Standards and Guidelines
MSc,
M
FSCAI
b
Section
,
and assessment of
recommends image-
stent thrombosis are
............. 7
............. 7
............. 7
.............10
.............10
...........12
.............13
.............13
.............13
.............13
Abbreviations: BMS, bare metal stents; DAPT, dual antiplatelet therapy; DCB, drug-coated balloons; DES, drug-eluting stents; ISR, in-stent restenosis; IVUS, intravascular ultra-
sound; MACE, major adverse cardiovascular events; OCT, optical coherence tomography; RCT, randomized clinical trial; ST, stent thrombosis.
Keywords: coronary stenting; in-stent restenosis; major adverse cardiovascular events; stent thrombosis; target vessel failure.
Corresponding author: Amir.Lot?MD@baystatehealth.org (A. Lot?).
https://doi.org/10.1016/j.jscai.2023.100971
Available online XX XXXX
2772-9303/? 2023 The Author(s). Published by Elsevier Inc. on behalf of Society for Cardiovascular Angiography and Interventions Foundation. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
Stent thrombosis ..................................... 7 References . ........................................13
sensitive with mechanistic implications of in-stent restenosis is proposed. Emphasis is placed on frequent use of intracoronary imaging
timing to determine the precise etiology because that information is crucial to guide selection of the best treatment option. SCAI
guided coronary stenting at the time of initial implantation to minimize the occurrence of stent failure. When in-stent restenosis and
encountered, imaging should be strongly considered to optimize the subsequent approach.
Table of Contents
Introduction. . . ...................................... 2
Methodology . . . ................................. 2
In-stent restenosis . . . ................................. 2
Risk factors ...................................... 2
Pathogenesis and contributory factors. . . ................ 2
De?nition and classi?cation .......................... 3
Imaging adjuncts to diagnosis . . ...................... 3
Physiologic assessment . . ........................... 3
Proposed treatment strategies . . ...................... 3
Incidence and clinical presentation . . . .....
Classi?cation . . ......................
Pathogenesis. . ......................
Correlates of timing of ST and mechanism . .
Diagnostic imaging modalities ...........
Mechanical and pharmacologic treatment of ST
Conclusion . ...........................
Declaration of competing interest. ...........
Funding sources . . ......................
Supplementary material . . . ................
York, New York;
d
Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
e
Clinical Trials Center, Cardiovascular
Research Foundation, New York, New York;
f
DeMatteis Cardiovascular Institute, St. Francis Hospital & Heart Center, Roslyn, New York;
g
Division of
Cardiology, Duke University School of Medicine, Durham, North Carolina;
h
Allina Health Minneapolis Heart Institute, Minneapolis, Minnesota;
i
Department
of Interventional Cardiology, Baylor Scott & White Health – The Heart Hospital, Plano, Texas;
j
Zena and Michael A. Wiener Cardiovascular Institute, Mount
Sinai Medical Center, New York, New York;
k
Division of Cardiology, NYU Langone Health System, New York, New York;
l
Division of Cardiology, University of
Massachusetts Chan Medical School – Baystate, Spring?eld, Massachusetts
ABSTRACT
Stent failure remains the major drawback to the use of coronary stents as a revascularization strategy. Recent advances in imaging have substantially
improved our understanding of the mechanisms underlying these occurrences, which have in common numerous clinical risk factors and mechanical ele-
ments at the time of stent implantation. In-stent restenosis remains a common clinical problem despite numerous improvements in-stent design and polymer
coatings over the past 2 decades. It generates signi?cant health care cost and is associated with an increased risk of death and rehospitalization. Stent
thrombosis causes abrupt closure of the stented artery and therefore carries a high risk of myocardial infarction and death. This Society for Cardiovascular
Angiography & Interventions (SCAI) Expert Consensus Statement suggests updated practical algorithmic approaches to in-stent restenosis and stent
thrombosis. A pragmatic outline of assessment and management of patients presenting with stent failure is presented. A new SCAI classi?cation that is time-
SCAI Expert Consensus Statement on Management
and Stent Thrombosis
Lloyd W. Klein, MD, MSCAI
a
, Sandeep Nathan, MD,
FSCAI
c
, John Messenger, MD, SCAI
d
, Gary S. Mintz,
Jennifer Rymer, MD, FSCAI
g
, Yader Sandoval, MD,
Roxana Mehran, MD, MSCAI
j
, Sunil V. Rao, MD, FSCAI
a
Division of Cardiology, University of California, San Francisco, San Francisco, California;
Chicago, Chicago, Illinois;
c
Center for Interventional Vascular Therapy, Division of Cardiology
of In-Stent Restenosis
FSCAI
b
, Akiko Maehara, MD,
D
e
, Ziad A. Ali, MD, DPhil, FSCAI
f
,
h
, Karim Al-Azizi, MD, FSCAI
i
,
k
, Amir Lot?, MD, FRCP, FSCAI
l,
of Cardiology, Department of Medicine, University of
Columbia University College of Physicians and Surgeons, New
and organizational approval. Detailed author disclosures are included
as Supplemental Table 1. The work of the writing committee was
an increased risk of death and rehospitalization. The incidence of ISR is
Neoatherosclerosis is an increasingly recognized mechanism of
stent failure seen with current generation DES. It is characterized by
endothelium allows incorporation of low-density lipoprotein into the
artery wall early after DES implantation. At later stages, the healed
in-stent neointima is prone to atherosclerosis development.
