissue.
with BMS but less accelerated than
with early-generation DES, lower
lipid content than with early-
generation DES.
Poor in smooth muscle cells.
Rich in proteoglycan content.
Peristrut inflammation less frequent.
Complete endothelialization by 3-6 mo.
Thrombus rare.
Neoatherosclerosis over the long term.

BMS ¼ bare metal stent; DES ¼ drug-eluting stent; ISR ¼ in-stent restenosis; OCT ¼ optical coherence tomography.

open-cell design appear to have a lower risk of frac-
ture.37 The incidence of DES fracture has been re-
ported to range from 1% to 8%, and the need for
revascularization of fractured stents ranges from 15%
37
to 60%. Finally, thinner stent struts are associated
with improved local blood rheology and less NIH in
intracoronary imaging studies.38 These benefits have
also been demonstrated in larger RCTs comparing
thinner-strut DESs vs thicker-strut DESs.39 However,
they may not be uniformly beneficial in all subsets of
lesions. For example, in the setting of chronic total
occlusions (CTOs), ultrathin-strut (60 m m) DES resul-
ted in higher degrees of late lumen loss at angio-
graphic follow-up compared with thin-strut (81 mm)
everolimus-eluting stents. 40
HISTOPATHOLOGY OF ISR
Smooth muscle cell proliferation embedded in a
collagen-rich extracellular matrix is one of the
dominant pathologic processes leading to restenosis
after coronary stent implantation (Figure 4).9,41
Several histopathologic differences have been
described in ISR between BMS and DES (Table 1).
BMS-ISR is characterized by homogeneous tissue with
greater smooth muscle cell density, whereas DES
restenosis is more often hypocellular and proteogly-
can-rich.42 Also, the smooth muscle cell phenotype is
more frequently synthetic in BMS-ISR and contractile
43
or intermediate in DES-ISR.
Neoatherosclerosis has been described as a po-
tential cause of late (>1 year) DES failure respon-
sible for both DES restenosis and thrombosis.36
Histologically, in-stent neoatherosclerosis is char-
acterized by accumulation of lipid-laden foamy
macrophages within the neointima, with or without
necrotic core formation and calcifications.36
Different from atherosclerosis of native vessels,
neoatherosclerosis develops over months to years,
representing an accelerated form of atherosclerosis
secondary to dysfunctional endothelial coverage of
the stented vascular segment. 36 The accumulation
of foamy macrophages within the neointima leads
to the formation of an in-stent neoatheroma which
can further progress to form a thin cap that can lead
to in-stent plaque rupture and acute myocardial
infarction. 36
PATTERNS AND IMAGING CHARACTERIZATION
OF ISR
ANGIOGRAPHY. Angiographically, ISR appears as a
narrowing lumen within a previously stented vascular
segment. Coronary angiography remains the criterion
standard to address the severity and functional sig-
nificance of ISR lesions. Based on the angiographic
appearance, ISRs differ in their morphologic patterns,
which in turn are associated with prognostic and
therapeutic implications. One of the most accepted
angiographic classifications of ISR was the one pro-
posed by Mehran et al.44 Before the introduction of
this classification, patterns of ISR were broadly clas-
sified as focal (in-stent lesion <10 mm in length) or
diffuse (in-stent lesion >10 mm in length). The Mehran
classification, described in the BMS era, further
enhanced this simple characterization by describing
the topographic relation between NIH and the
implanted stent (Table 2).44 Currently, the most
widely used definition for reporting ISR is the one
proposed by the Academic Research Consortium.45
This definition requires either a lumen narrowing of
at least 50% of the vessel diameter associated with
evidence of functional significance (ischemic symp-
toms or abnormal fractional flow reserve) or a luminal
narrowing of at least 70% in the absence of ischemic
symptoms within 5 mm proximal or distal of the
implanted stent. 45
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Coronary In-Stent Restenosis JULY 26, 2022:348–372

T A B L E 2 Angiographic and Multimodality Coronary Imaging Characterization of ISR

Type/Group Description

Angiography
Mehran classification44 Class I (focal ISR) Lesions are #10 mm in length and are placed at (type Ia) the unstented segment
(articulation or gap), (type Ib) the body of the stent, (type Ic) the proximal or distal
margin, or (type Id) a combination of these sites (“multifocal ISR”)
Class II (diffuse ISR) Lesions are >10 mm in length and are confined to the stented segment, without
extending outside the margin(s)
Class III (diffuse proliferative) Lesions are >10 mm in length and extend beyond the margin(s) of the stented segment.
Class IV (total occlusion) Lesions with a TIMI flow grade of 0
IVUS
Kang et al104 Focal ISR Defined as lumen area <4 mm 2 and length #10 mm, subcategorized by the location
within the stent:
! “Focal body type,” confined to the body of stent
! “Focal marginal type,” extending to the margins of stent
Multifocal ISR Defined as the presence of multiple focal lesions, with subcategories:
! “Multifocal body type,” confined to the body of the stent
! “Multifocal marginal type,” involving stent margins
Diffuse ISR Defined as MLA <4 mm 2 and length >10 mm, with subcategories:
! “Diffuse body type,” confined to the stent body
! “Diffuse marginal type,” associated with stent involvement
OCT
Gonzalo et al49 Qualitative parameters Restenotic tissue structure:
! Homogeneous: uniform optical proprieties without focal variation in backscat-
tering pattern
! Heterogeneous: focal changes in optical properties and various backscattering
pattern
! Layered: concentric layers with abluminal high scattering layer and abluminal
low scattering layer
Restenotic tissue backscatter:
! High: predominant bright tissue with backscatter
! Low: predominant dark tissue with low backscatter
Lumen shape:
! Irregular: sharp delineation of lumen border which appears smooth and circular
! Regular: irregular border with tissue protusion from the vessel wall into the
lumen
Intraluminal material:
! Presence: visible material within the vessel lumen
! Absence
Microvessels:
! Presence: well delineated structures <200 mm in diameter with a course within
the vessel wall
! Absence
Quantitative parameters ! Mean lumen area (mm 2 )
! MLA (mm 2 )
! Mean stent area (mm 2 )
! Mean restenotic tissue area (mm 2 )
! Restenotic tissue burden (%)
Ali et al52 Type I Thin-cap neoatheroma: defined as $1 area of thin cap, neoatherosclerosis located
(OCT classification of between the lumen and the stent struts
neoatherosclerosis) Type II Thick-cap neoatheroma: defined as the absence of thin cap, neoatherosclerosis located
between the lumen and the stent struts
Type III Peristrut neoatheroma: defined as neoatherosclerosis located around the stent struts
Type IV Preexisting fibroatheroma: defined as native preexisting atherosclerosis displaying as
poor region signals with diffuse border between the stent struts and the adventitia

ISR ¼ in-stent restenosis; MLA ¼ minimal lumen area; TIMI ¼ Thrombolysis in Myocardial Infarction; OCT ¼ optical coherence tomography.

The initial morphologic angiographic pattern of
restenosis has been shown to predict the outcomes of
44
PCI of ISR. In the original study by Mehran et al,
rates of TLR were 19%, 35%, 50%, and 83% in clas-
ses I (focal) to IV (occlusive), respectively, and the
type of ISR was an independent predictor of TLR at
follow-up. In another study, by Latib et al,46 patients
44
with diffuse ISR had higher rates of TLR at 3 years of
follow-up compared with patients with focal ISR. Of
note, the initial pattern of ISR predicted the pattern of
JACC VOL. 80, NO. 4, 2022 Giustino et al 357
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

F I G U R E 5 Representative Multimodality Imaging Patterns of ISR

(A) Includes concentric NIH; (B) includes NIH with neoatherosclerosis and calcifications; (C) includes neoatherosclerosis with evidence of plaque rupture on OCT; (D) includes
stent-edge NIH; (E) includes 2-layer ISR underexpansion; (F) shows examples of stent fracture (F1), stent thrombosis (F2), stent gap (F3), and normal endothelialization (F4).
(F) Reproduced with permission from Biscaglia et al.105 Arrows refer to the OCT image of the vessel segment on the angiogram. ISR ¼ in-stent restenosis; NIH ¼ neointimal
hyperplasia; OCT ¼ optical computed tomography.

recurrent ISR, occlusive ISR reoccluded in 66.7%,
diffuse ISR recurred as diffuse or occlusive in 57.9%,
and focal recurred as focal in 67.2%. The morphologic
pattern of ISR also correlates with the timing and type
of clinical presentation. 47 For example, in the BMS
era, patients with diffuse ISR were more likely to
present with an acute coronary syndrome and earlier
after the index stent implantation (ie, 6-8 months
after the index PCI).47
INTRAVASCULAR ULTRASOUND. Intravascular
trasound (IVUS) has provided further insight into the
understanding of vascular remodeling after stent
implantation, the role of stent underexpansion, and
the distribution of NIH in ISR. In clinical practice,
IVUS plays an essential role in evaluating the under-
lying mechanism of ISR to guide treatment and in
accurate vessel sizing. In fact, IVUS can delineate the
external elastic lamina behind the stent struts,
providing information on actual vessel size and
optimization of stent expansion.
A classification system for DES-ISR according to the
IVUS findings was proposed in the early-generation
DES era (Table 2).48 The same study reported that
stent underexpansion was the underlying etiology of
ISR in 21% of cases, and NIH in 88% of cases. Focal ISR
was the most common pattern of ISR encountered
(47%). Of note, patients with diffuse ISR on IVUS had
ul- longer total stent lengths and a higher rate of stent
underexpansion (39%) at the minimal lumen site
compared with focal (6%) and multifocal (22%) ISR.
OPTICAL COHERENCE TOMOGRAPHY. Optical coher-
ence tomography (OCT) allows for better tissue
characterization, delineation of the lumen-
neointimal interface, and stent struts distribution.
ISR of BMS generally shows a homogeneous high-
signal tissue band on OCT, reflecting NIH rich in
358 Giustino et al
Coronary In-Stent Restenosis
F I G U R E 6 ISR Due to Underexpansion
Underexpansion due to calcified plaque outside of the stent: (A) appearance on optical computed tomography; (B) appearance on
intravascular ultrasound (asterisks). Arrows refer to the OCT and IVUS image of the vessel segment on the angiogram. ISR ¼ in-stent
restenosis
smooth muscle cells. Conversely, DES-ISR is charac-
terized by a heterogeneous or layered appearance on
OCT, reflecting hypocellular neointima with high
proteoglycan or fibrin content. Gonzalo et al 49
described the morphologic and structural features of
BMS- and DES-ISR according to quantitative and
qualitative OCT parameters and evaluated the rela-
tionship between the angiographic appearance of ISR
and the OCT characteristics (Table 2).
OCT has substantially helped in characterizing
neoatherosclerosis as a common pathway for both
DES restenosis and thrombosis. In fact, in the PRES-
TIGE (Prevention of Late Stent Thrombosis by an
Interdisciplinary Global European Effort) registry, 50
in which 231 patients presenting with ST underwent
OCT imaging, neoatherosclerosis was
common finding (33.3%) among patients presenting
JACC VOL. 80, NO. 4, 2022
JULY 26, 2022:348–372
with very late (>1 year) ST. Kang et al51 reported a
high prevalence of neoatherosclerosis in an OCT
study of 50 patients with very late DES-ISR
(>20 months after PCI). In that study, 52% of lesions
had at least 1 site containing thin-cap fibroatheroma,
58% had at least 1 site of in-stent neointimal rupture,
and 58% had evidence of thrombus. Ali et al 52 further
characterized the types of neoatherosclerosis with
the use of OCT and near-infrared spectroscopy (NIRS)
in consecutive patients with BMS- and DES-ISR
(Table 2). Neoatherosclerosis was significantly more
common in DES compared with BMS. DES-ISR had
more thin-cap neoatherosclerosis, and on NIRS
assessment DES-ISR had greater total lipid burden
and density.
the most OCT characteristics of restenotic lesions such
as neointimal or peristent calcium have also been
JACC VOL. 80, NO. 4, 2022
JULY 26, 2022:348–372
shown to be predictive of new DES underexpansion
and recurrent ISR.53 Recently, a new classification
scheme to characterize the mechanisms of ISR by
means of OCT to guide treatment has been pro-
posed. 9 This classification schema differentiates
between mechanical (type I, which includes under-
expansion [1a] and stent fracture [1b]), biological
(type II, which includes NIH [2a], neoatherosclerosis
without calcifications [2b], and neoatherosclerosis
with calcifications [2b]), mixed-causes (type III)
(combining mechanical and biological mechanisms),
chronic total occlusion (type IV), and 2-layer (type V)
ISR.9
Examples of angiographic, IVUS, and OCT appear-
ances of different types and mechanisms of ISR are
shown in Figures 5 and 6.
MANAGEMENT STRATEGIES
Management of ISR is challenging because of its
heterogeneous mechanisms and the relatively high
rate of recurrence. Most patients with ISR present
with stable angina, so the type and timing of
intervention should be carefully planned. As for
native CAD, when the angiographic severity of ISR
is unclear, physiologic guidance with the use of
fractional flow reserve or nonhyperemic indices
should be used to determine the hemodynamic
severity. Systematically, details on the original
intervention, including lesion complexity, type of
stent used, and implantation technique should be
carefully reviewed to identify potential technical
issues that could have caused ISR and plan the
optimal treatment strategy. Intracoronary imaging
modalities, such as IVUS or OCT, are essential tools
to characterize the mechanisms and substrate of ISR
and should be routinely used.
A practical approach for the management of ISR is
summarized in the Central Illustration, and a sum-
mary of the evidence from RCTs and large registries
supporting the use of each technique to treat ISR
is presented in Table 3 and Online Tables 2 and 3.
Current European guidelines recommend, with a
Class I indication, either DES or DCBs to treat ISR.54
However, DCBs are not approved for commercial use
in coronary artery interventions in the United States.
In the most recent American College of Cardiology
(ACC)/American Heart Association (AHA) coronary
revascularization guidelines, repeated DES has a class
1A indication for the treatment of ISR with the use of
PCI.55 Both the European and U.S. guidelines recom-
mend, with a Class IIa indication, the use of intra-
coronary imaging with IVUS or OCT to elucidate the
mechanisms of ISR.54,55
Giustino et al 359
Coronary In-Stent Restenosis
Lesion preparation is critical to achieve optimal
results in the treatment of ISR. Cutting or scoring
balloon angioplasty should be used in preference of
plain BA to reduce balloon slippage outside of the
stent.11,56 Aggressive (ie, high-pressure) balloon pre-
dilatation of the underlying stent should be used,
particularly if underexpansion is the predominant
mechanism of ISR. Based on clinical evidence from
multiple RCTs and meta-analyses, after adequate
lesion preparation and expansion, PCI with a second
DES or DCB should be performed. 11,56 Clinical factors
to guide decision making between repeated DES or
DCB are summarized in Table 4. In case of resistant
stent underexpansion, very-high-pressure BA, intra-
vascular lithotripsy (IVL), excimer laser atherectomy
(ELCA) or rotational atherectomy (RA) should be
considered.11 Among patients with multilayer ISR (>2
layers), coronary artery bypass grafting (CABG)
should be considered, considering the excessively
high rate of ISR recurrence. 11,15,16,56 However, if PCI of
multilayer ISR is attempted, an additional DES should
be avoided, and instead, DCB and, high-pressure
cutting or scoring BA with addition of intravascular
brachytherapy (IVBT) can be considered to poten-
tially improve long-term patency. 57
BALLOON ANGIOPLASTY. Plain BA has historically
been the mainstay of treatment of both BMS-ISR and
DES-ISR. However, this has now been proven to be
inferior to other treatment modalities owing to the
high recurrence of ISR. 58,59 However, use of high-
pressure BA still has an important role in treating
DES-ISR due to underexpansion. High-pressure BA is
typically performed using short noncompliant bal-
loons. A longer balloon can be used to reduce balloon
slippage, particularly in long lesions. This could be
followed by implantation of a second DES (if 1-layer
ISR) or DCB (particularly in 2-layer ISR).
CUTTING OR SCORING BA. Cutting or scoring BA
was introduced in the 1990s with the intent of
improving the efficacy of plain BA particularly in
complex coronary lesions.8-10 Cutting balloons are
angioplasty balloons with 3-4 longitudinally
attached microtomes designed to create discrete
longitudinal incisions in the atherosclerotic plaque
or fibrotic/calcified tissue. By doing so, cutting BA
can achieve larger lumen diameters at lower infla-
tion pressures and reduce elastic recoil in native
lesions. 60 Scoring balloons such as the AngioSculpt
device (Philips Healthcare) consists of a double-
lumen catheter with a semicompliant nylon
balloon surrounded by an external nitinol-based
helical scoring edge. In the setting of ISR, cutting
BA has been evaluated in multiple RCTs. In RESCUT
(Restenosis Cutting Balloon Evaluation Trial), 56 428
360 Giustino et al JACC VOL. 80, NO. 4, 2022