Additional mechanisms of ISR include elastic recoil and relocation/
subluxation of axially transmitted plaque (tissue intrusion) (especially
early) and reorganization of thrombus, neointima formation, and
remodeling (especially late).
6–16
Mechanical factors. The primary mechanical cause of ISR is under-
expansion. This may result from stent undersizing, low deployment
pressures, or underlying calci?ed lesions. Other mechanical causes
include stent recoil, longitudinal stent deformation, stent fracture,
crushed stents, dislocated stents, and geographic miss. Geographic
missresultsfromincorrectplacementofthestentsothatitdoesnotfully
2 L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
10%;25%ofISRcasespresentwithacutemyocardialinfarction(MI)with
a 30-day mortality rate of 10% to 25%.
1–4
Risk factors
Clinical. The incidence of ISR varies depending on individual pa-
tient, angiographic and procedural characteristics as listed in
Table 1.
1–15
Second-generation drug-eluting stents (DES) have a 5.7%
ISR rate in patients without diabetes, and 8.7% rate in those with dia-
betes.
5
Beyond 1 year, there is a gradual increase in major adverse
cardiovascular events (MACE); the 5-year ISR rate is 9% to 12% in
noncomplex lesions.
6
Recurrent ISR is not unusual in contemporary practice. The failure to
appreciate and address the original mechanism of ISR underlies re-
fractory cases of recurrence. As in ?rst ISR, the use of intracoronary
imaging may provide insights into the underlying mechanisms. Recur-
rent ISR occurs in approximately 20% of all ISR cases.
7,8
Recurrence is
supported exclusively by SCAI, a nonpro?t medical specialty society,
without commercial support. Writing group members contributed to
this effort on a volunteer basis and did not receive payment from SCAI.
Group members in each section performed literature searches, and the
section leads in collaboration authored initial section drafts with other
members of the writing group. The draft manuscript was peer reviewed
in February 2023 and the document was revised to address pertinent
comments. The writing group unanimously approved the ?nal version
of the document. The SCAI Publications Committee and Executive
Committee endorsed the document as of?cial society guidance in
March 2023. SCAI statements are primarily intended to help clinicians
make decisions about treatment alternatives. Clinicians also must
consider the clinical presentation, setting, and preferences of individual
patients to make judgments about the optimal approach.
In-stent restenosis
ISR remains a common clinical problem despite numerous im-
provements in-stent design and polymer coatings over the past 2 de-
cades. ISR generates signi?cant health care cost and is associated with
and assessment of timing to determine the precise etiology, as that in-
formation is crucial to guide selection of the best treatment option.
Methodology
This statement has been developed according to SCAI Publications
Committee policies for writing group composition, disclosure and
managementofrelationshipswithindustry,internalandexternal review,
Introduction
Coronary stenting has transformed revascularization strategy, pro-
ducing excellent procedural and clinical outcomes in myriad clinical
settings. Despite proven short and long-term bene?ts, in-stent reste-
nosis (ISR) and stent thrombosis (ST) continue to be limitations. There
remains no de?nitive management approach for either condition
despite a greater understanding of the underlyingmechanismsensuing
from advances in intracoronary imaging.