Coronary In-Stent Restenosis JULY 26, 2022:348–372

C E NTR AL IL L USTR AT I O N A Proposed Treatment Algorithm for In-Stent Restenosis

Giustino G, et al. J Am Coll Cardiol. 2022;80(4):348–372.

In patients presenting with ISR, intracoronary imaging with IVUS or OCT should be performed to identify the underlying mechanism and substrate of ISR. Repeated DES
implantation after proper lesion preparation is the most effective treatment strategy for 1-layer DES-ISR. Among patients with 2-layer ISR, a third layer of stent should
be avoided. CABG should be considered in patients with high-risk anatomy and good surgical candidates. BA ¼ balloon angioplasty; CABG ¼ coronary artery bypass
grafting; CBA ¼ cutting balloon angioplasty; CTO ¼ chronic total occlusion; DCB ¼ drug-coated balloon; ELCA ¼ excimer laser atherectomy; ISR ¼ in-stent restenosis;
IVBT ¼ intravascular brachytherapy; IVL ¼ intravascular lithotripsy; LAD ¼ left anterior descending artery; RA ¼ rotational atherectomy.
JACC VOL. 80, NO. 4, 2022 Giustino et al 361
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

T A B L E 3 Selected Randomized Controlled Trials (>100 Randomized Patients) Evaluating Management Strategies for ISR

Sample Angiographic Stent Pattern of DAPT Type and

Study Year Size Stenosis, % Type ISR, % (n) Treatments Duration Follow-Up Study Finding

Intravascular brachytherapy
Gamma-187 2001 252 >60 BMS N/A Placebo vs Aspirin 325 mg daily Angiographic: ! 6-mo MLD: 1.37 $ 0.64 vs 1.78 $
IVBT (indefinitely) þ 6 mo; 0.87 mm (P < 0.001)
ticlopidine 250 mg clinical: 9 ! 6-mo in-stent restenosis: 50.5% vs
twice daily or mo 21.6% (P ¼ 0.005)
clopidogrel 75 mg ! 6-mo in-lesion restenosis: 55.3% vs
daily for 8 wk 32.4% (P ¼ 0.01)
! 9-mo death, MI, or TLR: 43.8% vs
28.2% (P ¼ 0.02)
START105 2002 476 >50 BMS N/A Placebo vs Aspirin 325 mg daily Angiographic: ! 8-mo TVR: 26.8% vs 17.0% (P ¼ 0.015)
IVBT (indefinitely) þ 8 mo; ! 8-mo composite of death, MI, and
ticlopidine 250 mg clinical: 2 y TVR: 28.7% vs 19.1% (P ¼ 0.024)
twice daily or ! 8-mo restenosis: 45.2% vs 28.8%
clopidogrel 75 mg (P ¼ 0.001)
daily for $6 wka ! 2-y TVR: 36.6% vs 27.5%
! Freedom from MACE: 68.0% vs 58.9%
(P ¼ 0.035)
Reynen 2006 165 >50 BMS N/A PB vs IVBT Aspirin 300 mg daily þ Angiographic: ! 6-mo restenosis or reocclusion: 40%
et al106 clopidogrel 75 mg 6 mo; vs 24% (P ¼ 0.04)
daily for 6 mob clinical: 1 y ! 1-y freedom from death, MI, or TVR:
74% vs 87% (P ¼ 0.05)
Cutting balloon angioplasty
RESCBA56 2004 428 >50 BMS Focal: 44.6 PB vs CBA Aspirin 100-325 mg daily 7 mo ! Restenosis: 31.4% vs 29.8% (P ¼ 0.82)
(174), multifocal/ indefinitely þ ! No. of balloons used (only 1 balloon):
diffuse/ ticlopidine 25 mg 75% vs 82.3% (P ¼ 0.03)
proliferative: twice daily or
55.4 (216) clopidogrel 75 mg
daily for 1 wk
Rotational atherectomy
ARTIST80 2002 298 >70 BMS N/A PB vs RA Aspirin þ ticlopidine 6 mo ! Remaining stenosis <30% (89% vs
500 mg daily for 2 wk 88%)
! Mean net gain in MLD: 0.67 mm vs
0.45 mm (P ¼ 0.0019)
! Mean gain in DS: 25% vs 17% (P ¼ 0.002)
! Restenosis ($50%): 51% vs 65%
(P ¼ 0.039)
ROSTER81 2004 200 N/A BMS Diffuse: 100; PB vs RA Aspirin 325 mg daily Angiographic: ! TLR: 45% vs 32% (P ¼ 0.042)
proliferative: 34 indefinitely þ 6-9 mo; ! Residual intimal hyperplasia area (IVUS):
ROTA, 28 PB ticlopidine 500 mg clinical: 12 3.3 $ 1.8 mm2 vs 2.1 $ 0.9 mm2
daily for 4 wk if stent mo (P ¼ 0.005)
implanted
Bare-metal stents
RIBS107 2003 450 >50 BMS N/A PB vs BMS Aspirin 325 mg daily Angiographic: ! MLD: 2.25 $ 0.5 mm vs 2.77 $ 0.4
indefinitely þ 6 mo; (P < 0.001)
ticlopidine 500 mg clinical: 12 ! Binary restenosis: 39% vs 38%
daily for 1 mo mo ! 1-y event-free survival: 71% vs 77%
(P ¼ 0.19)
Drug-eluting stents
ISAR 2005 300 $50 BMS Focal: 56.3 PB vs SES Aspirin 100 mg twice Angiographic ! Restenosis SES vs PB: 14.3% vs
DESIRE108 (169); diffuse: vs PES daily indefinitely þ 6/8 mo; 44.6% (RR: 0.32; 95% CI: 0.18-
38.7 (116); clopidogrel 75 mg clinical: 12 0.56); PES vs PB: 21.7% vs 44.6%
proliferative: 1.7 twice daily until mo (RR: 0.49; 95% CI: 0.31-0.76)
(5); occlusive: discharge and daily ! TVR: SES vs PB: 8% vs 33% (RR: 0.24;
3.3 (10) for $6 mo 95% CI: 0.12-0.50); PES vs PB: 19%
vs 33% (RR: 0.58; 95% CI: 0.35-
0.94)
RIBS II109 2006 150 >50 BMS Focal: 26.7 (40); PB vs SES Aspirin 100-300 mg daily Angiographic ! Recurrent restenosis at 9 mo: 39% vs
diffuse: 61.3 indefinitely þ and IVUS: 11% (P < 0.001)
(92); clopidogrel 75 mg 9 mo; ! 1-y TVR: 29.7% vs 10.5% (HR: 3.16;
proliferative: daily for 9 mo clinical: 12 95% CI: 1.4-7.09; P ¼ 0.003)
12.0 (18) mo
Continued on the next page