In this Society for Cardiovascular Angiography & Interventions (SCAI)
Expert Consensus Statement, practical algorithmic approaches to ISR
and ST are offered. A pragmatic outline of assessment and management
of patients presenting with stent failure is presented. A new SCAI clas-
si?cation that is time-sensitive with mechanistic implications of ISR is
proposed. Emphasis is placed on frequent use of intracoronary imaging
accumulation of lipid-laden foamy macrophages sometimes with
necrotic core formation within stented segments.
16
Injury to the vessel
by balloon in?ation and stent deployment stimulates neointima for-
mation. The subsequent intimal and medial damage leads to prolifer-
ation and migration of vascular smooth muscle cells, macrophages, and
extracellular matrix formation. These activate the coagulation cascade
and an in?ammatory response. This combination of events, along with
elution of antiproliferative drug, inhibits endothelialization. The lack of
independently predicted by the number of stents placed at the loca-
tion.
9,10
The 1-year MACE (43.1%) and target lesion revascularization
(41.2%) rates were signi?cantly higher in the C213 stent layer group than
in the 1-stent-layer and 2-stent-layer groups. Importantly, on multivari-
able analysis, the number of metallic layers and hemodialysis require-
ment were identi?ed as independent predictors of MACE. A third layer
of metal is almost always associated with underexpansion and should
be avoided.
Pathogenesis and contributory factors
The preferred treatment strategy depends on a precise diagnosis
and understanding of the cause. Consequently, identifying the mech-
anism in each case using intracoronary imaging and optimizing the
interventional result are critical steps (Table 1).
Biologic factors. The primary biologic mechanism of ISR is neointimal
tissue proliferation or hyperplasia, an exaggerated homeostatic healing
response to arterial wall damage sustained during stent implantation.
1
Thedistributionofneointimaltissueproliferationmaybefocalordiffuse
along the length of the stent. Causative factors are local in?ammation
resulting from mechanical disruption of the intima/media leading to
aggressive neointimal hyperplasia/proliferation that consists of smooth
muscle cells and extracellular matrix. Hypersensitivity reactions to the
metal and/or the polymer of early-generation DES are also recognized
mechanisms of neointimal hyperplasia.
1
Table 1. In-stent restenosis risk factors
1–15
Patient factors Angiographic factors Procedural factors
C15 Diabetes
mellitus
C15 Renal
insuf?ciency
C15 ACS
presentation
C15 Female
C15 Recurrent ISR
C15 Lesion length >20 mm
C15 Diameter <3mm
C15 Chronic total occlusion
C15 Ostial location
C15 Bifurcation
C15 Saphenous vein graft
C15 Severe Calci?cation
C15 Multivessel CAD
C15 Underexpansion
C15 Stent fracture
C15 Bare metal stent
C15 Stenoses proximal and distal
to stent
C15 Major arterial dissection
involving media or >3mm
length
C15 Multiple stent layers
ACS, acute coronary syndrome; CAD, coronary artery disease; ISR, in-stent
restenosis.
coverthe diseasedsegment. Stent fracture may be seenat hingepoints
in the coronary artery and after stenting a calci?ed nodule. Other
?ndings, such as early-stent malapposition, tissue prolapse, and
asymmetry/eccentricity have little or no prognostic value. Stent
underexpansion may occur as a result of undersizing, low deployment
pressures, or heavily calci?ed lesions.
9–13
Some interventional cardiologists favor routine poststent placement
dilation with high-pressure balloons; while this can be an effective
strategy, it can also lead to edge dissections. Instead, postprocedural
imaging might be a more effective use of time and effort.
De?nition and classi?cation
assessment of the native artery and stented segment (Figure 1A, B).
Physiologic assessment
Classi?cation Time interval Morphologic substrates
L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx 3
Early <30 d C15 Undersizing
C15 Underexpansion
C15 Stent fracture
Late 30 d to 1 y C15 Delayed healing (including drug induced)
C15 Uncovered stent struts
C15 Intimal hyperplasia (especially in BMS ISR)
Very late >1y C15 Neoatherosclerosis
C15 Intimal hyperplasia
C15 Stent fracture
BMS, bare metal stent; ISR, in-stent restenosis.