patients with BMS-ISR were randomized to cutting use of fewer balloons and a lower incidence of
BA or conventional BA. Cutting BA did not result in balloon slippage.56 Most recently, scoring BA was
lower rates of recurrent angiographic ISR at tested against plain BA when using DCBs to treat
7 months of follow-up, but it was associated with ISR, with the hypothesis that NIH modification with
362 Giustino et al JACC VOL. 80, NO. 4, 2022

Coronary In-Stent Restenosis JULY 26, 2022:348–372

T A B L E 3 Continued

Sample Angiographic Stent Pattern of DAPT Type and

Study Year Size Stenosis, % Type ISR, % (n) Treatments Duration Follow-Up Study Finding

SISR88 2006 384 >50 BMS N/A SES vs Aspirin 325 mg daily þ Angiographic ! 6-mo restenosis: 19.8% vs 29.5%
IVBT ticlopidine 250 mg and IVUS: (RR: 1.5; 95% CI: 1.0-2.2; P ¼ 0.07)
twice daily or 6 mo; ! 6-mo MLD: 1.8 mm vs 1.52 mm
clopidogrel 75 mg clinical: 9 (difference: %0.27; 95% CI: %0.42
daily mo to %0.12; P < 0.001)
! 6-mo net lumen gain: 1.0 mm vs
0.68 mm (difference: %0.32;
95% CI: %0.46 to %0.18; P < 0.001)
! 9-mo TVF: 12.4% vs 21.6% (RR: 1.7;
95% CI: 1.1-2.8; P ¼ 0.02)
! 9-mo TLR: 8.5% vs 19.2% (RR: 2.3;
95% CI: 1.3-3.9; P ¼ 0.004)
TAXUS V 2006 396 N/A BMS Focal: 23.9 (94); IVBT vs Aspirin 325 mg daily $9 Angiographic ! Restenosis: 31.2% vs 14.5% (RR:
ISR89 diffuse: 53.9 PES mo þ clopidogrel and 0.47; 95% CI: 0.30-0.71; P < 0.001)
(212); 75 mg daily $6 mo clinical: 9 ! TLR: 13.9% vs 6.3% (RR: 0.45;
proliferative: or $12 mo in patients mo 95% CI: 0.24-0.86; P ¼ 0.01)
21.4 (84); with IVBT þ new stent ! TVR: 17.5% vs 10.5% (RR: 0.60;
occlusive: 0.8 (3) 95% CI: 0.36-1.0; P ¼ 0.046)
! MACE: 20.1% vs 11.5% (RR: 0.57;
95% CI: 0.35-0.93; P ¼ 0.02)
INDEED110 2008 129 >50 BMS Diffuse: 100 SES vs Aspirin 200 mg daily Angiographic ! LLL: 0.15 $ 0.62 vs 0.55 $ 0.69 mm
(129) IVBT indefinitely, and IVUS: (P ¼ 0.003)
clopidogrel 75 mg 6 mo; ! Restenosis: 8.0% vs 30.2% (P ¼ 0.006)
daily for 6 mo, þ clinical 12 ! TLR: 4.6% vs 18.8% (P ¼ 0.014)
cilostazol 200 mg mo ! MACE: 7.7% vs 18.8% (P ¼ 0.073)
daily for 1 mo
ISAR-DESIRE 2010 450 $50 DES Focal: 62.9%; SES vs PES Aspirin 200 mg daily Angiographic ! LLL: 0.40 $ 0.65 vs 0.38 $ 0.59 mm
263 diffuse: 32.7%; indefinitely þ 6–8-mo (P ¼ 0.85)
proliferative: clopidogrel 150 mg follow-up ! Restenosis: 19.6% vs 20.6% (P ¼ 0.69)
0.2%; occlusive: daily for 3 days then ! Death/MI: 6.1% vs 5.8% (P ¼ 0.86)
4.1% 75 mg daily for $6 mo ! ST: 0.4% vs 0.4% (P > 0.99)
CRISTAL111 2012 197 $50 DES N/A SES vs PB Aspirin 75 mg daily 12 mo ! Immediate gain: 1.39 $ 0.51 vs 0.97
indefinitely þ $ 0.54 mm (P < 0.0001)
clopidogrel 75 mg ! Net gain: 1.07 $ 0.69 vs 0.49 $
daily for 1 mo or $6 0.67 mm (P < 0.0001)
mo after SES ! MLD: 2.14 $ 0.62 vs 1.71 $ 0.55 mm
implantation (P < 0.0001)
! Diameter stenosis: 21 $ 19.24% vs
29.82 $ 18.47% (P ¼ 0.001)
! LLL: 0.37 $ 0.57 vs 0.41 $ 0.63
(P ¼ 0.73)
! In-stent restenosis: 11.1% vs 14%
(P ¼ 0.59)
! TLR: 5.9% vs 13.1% (P ¼ 0.097)
RIBS V75 2014 189 $50 BMS Focal: 38.1 (72); EES vs PEB Aspirin indefinitely þ Angiographic: ! MLD: 2.36 $ 0.6 vs 2.01 $ 0.6 mm
diffuse: 46.0 clopidogrel 75 mg 9 mo, (P < 0.001)
(87); daily for 1 y after EES clinical: 1 y ! Diameter stenosis: 13% $ 17% vs
proliferative/ implantation and 3 mo 25% $ 20% (P < 0.001)
occlusive: 15.9 after DCB therapy ! LLL: 0.04 $ 0.5 vs 0.14 $ 0.5 mm
(30) (P ¼ 0.14)
! Binary restenosis: 4.7% vs 9.5%
(P ¼ 0.22)
! MACE: 6% vs 8% (RR: 0.76; 95% CI:
0.26-2.18; P ¼ 0.6)
! TVR: 2% vs 6% (RR: 0.32; 95% CI:
0.07-1.59; P ¼ 0.17)
RIBS IV74 2015 309 >50 DES Focal: 63.4 EES vs PEB Aspirin 100 mg daily Angiographic: ! MLD: 2.03 $ 0.7 vs 1.80 $ 0.6 mm
(196); diffuse: indefinitely þ 6-9 mo; (P < 0.01)
31.4 (97); clopidogrel 75 mg clinical: 12 ! Net lumen gain: 1.28 $ 0.7 vs 1.01 $
proliferative: 5.2 daily $6 mo mo 0.7 mm (P < 0.01)
(16) ! Diameter stenosis: 23% $ 22% vs
30% $ 22% (P < 0.01)
! Binary restenosis: 11% vs 19%
(P ¼ 0.06)
! MACE: 10% vs 18% (RR: 0.58;
95% CI: 0.35-0.98,-P ¼ 0.04)
Continued on the next page
JACC VOL. 80, NO. 4, 2022 Giustino et al 363
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T A B L E 3 Continued

Sample Angiographic Stent Pattern of DAPT Type and

Study Year Size Stenosis, % Type ISR, % (n) Treatments Duration Follow-Up Study Finding

Drug-coated balloons
PEPCAD II73 2009 131 $70 BMS Focal: 42.7 (56); PEB vs PES Aspirin $100 mg daily Angiographic: ! In-segment LLL: 0.38 $ 0.61 mm vs
diffuse: 35.1 indefinitely þ 6 mo; 0.17 $ 0.42 mm (difference: %0.21;
(46); clopidogrel 75 mg clinical: 12 95% CI: %0.40 to %0.02; P ¼ 0.03)
proliferative: daily for 3 mo after mo ! Restenosis: 7% vs 20.3% (difference:
19.9 (26); PEB or 6 mo after PES %0.13; 95% CI: %0.27 to 0.01;
occlusive: 2.3 (3) implantation P ¼ 0.06)
! MACE: 9.1% vs 21.5% (difference:
%0.12; 95% CI: %0.26 to 0.01;
P ¼ 0.08)
! TLR: 6.3% vs 15.4% (difference:
%0.09; 95% CI: %0.21 to 0.03;
P ¼ 0.15)
PACCOCATH- 2012 108 $70 BMS Focal: 65.5 (72); PCB vs PB Aspirin 100 indefinitely þ 5-y follow-up ! MACE: 27.8% vs 59.3% (OR 0.26;
ISR I/II68 (96%) diffuse: 34.5 (38) clopidogrel 75 mg 95% CI: 0.118-0.592; P ¼ 0.009)
DES (4%) daily for 1 mo ! TLR: 9.3% vs 38.9% (OR 0.16;
95% CI: 0.055-0.468; P ¼ 0.004)
PEPCAD 2012 110 $70 DES Focal: 52.1 (111); PCB vs PB Aspirin 100 mg daily 6 mo ! LLL: 0.43 $ 0.61 mm vs 1.03 $ 0.77
DES112 or $50 diffuse: 43.7 indefinitely þ (P < 0.001)
and (93); clopidogrel 75 mg ! Restenosis: 17.2% vs 58.1% (P < 0.001)
ischemia proliferative: 4.2 daily for 6 mo ! MACE: 16.7% vs 50.0% (P < 0.001)
(9)
ISAR DESIRE 2013 402 $50 DES Focal: 66.8 PEB vs PES Aspirin 200 mg daily Angiographic: ! Diameter stenosis (PEB vs PES):
371 (334); diffuse: and PEB/ indefinitely þ oral 6-8 mo; 38.0% vs 37.4% (P for
27.6 (138); PES vs PB platelet ADP-receptor clinical: 12 noninferiority ¼ 0.011)
proliferative: 1.4 antagonist $6 mo mo ! Diameter stenosis (PB): 54.1% (P for
(7); occlusive: superiority [PEB and PES vs
4.2 (21) PB]: <0.0001 for both comparisons)
Habara et al67 2013 210 $50% BMS Focal: 52.1 (111); PCB vs PB Aspirin 100 mg daily þ Angiographic ! TVF: 6.6% vs 31.0% (P < 0.001)
(58%) diffuse: 43.7 ticlopidine 200 mg and ! Restenosis: 4.3% vs 31.9% (P < 0.001)
DES (93); daily or clopidogrel clinical: 6 ! LLL: 0.11 $ 0.33 vs 0.49 $ 0.50 mm
(42%) proliferative: 4.2 75 mg daily for $3 mo mo (P < 0.001)
(9)
PEPCAD 2014 215 $70 DES Focal: 63.3 PCB vs PES Aspirin 100 mg daily Angiographic: ! 9-mo in-segment LLL: 0.46 $ 0.51 vs
China or $50 (140); diffuse: indefinitely þ 9 mo; 0.55 $ 0.61 mm (P for
ISR94 and 19.5 (43); clopidogrel 75 mg clinical: 12 noninferiority ¼ 0.0005)
ischemia proliferative: daily for $12 mo mo ! 12-mo TLF: 16.5% vs 16.0% (P ¼ 0.92)
15.4 (34);
occlusive: 1.8 (4)
DARE113 2018 278 >50 DES Focal: 42.4 (118); PEB vs EES Aspirin for lifelong þ Angiographic: ! In-segment MLD: 1.71 $ 0.51 vs 1.74
diffuse: 27 (75); P2Y12 inhibitor for 12 6 mo; $ 0.61 (P ¼ 0.65)
proliferative: 6.5 mo clinical: 12 ! MACE: 10.9% vs 9.2% (P ¼ 0.66)
(18); occlusive 5 mo
(14)
BIOLUX114 2018 229 >50 DES Focal: 68.8 PCB vs EES Aspirin þ P2Y12 inhibitor Angiographic: ! In-stent LLL: 0.03 $ 0.40 vs 0.20 $
(167); diffuse: 28 per local standard 6 mo; 0.70 mm (difference: %0.17 $
(68); practice clinical: 12 0.52 mm; P for
proliferative: 2.5 mo noninferiority < 0.0001)
(6); occlusive: ! TLF: 16.7% (95% CI: 11.6%-23.7%) vs
0.4 (1) 14.2% (95% CI: 7.9%-24.7%;
P ¼ 0.65)

a
Patients enrolled from September 1998 to November 1998 who had a new stent placed received 250 mg ticlopidine twice daily for 14 days after the procedure. After November 1998, patients were treated
with 250 mg ticlopidine twice daily or 75 mg clopidogrel daily for $60 days. bAspirin was reduced to 100 mg daily after 6 months. Since the end of 2000, all patients enrolled had clopidogrel intake
extended to 12 months.
ADP ¼ adenosine diphosphate; BMS ¼ bare metal stent; CBA ¼ cutting balloon angioplasty; DAPT ¼ dual antiplatelet therapy; DCB ¼ drug-coated balloon; DES ¼ drug-eluting stent; DS ¼ diameter
stenosis; EES ¼ everolimus-eluting stent; ISR ¼ in-stent restenosis; IVBT ¼ intravascular brachytherapy; IVUS ¼ intravascular ultrasound; LLL ¼ late lumen loss; MACE ¼ major adverse cardiac event;
MI ¼ myocardial infarction; MLD ¼ minimum lumen diameter; PB ¼ plain balloon angioplasty; PCB ¼ paclitaxel-coated balloon; PEB ¼ paclitaxel-eluting balloon; PES ¼ paclitaxel-eluting stent;
ROTA ¼ rotablation; SES ¼ sirolimus-eluting stent; ST ¼ stent thrombosis; TLF ¼ target lesion failure; TLR ¼ target lesion revascularization; TVF ¼ target vessel failure; TVR ¼ target vessel revascularization.

scoring BA may enhance the efficacy of DCB ther-
apy.61 In the ISAR-DESIRE 4 (Intracoronary Stenting
and Angiographic Results: Optimizing Treatment of
Drug-Eluting Stent In-Stent Restenosis) trial, 61 252
patients with DES-ISR were randomized to pre-
dilatation with plain BA or scoring BA before DCB
treatment. At 6-8 months of angiographic follow-up,
patients who received scoring BA plus DCB had
significantly lower rates of in-segment diameter
percentage stenosis and binary angiographic reste-
nosis compared with BA plus DCB.61 A paclitaxel-
coated scoring balloon also has been developed
and performed favorably compared with an un-
coated scoring balloon in treating ISR. 62
364 Giustino et al JACC VOL. 80, NO. 4, 2022