In-stent restenosis is established angiographically as a binary event,
de?ned as recurrent diameter stenosis at the stent segment >50% of
the vessel diameter.
16
Additional criteria for clinically relevant ISR
include: recurrent angina, objective signs of ischemia, or abnormal
fractional ?ow reserve.
17–19
Morphologic patterns. Coronary angiography remains the standard
diagnostic method to determine ISR severity and morphologic pattern:
Mehran. The Mehran System
19
classi?es restenotic lesions on the basis
of morphology and extent of disease, with 4 subclasses based on
location within the stented segment. Lesions were classi?ed as focal
(class I), diffuse intrastent (class II), diffuse proliferative (class III), and
total occlusion (class IV). This schema was highly relevant to bare metal
stenting (BMS), but its applicability to DES ISR is uncertain.
Waksman. The Waksman ISR Classi?cation
20
is based on mechanistic
considerations informed by intracoronary imaging. There are 5 groups
of DES ISR identi?ed: mechanical (type I; underexpansion I A, stent
fractureIB),biologic(typeII;intimalhyperplasiaIIA,neoatherosclerosis
noncalci?ed II B, neoatherosclerosis calci?ed II C), mixed pattern (type
III), chronic total occlusions (type IV), and lesions previously treated with
>2 stents (type V).
Intravascular ultrasound- and optical coherence tomography-based
classi?cations. Kang et al
21
has proposed an intravascular ultrasound
(IVUS)-based classi?cation that incorporates length of the restenosis as
well as minimal luminal area. Gonzalo et al
22
and Ali et al
23
have pro-
posed optical coherence tomography (OCT) classi?cations that rely on
both quantitative and qualitative parameters.
Timing. Table 2 is the proposed new SCAI classi?cation incorporating
the cause of ISR based on time from implantation. SCAI recommends
that early (<30 days), late (30 days to 1 year), and very late (>1 year)
timing categories be adopted for all future diagnostic and therapeutic
studies. By integrating mechanistic etiology with timing, this classi?-
cation will be useful to determine best treatment options.
Table 2. SCAI classi?cation of in-stent restenosis: a system based on time
interval and causative factor
Patients with ISR of intermediate range severity on coronary angi-
ography present a clinical challenge because of potential short and
long-term complications, and it is recommended that objective evi-
dence of myocardial ischemia is demonstrated prior to proceeding with
repeat intervention. Even though there are no randomized clinical trials
(RCTs) assessing coronary physiology to guide management of ISR,
there are several retrospective observational trials that suggest that it
may assist in clinical decision-making.
36,37
Deferral of coronary revas-
cularization in patients with ISR and fractional ?ow reserve >0.80 was
associated with similar outcomes over 36 months to patients with de
novo coronary stenosis.
37
Further studies may de?ne the value of cor-
onary physiology assessment in developing decision strategy before
and after intervention.
Proposed treatment strategies
A summary of existing RCTs and registries,
20,38–51
including clinical
situations in which particular treatment modalities have been shown to
be advantageous, are presented in Table 4.
52–55
The most common
treatment approach for the ?rst episode of ISR is to implant a second
DES, based on the rationale that DES therapy has superior ef?cacy over
balloon angioplasty alone. However, this is not always necessary and
may not bethe bestsolution,particularlywhenthe referencevesseland
the resultant minimal lumen area are small.
20
If the underlying etiology
is not directly addressed and corrected, there is a high likelihood of
recurrent ISR, and the rate of ISR in second layer DES is high: 12% to
16% at 12 months and 33% at 3 to 5 years.
56–58
General strategic approach. The critical principle is to obtain the
largest acute lumen gain as possible by maximizing the immediate
Recentintravascularimagingstudiesdemonstratethatsuboptimalstent
deployment is common—occurring in 31% to 58% of patients—and
that suboptimal stent deployment confers an increased risk of adverse
events.
30–33
The relative advantages of IVUS and OCT are summarized
in Table 3.
34,35
Suboptimal minimal stent area (MSA) is a major predictor of stent
failure, and an IVUS optimized MSA of >5.0 mm
2
or OCT optimized
MSA of >4.5 mm
2
are optimal goals. Another useful criterion is to
achieve a target MSA >90% of the closest proximal or distal reference
segment. In addition, intraluminal diagnostic imaging should be per-
formed to ensure that there are no in?ow or out?ow obstructions within
5 mm of the proximal or distal stent edge. In particular, any major edge
dissections (de?ned as >60
C14
, >3 mm in length, or penetrating the
media) should be stented.