Coronary In-Stent Restenosis JULY 26, 2022:348–372

types of DCBs are lacking and a class effect for all

T A B L E 4 Factors Favoring the Use of Drug-Coated Balloons vs DES Implantation
in ISR
Favors Drug-Coated Balloon Favors Repeated DES
! ISR with less aggressive pattern ! ISR with more aggressive pattern of ISR (eg,
of ISR (eg, focal) with good diffuse or occlusive) at high risk of
lumen expansion after balloon recurrence
dilatation ! ISR of DES
! ISR of BMS ! Single-layer ISR
! Multilayer ISR ! Presence of a stent-related mechanism (eg,
! Patients at high bleeding risk who stent fracture or stent gap)
cannot tolerate DAPT ! Suboptimal lumen expansion after balloon
! Major side branch involved to dilatation
avoid jailing
BMS ¼ bare-metal stent; DAPT ¼ dual antiplatelet therapy; DES ¼ drug-eluting stent; ISR ¼ in-stent restenosis.
REPEATED DES IMPLANTATION. Repeated
implantation is the most effective treatment of ISR
not due to stent underexpansion (Figure 7).58,59 In a
large network meta-analysis of RCTs evaluating
treatment strategies for ISR, everolimus-eluting stent
(EES) implantation was the most effective treatment
in improving diameter percentage stenosis at angio-
graphic follow-up, followed by DCB. 59 Also, ISR-PCI
with EES was consistently associated with a signifi-
cantly lower risk of TLR compared with all other
treatment strategies, with relative risk reductions
ranging from 64% (compared with DCBs) to 99%
(compared with standard BA). 59
Antiproliferative drug resistance has been pro-
posed as a potential mechanism of DES-ISR. However,
there is no clear evidence or consensus that a
different type of DES should be used when treating
DES-ISR. In the ISAR-DESIRE 2 trial, in which patients
with sirolimus DES-ISR were randomized to repeated
sirolimus-eluting stent or switch to paclitaxel-eluting
stent, there was similar antirestenotic efficacy be-
tween the 2 types of DES.63
DRUG-COATED BALLOONS. Coronary DCBs, though
not available in the United States, are widely avail-
able worldwide and constitute an important treat-
ment modality for ISR. DCBs consist
semicompliant balloon coated with antiproliferative
agents encapsulated in a lipophilic matrix that is
released into the wall after balloon inflation. Several
types of DCBs are available for commercial use
outside of the United States, which mostly use
paclitaxel as the antiproliferative drug because it is
more lipophilic and has faster cellular uptake
compared with limus-based drugs.64
generation sirolimus-eluting DCBs using different
delivery technologies to enhance tissue absorption
have been developed and have demonstrated prom-
ising results in registry data 64 and a recent RCT. 65
However, head-to-head RCTs comparing different
DCBs cannot be assumed.54 DCBs have been shown to
be effective and safe in the treatment of ISR in mul-
tiple RCTs. For BMS-ISR, DCBs have been demon-
strated to be superior to plain BA66–69 and to be at
least similar to first-generation DES. 70-72 Also, in DES-
ISR, DCBs have been proven to be superior to plain
BA67-73 and at least similar to first-generation DES. 71
However, in several studies, DCBs have been shown
to have inferior late angiographic outcomes compared
with new-generation DES in DES-ISR.74 In the RIBS
(Restenosis Intrastent of Bare Metal Stents) V trial, 75
309 patients with DES-ISR were randomized to DCB
vs EES. At angiographic follow-up (median 247 days),
DES EES resulted in larger minimal lumen diameter and
lower diameter percentage stenosis and binary
restenosis rate compared with DCBs. Also, at 1 year of
follow-up, EES resulted in significantly lower rates of
cardiac death, myocardial infarction, and TLR
compared with DCBs, mostly driven by lower rates of
TLR. These findings were confirmed in a large
patient-level pooled analysis of all RCTs comparing
DCB with repeated DES in patients with ISR: DCBs
were associated with similar rates of TLR at 3 years
compared with repeated DES in patients with BMS-
ISR (9.2% vs 10.2%; HR: 0.83; 95% CI: 0.51-1.37),
whereas they were significantly less effective than
repeated DES in DES-ISR (20.3% vs 13.4%; HR: 1.58;
95% CI: 1.16-2.13).76 Finally, in 2 large study-level
network meta-analyses of RCTs, DCBs were the sec-
ond most effective treatment of ISR after PCI with
EES (Figure 7).58,59
WHEN TO IMPLANT ANOTHER DES AND WHEN TO
USE DCBs. A summary of the factors that influence
the decision making between repeated DES and DCBs
in ISR is presented in Table 4. Repeated DES im-
plantation is the most effective treatment for DES-ISR
and should be preferred to improve long-term
patency of restenotic lesions with more aggressive
of a angiographic patterns (eg, diffuse or occlusive) at
high risk of recurrent restenosis or in case of stent
fracture or stent gap. DCBs offer the advantage of
releasing an antiproliferative drug while avoiding the
implantation of an additional metallic layer.8-10 DCBs
could be preferentially used in less complex rest-
enotic lesions (eg, focal or edge-related), multilayer
ISR to avoid the implantation of an additional layer of
Newer- DES, BMS-ISR, and patients at high risk for bleeding
who cannot tolerate prolonged periods of DAPT.
When treating ISR, DCBs are associated with smaller
final minimal lumen diameter compared with
repeated DES, which in turn is associated with higher
risk of TLR at follow-up.76 Therefore, ensuring
JACC VOL. 80, NO. 4, 2022 Giustino et al 365
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

F I G U R E 7 Network Meta-Analyses Comparing Treatment Strategies for In-Stent Restenosis

OR (95% CI) OR (95% CI)

EES vs DCB 0.36 (0.14-0.94) DCB vs EES 2.78 (1.06-7.14)

EES vs PES 0.34 (0.12-1.00) DCB vs PES 0.93 (0.51-1.71)

EES vs SES 0.34 (0.12-0.97) DCB vs SES 0.93 (0.55-1.58)

EES vs VBT 0.17 (0.06-0.51) DCB vs VBT 0.47 (0.26-0.86)

EES vs BMS 0.14 (0.04-0.47) DCB vs BMS 0.38 (0.17-0.84)

EES vs Rota 0.09 (0.03-0.31) DCB vs Rota 0.26 (0.12-0.55)

EES vs BA 0.09 (0.03-0.25) DCB vs BA 0.24 (0.15-0.40)

0.01 0.1 1 10 100 0.01 0.1 1 10 100

Group 1 Better Group 2 Better Group 1 Better Group 2 Better

Effect on target lesion revascularization.59 DCB ¼ drug-coated balloon; EES ¼ everolimus-eluting stent; Rota ¼ rotational atherectomy; VBT ¼ intravascular
brachytherapy; other abbreviations as in Figure 1.