33–35
Imaging adjuncts to diagnosis
SCAI strongly recommends routine evaluation by intravascular im-
aging to determinethe cause of ISR,to inform therapeutic strategy, and
to con?rm effective treatment after percutaneous coronary intervention
(PCI).
24–29
Identifying the mechanism of stent failure is paramount
because the causative factors will in?uence the selection of treatment
and devices to manage the ISR, ultimately impacting the durability of
the repeat revascularization. Despite being the primary means of
assessing ISR in clinical practice, angiography alone is usually inade-
quate because of limited resolution and inherent de?ciency in quanti-
fying vessel size, stent size, stent expansion, number of stent layers,
in-stent calci?c neoatherosclerosis, and extrastent calci?c disease.
Identifying the mechanism of ISR depends on visualizing the stent and
its relation to the arterial wall, rather than the lumen itself.
In contrast to angiography, IVUS and OCT provide detailed
Figure 1.
4 L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
Neointimal HyperplasiaStent Under-expansion Stent Fracture Neoatherosclerosis
Minimum Stent Area 2.95 mm
2
Neointima Lumen AreaLipidic Neoatherosclerosis Old Stent StrutsCalcium
ABCD
Ac Bc Cc Dc
Acc Bcc Ccc Dcc
Coronary
Angiogram
OCT
Mechanism of
Stent Failure
Top
Neointimal HyperplasiaStent Under-expansion Stent Fracture Neoatherosclerosis
ABCD
Coronary
Angiogram
Bottom
In-Stent Restenosis
postprocedural minimal luminal area. To operationalize this concept, a
complete diagnostic evaluation of the cause of ISR must be pursued.
59
An algorithmic approach is provided in Figure 2. Repeat PCI should be
routinely performed following intracoronary imaging assessment. The
mechanism of the initial ISR should be determined, with correction of
any underlying mechanical factors with image guidance to ensure
optimal sizing and expansion. A second stent should be image-guided
to ensure correct stent expansion to ensure appropriate stent
expansion.
Besides repeat DES, a number of adjunct treatments exist that may
be highly effective.
58–69
If there is signi?cant underexpansion, it is
critical to increase expansion by applying high-pressure balloons. If
there is additional hyperplasia, perhaps preparation with scoring/cut-
ting balloons, rotational atherectomy (RA), orbital atherectomy (OAS),
drug-coated balloons (DCBs), vascular brachytherapy (VBT), excimer
laser coronary angioplasty (ELCA), or intravascular lithotripsy (IVL) may
be useful.
When ISR is predominantly because of neointimal hyperplasia,
treatment is dependent on the pattern of ISR. For focal ISR, a high-
pressure or scoring/cutting balloon may be suf?cient; ELCA or athe-
rectomy may be bene?cial in selected cases. For diffuse ISR, atherec-
tomy or scoring/cutting balloon angioplasty followed by repeat DES
implantation is typically advised.
If stent underexpansion is not because of calci?cation, atheroa-
blation should be used only if signi?cant neointimal hyperplasia is also
Neointima Lumen AreaCalcified Neoatherosclerosis Old Stent Struts
de novo Plaque
Minimum Stent Area 3.2 mm
2
Ac Bc Cc Dc
Acc Bcc Ccc Dcc
IVUS
Mechanism of
Stent Failure
Mechanisms of in-stent restenosis evaluated by intravascular
imaging. A
0
-D
0
are optical coherence tomography (OCT) or intra-
vascular ultrasound (IVUS) images corresponding to the in-stent
restenosis seen in the angiographic images (A-D, white arrows).
A
00
-D
00
are representative diagrams provided to clarify the intra-
coronary images, A
0
-D
0
. Top. Mechanisms of in-stent restenosis
evaluated by OCT. (A) A patient experienced recurrent in-stent
restenosis (ISR), and OCT visualized a severely underexpanded
stent because of circumferential thick calcium behind stent with only
a minimum amount of neointimal hyperplasia. (B) This patient was
treated with a single drug-eluting stent. At the time of ISR, the OCT
image showed a lack of stent struts over half of the arterial
circumference (double headed arrow) while stents struts were
overlapped at 7 to 9 o’clock. These are typical features of stent
fracture. (C) Excess amount of neointimal hyperplasia within a well-
expanded stent. (D) Lipidic neointima (strong signal attenuation)
within the stent struts indicating neoatherosclerosis. Bottom.