adequate lumen expansion with the use of intra-
coronary imaging is important when using DCBs. In
case of suboptimal results in terms of lumen expan-
sion, repeated DES should be considered.
ATHEROABLATIVE THERAPY. The rationale of me-
chanical atheroablative therapy in ISR is to remove
the obstructive restenotic tissue and allow larger
final luminal gain. RA and ELCA are the 2 most
used atheroablative techniques in ISR. RA and ELCA
act by debulking the coronary plaque and removing
calcified tissue, typically to supplement or assist BA
and stent implantation. RA has been used in clinical
practice for more than 3 decades. 77,78 RA produces
lumen enlargement by physical removal of the
atherosclerotic plaque with the use of a diamond-
coated elliptical burr that rotates at high speeds
77,78
(140,000-180,000 rpm) over a guidewire.
burr preferentially ablates hard inelastic tissue while
avoiding the healthy arterial wall tissue (differential
cutting). In the setting of diffuse ISR, RA ablates the
NIH tissue to facilitate further stent expansion with
the use of high-pressure BA. 79,80 However, whether
routine NIH ablation with RA improves clinical
outcomes compared with BA alone is uncertain owing
to conflicting results from RCTs. 80,81 Although the RA
burr is capable of producing metallic stent ablation, it
should be used carefully in underexpanded stents to
prevent burr entrapment. Therefore, it is important to
characterize the underlying mechanism and substrate
of ISR by means of IVUS or OCT before using RA
in ISR.
ELCA has been used in clinical practice for >20
years.82 The excimer laser produces monochromatic
light energy that is absorbed by the plaque and, via
the generation of heat and shock waves, produces
plaque disruption. In early phases, outcomes of ELCA
in de novo coronary lesions were not favorable
compared with BA alone, owing to higher rates of
restenosis and major adverse cardiac events.82
The Currently, ELCA has been proposed as an attractive
treatment option for certain challenging subsets of
lesions, such as heavily calcified undilatable lesions
or diffuse ISR. In the setting of ISR, ELCA ablates in-
stent NIH and has been shown in observational
studies to be associated with a high rate of procedural
success and a low rate of periprocedural
366 Giustino et al
Coronary In-Stent Restenosis
complications compared with BA alone.83,84 In
another observational study in patients with BMS-
ISR, ELCA plus BA resulted in similar post-
intervention luminal dimensions on IVUS compared
with RA plus BA; however, volumetric IVUS analysis
showed significantly greater reduction in NIH volume
after RA than after ELCA. 85 In the setting of under-
expanded stents, ELCA should be use with caution
owing to the possible risk of vessel perforation and
severe no-reflow phenomenon.
Finally, orbital atherectomy is another device
approved for use in de novo severely calcified coro-
nary lesions, producing atheroablation via an ellip-
tical burr mechanism. The experience with orbital
atherectomy in ISR is currently limited and the
studies that led to commercial approval of orbital
atherectomy excluded ISR lesions. 86
INTRAVASCULAR BRACHYTHERAPY. IVBT inhibits
neointimal formation within the stent by delivering
localized radioactive strontium-90/yttrium-90 b-
radiation to suppress fibroblast proliferation. 87
IVBT
was approved for commercial use about 20 years ago
as a treatment for ISR of BMS. In the original Gamma-
87
One Trial, localized intracoronary irradiation with
iridium-192 resulted in lower rates of clinical and
angiographic restenosis compared with placebo, but
higher rates of late thrombosis, particularly in pa-
tients who received a second stent and those who
discontinued DAPT. IVBT was subsequently largely
replaced by DES for the treatment of BMS-ISR based
on the results of the SISR (Sirolimus-Eluting Stent vs.
Intravascular Brachytherapy in In-Stent Restenotic
88
Coronary Artery Lesions) and TAXUS V (Random-
ized Trial Evaluating Slow-Release Formulation
Taxus Paclitaxel-Eluting Coronary Stent in the
Treatment of In-Stent Restenosis)89 trials, which
demonstrated that sirolimus-eluting and paclitaxel-
eluting stents were superior to IVBT for the treat-
ment of BMS-ISR. Currently, IVBT represents an
attractive treatment option to treat recurrent or 2-
layer ISR of DES and is a Class IIb recommendation
to treat recurrent ISR in the most recent ACC/AHA
guidelines.55 In a recent observational study, Var-
57
ghese et al evaluated the outcomes of IVBT in
recurrent DES-ISR with at least 2 layers of stents at
the lesion site. A total of 328 patients were included.
Nearly 79% of patients had 2 stent layers and 21% had
3 layers or more. Compared with patients who did not
receive IVBT, those who were treated with IVBT had
lower risk of death, myocardial infarction, or TLR at 1
year. IVBT can be used in conjunction with adjunctive
ISR debulking with RA or ELCA. This strategy may
further improve clinical outcomes by increasing the
JACC VOL. 80, NO. 4, 2022
JULY 26, 2022:348–372
efficacy of IVBT, although supporting data are limited
with no randomized data available.85-90
INTRAVASCULAR LITHOTRIPSY. IVL is a new tech-
nology in which multiple lithotripsy emitters
mounted on a traditional catheter platform deliver
localized pulsatile sonic pressure waves liberating
bursts of energy that modify the calcified coronary
plaque. In de novo calcified coronary lesions, IVL
has been shown to be feasible, safe, and effective at
inducing calcific plaque fracture and atheroa-
blation. 91 In the setting of ISR, IVL has been re-
ported in limited case series to be feasible and
effective. 92 In particular, IVL could represent an
attractive treatment strategy to treat calcium-
mediated undilatable stent underexpansion or
calcified NIH, in which RA or high-pressure cutting
BA may be associated with a higher risk of vessel
perforation or rupture and suboptimal results. 92 In
severely calcified lesions, it may be helpful to
perform some lesion modification with high-
pressure noncompliant BA or cutting BA to
improve the deliverability of IVL and avoid poten-
tial damage to the IVL balloon.
MEDICAL THERAPY. Several medical therapies have
been evaluated to prevent ISR, with negative results. 9
After treatment of ISR, antiplatelet therapy can be
tailored based on the type of therapy used (Figure 8),
but RCTs evaluating the optimal duration of DAPT
after treatment of ISR are lacking. In a secondary
analysis of the PRODIGY (Prolonging Dual Antiplate-
let Treatment After Grading Stent-Induced Intimal
Hyperplasia) trial,93 among 224 patients who had PCI
for ISR, a regimen of 24 months of DAPT resulted in
lower rates of death, nonfatal myocardial infarction,
and cerebrovascular accidents compared with
6 months of DAPT, while no significant differences
were observed in patients who underwent PCI of de
novo lesions. In that study, all patients were treated
with repeated DES implantation and most patients
presented with acute coronary syndrome. In patients
treated for ISR with DCB, the largest RCTs have rec-
ommended durations between 3 and 12 months of
DAPT.71-74,94 Consistent with the most recent Euro-
pean Society of Cardiology and ACC/AHA guidelines,
after PCI for ISR in patients presenting with an acute
coronary syndrome, DAPT with 75-100 mg aspirin
daily plus a P2Y12-receptor inhibitor for at least 1 year
should be considered. Patients with ISR presenting
with stable CAD symptoms who are treated with a
DES should also receive at least 1 year of DAPT.
Shorter durations of DAPT can be considered if pa-
tients are treated with DCBs or cutting BAs, particu-
larly if at high risk for bleeding. Patients who received
JACC VOL. 80, NO. 4, 2022 Giustino et al 367
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

F I G U R E 8 Proposed Antithrombotic Treatment After PCI for ISR

In-Stent Restenosis

Stable Acute
coronary coronary
artery disease syndrome

ISR-PCI
Strategy DCB or CBA Repeat DES IVBT DCB or CBA Repeat DES

Recommended ≥3 Months ≥1 Year ≥1 Year ≥6 Months ≥1 Year

DAPT duration DAPT DAPT DAPT DAPT DAPT

• Patients at high bleeding risk should receive the minimum mandatory period of DAPT
Clinical • Ticagrelor or prasugrel should be used among patients who present with ACS
considerations
• Extension of DAPT beyond an initial mandatory period can be considered in patients
at high risk for recurrent ischemic events in absence of high-bleeding risk features

Following treatment of ISR, decisions concerning antiplatelet therapy should be based on the index clinical presentation, the type of treatment used, and the individual
bleeding risk profile. Dedicated randomized controlled trials evaluating antithrombotic strategies after treatment of ISR are lacking. ACS ¼ acute coronary syndrome;
CAD ¼ coronary artery disease; CBA ¼ cutting balloon angioplasty; DCB ¼ drug-coated balloon; other abbreviations as in Figure 1.