Mechanisms of in-stent restenosis evaluated by IVUS (A) IVUS visu-
alized an underexpanded stent with a minimum amount of neo-
intimal hyperplasia. By looking at the adjacent segment, the cause
of underexpansion was a small vessel with a myocardial bridge. (B)
IVUS delineates overlapped struts within a single stent at 7 to 10
o’clock indicating stent fracture. (C) Excess amount of neointimal
hyperplasia within a well-expanded old stent. (D) Calci?ed plaque
(super?cial hyperintensity with acoustic shadow from 8 to 12 o’clock)
within the stent indicates neoatherosclerosis.
present. RA, OAS, and ELCA may debulk neointima hyperplasia,
although mechanistic evaluations fail to demonstrate this effect. In
cases where intravascular imaging identi?es an arc of calcium>270
C14
or
>0.67 mm in thickness, atherectomy vessel preparation should be
considered to optimize lesion and stent expansion.
60–69
If stent underexpansion is due to signi?cant peri-stent calcium
(>90
C14
), RA, OAS, and ELCA may be employed to improve stent
underexpansion by disrupting the calci?ed plaque behind the stent.
IVL may also be useful. These techniques are associated with cal-
cium modi?cation and/or fracture, and when followed by high-
pressure in?ations may reduce stent underexpansion. However, if
unsuccessful, coronary artery bypass grafting may be necessary (see
Figure 3).
Balloon angioplasty. Balloon angioplasty should be the initial step in
focal lesions or if short dual antiplatelet therapy (DAPT) duration is
required. In the setting of stent underexpansion, high-pressure non-
compliant balloon in?ations are the preferred strategy.
Super high-pressure balloons. Double layer, noncompliant coronary
balloons (OPN NC, SIS Medical) capable of in?ation pressures ranging
from 35 to 55 atm have recently become available in the United States.
This class of percutaneous transluminal coronary angioplasty balloon
has performed favorably in severely calci?ed de novo lesions and may
be a consideration in ISR secondary to an underexpanded stent.
Repeat DES. In general, repeat DES implantation has historically
shown superior results compared with balloon angioplasty alone.
However, this approach should only be undertaken once appropriate
sizing and expansion of the original stent has been assured using
intravascular imaging. A second stent may not be necessary of the
original stent was underdeployed and can be corrected.
If focal edge restenosis, stent gap, or stent fracture is identi?ed,
conventional or high-pressure balloon dilation at the site of the me-
chanical complication should be the initial treatment. This should then
be followed by repeat DES implantation when the ISR is focal. Repeat
DES to cover the entire diseased segment can be performed when the
ISR is diffuse or proliferative, but care should be taken to minimize the
stentcoverageasmuchaspossible.
44–52
Thereisnode?nitiveevidence
regarding which type of DES should be used to treat ISR of a previously
implanted DES, and there is no consensus on whether a different stent
type or drug should be used when an additional DES is implanted.
However, the RIBS III trial
38
assessed the impact of selecting a different
DES for treatment of ISR and demonstrated better angiographic and
clinical outcomes at 9-month follow-up in the cohort that received a
different DES than the ?rst implanted stent.
Cutting and scoring balloons. The use of balloons incorporating
cuttingorscoringelements hasbeenshowninverysmall seriesto result
Table 3. Applications of OCT vs IVUS
34,35
IVUS OCT
Assessing lesion severity in left main disease ttt t
Assessing de novo lesion characteristics
Thin cap ?broatheroma C0 ttt
Thrombus t ttt
Plaque rupture tt ttt
Calci?ed nodule t ttt
Dissection tt ttt
Positive remodeling ttt t
Plaque burden ttt t
Aorto-ostial disease ttt C0
Stent optimization
Expansion tt ttt
Apposition tt ttt
Stent failure
Neointimal hyperplasia t
Underexpansion tt ttt
Malapposition tt ttt
Renal impairment ttt t
ttt Excellent; tt Good; t Poor; C0 Not advised
IVUS, intravascular ultrasound; OCT, optical coherence tomography.