IVBT should be treated with extended duration of
DAPT if not at high risk for bleeding. Although there is
no robust evidence that more intense lipid-lowering
therapy reduces the risk of DES-ISR,
controlled pre-PCI low-density lipoprotein choles-
terol has been shown to be associated with higher risk
of early neoatherosclerosis. 95 In addition, in a recent
post hoc analysis from the FOURIER (Further Car-
diovascular Outcomes Research With PCSK9 Inhibi-
tion in Subjects With Elevated Risk) trial, 96 intense
lipid-lowering therapy with the PCSK9 inhibitor evo-
locumab resulted in significantly lower risk of
repeated revascularization due to ISR or ST among
patients with a history of PCI.
CORONARY ARTERY BYPASS GRAFTING. CABG is
associated with lower rates of repeated revasculari-
zation compared with PCI owing to the protective
effects of surgical grafts on progressive atheroscle-
rosis developing proximal to the anastomosed coro-
nary segment. Among patients who have undergone
PCI who develop recurrent ISR in large epicardial
vessels, such as the left main complex, or in those
with multivessel CAD, CABG should be considered
after heart team discussion instead of attempting a
repeated PCI, particularly in case of a 2-layer
ISR.11,54,55 While previous PCIs may influence and/or
compromise the choice of vascular targets for the
surgical anastomosis, in a large registry a history of
poorly previous PCI was not associated with worse mid- or
long-term outcomes after CABG.97
SPECIAL ISR SUBSETS
CHRONIC TOTAL OCCLUSION ISR. CTO-ISR consti-
tutes a challenging subset of ISR and is associated
with higher risk of revascularization failure at follow-
up compared with CTO of native coronary arteries
(Figure 9).98 In case of CTO-ISR, implementation of
advanced percutaneous CTO revascularization tech-
niques have improved the procedural success of
CTO-PCI.98 In a large patient-level pooled analysis of
4 multicenter registries including 11,961 CTO PCIs,
ISRs constituted 15% of all CTOs.98 Technical and
procedural success was similar for CTO-PCI of ISR and
de novo CTOs (both 85%). Antegrade wiring was the
most common successful strategy for CTO-ISR (70%)
followed by retrograde crossing and antegrade
dissection re-entry technique. 98 At 12 months, pa-
tients who had PCI of CTO-ISR had higher rates of
major adverse cardiac events compared with CTO-PCI
of de novo lesions.98
368 Giustino et al
Coronary In-Stent Restenosis
F I G U R E 9 Chronic Totally Occluded In-Stent Restenosis PCI
Example of PCI of CTO-ISR with OCT imaging (A) after wiring and ballooning and (B) after final stenting. Abbreviations as in Figures 1 and 4.
ISR IN SAPHENOUS VEIN GRAFTS. PCI of saphenous
vein grafts (SVGs) are associated with a high risk of
adverse ischemic events compared with PCI of de
novo lesions.99 In a recent analysis from the DIVA
(Drug-Eluting Stents vs. Bare Metal Stents in Saphe-
nous Vein Graft Angioplasty) trial, ISR developed in
21% of patients treated with BMS or DES at a median
follow-up of 2.7 years. 100 Considering the high risk of
adverse events associated with treatment of ISR
within SVGs, treatment of the native vessels, in
presence of adequate targets for revascularization
should be preferred.101
LEFT MAIN ISR. The need for a repeat procedure
after PCI of the left main coronary artery (LM) may
be associated with substantial morbidity and mor-
tality owing to the large amount of subtended
myocardium at risk. 102 In the EXCEL (Evaluation of
Xience vs Coronary Artery Bypass
for Effectiveness of Left Main Revascularization)
trial,102 the need for repeated revascularization of
the target LM lesion was associated with higher risk
of all-cause and cardiovascular mortality compared
with patients who did not require repeated revas-
cularization, after both PCI and CABG. Although the
early outcomes of PCI of LM-ISR are similar to PCI of
JACC VOL. 80, NO. 4, 2022
JULY 26, 2022:348–372
de novo LM lesions, LM-ISR is associated with higher
rates of TLR over time. 103 CABG after heart team
discussion should be strongly considered in good
surgical candidates with LM-ISR.
CONCLUSIONS
The global burden of ISR remains a significant clinical
problem even with contemporary DES platforms.
In fact, the need for TLR after DES implantation con-
tinues to occur at absolute rates of 1%-2% per year,
and 10%-20% of patients who develop a first event
of ISR develop recurrent ISR. The mechanisms of
ISR are heterogeneous, and its management remains
challenging. Characterization and identification of
the underlying mechanisms and substrate of ISR
with the use of intracoronary imaging should be
Surgery performed to guide clinical management. Repeated
DES implantation is the most effective treatment
for single-layer ISR in reducing the need for repeated
TLR, particularly in subsets of more severe patterns
of ISR. DCBs are an attractive treatment option for
multilayer ISR and restenosis within small vessels;
however, this technology is currently not approved
for use in the United States. Finally, a heart team
JACC VOL. 80, NO. 4, 2022 Giustino et al 369
JULY 26, 2022:348–372 Coronary In-Stent Restenosis

approach is advised for patients with recurrent ISR
who are surgical candidates, particularly in presence
of multivessel CAD. While future iterations in DES
technology may continue to reduce the risk of ISR over
time and need for repeated revascularization, further
research is needed to expand the interventional
armamentarium to treat ISR.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Giustino has received advisory board fees from Bristol Myers
Squibb/Pfizer. Dr Mehran has received institutional research pay-
ments from Abbott, Abiomed, Alleviant Medical, AM-Pharma,
Applied Therapeutics, Arena, AstraZeneca, BAIM, Bayer, Beth
Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol
Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi,
Concept Medical, CSL Behring, DSI, Duke University, Element Sci-
ence, Humacyte, Insel Gruppe, Janssen, Magenta, Medtronic,
Novartis, OrbusNeich, Philips, Vivasure, and Zoll, Dr Stone has
received speaker and other honoraria from Cook, Terumo, Orchestra
Biomed, and Qool Therapeutics; has served as a consultant to
TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore,
Ablative Solutions, Matrizyme, Miracor, Neovasc, V-Wave, Abiomed,
Shockwave, MAIA Pharmaceuticals, Cardiomech, SpectraWave, Val-
fix, Ancora, and Vectorious; and owns equity/options in Applied
Therapeutics, Biostar family of funds, MedFocus family of funds,
Aria, Cardiac Success, Cagent, SpectraWave, Valfix, Ancora, Or-
chestra Biomed, and Qool Therapeutics. Dr Sharma has received
honoraria as a Speakers Bureau member from Abbott Vascular,
Boston Scientific, and Cardiovascular Systems. All other authors
have reported that they have no relationships relevant to the con-
tents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr Samin K.
Sharma, Zena and Michael A. Wiener Cardiovascular
Institute, Icahn School of Medicine at Mount Sinai,
One Gustave L. Levy Place, Box 1030, New York, New
York 10029-6574, USA. E-mail: samin.sharma@
mountsinai.org.

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KEY WORDS coronary artery disease,
drug-eluting stent, in-stent restenosis,
revascularization
A PPE NDI X For supplemental material,
please see the online version of this paper.