Table 4. Summary of in-stent restenosis and stent thrombosis management strategies
Modalities of
treatment
When to consider Other considerations
In-stent restenosis
1,2,20,38–51
Balloon angioplasty C15 Focal, discrete lesions
C15 Stent underexpansion
C15 Need for short DAPT
C15 Risk of recurrence and edge dissection high
C15 Use of DCB associated with lower risk of TLR and binary restenosis
Repeat DES C15 If only one prior layer, may consider over balloon
angioplasty alone
a
C15 Focal edge restenosis, stent gap, stent fracture
C15 Reduction in need for target revascularization compared with angioplasty alone
C15 No de?nitive consensus for change in-stent type but RIBS III trial showed reduction of
restenosis rate and improved event-free survival in cohort receiving a different DES
platform
Cutting and scoring
balloons
C15 May modify neointimal growth
C15 May help to avoid additional stent layer
C15 Scoring balloon angioplasty superior to PTA alone at 6-8 mo (improved angiographic
outcomes and reduced stenosis)
Atheroablation C15 Should be considered if mode of stent underexpansion
calci?cation and resistant to high-pressure balloons
C15 Should be considered when signi?cant neointimal
hyperplasia present
C15 Clinical trials for use of atheroablation for ISR negative
DCB C15 May help to avoid additional stent layer C15 Treatment with DCB non-inferior to DES in terms of 6-mo MLD
Vascular
brachytherapy
C15 Refractory ISR
C15 Limited availability
C15 Due
C15 Treatment
Intravascular
lithotripsy
C15 May be considered when there is highly calci?ed
neoatherosclerosis
C15 Limited
Stent thrombosis
52–55
Balloon angioplasty C15 May be needed in addition to repeat DES and/or
aspiration thrombectomy to restore coronary blood ?ow
Repeat DES C15 May be needed in addition to PTA and/or aspiration
thrombectomy to restore coronary blood ?ow
C15 Should normally limit to signi?cant residual dissections
after PTA
C15 No
Aspiration
thrombectomy
C15 Consider when heavy thrombus burden present
C15 Consider adjunctive glycoprotein IIb/IIIa inhibitors if
persistent heavy thrombus burden after aspiration
C15 Associated
C15 Majority
Pharmacologic
therapies
C15 Consider glycoprotein IIb/IIIa inhibitor infusion
C15 Assess compliance and consider switch to higher
potencyantiplatelettherapy ifthepatient wascompliant
and still taking DAPT
C15 May consider drug resistance testing and prolonged
DAPT duration
C15 Consider
inhibitor
C15 Prolonged
thrombus
DAPT, dual antiplatelet therapy; DCB, drug-coated balloon; DES, drug-eluting stent; ISR,
intervention; PTA, percutaneous transluminal angioplasty; STEMI, ST-elevation myocar
a
Avoid when there are already 2 layers of stent
L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx 5
to delay in endothelialization, patients may need lifelong DAPT
can be repeated every 12 mo
data to suggest proper case selection
stent type associated with reduction in ST
with improved microvascular perfusion during STEMI because of ST
of patients undergoing aspiration thrombectomy had successful recanalization
patient’s renal function and bleeding risk when continuing glycoprotein IIb/IIIa
after PCI
anticoagulation and antiplatelet therapy may be bene?cial when residual
is detected following intervention
in-stent restenosis; MLD, minimal lumen diameter; PCI, percutaneous coronary
dial infarction; TLR, target lesion revascularization.
6 L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
in better acute angiographic outcomes in ISR compared with BA.
58,59
Small IVUS-guided studies suggest that the use of cutting compared
with traditional balloons is associated with larger lumen gain, lower
lumen loss, and preserved angiographic result at follow-up.
45,69
How-
ever, a randomized study comparing standard balloons vs cutting bal-
loons for the treatment of ISR failed to demonstrate superiority of the
cutting balloon in terms of recurrent ISR and MACE.
58
Atheroablation. Despite the appealing concept of atheroablation,
clinical trials for the treatment of ISR have been negative.
62–64
The
utilization of RA when IVUS or OCT con?rms the presence of calcium
within neoatherosclerotic plaques is reasonable, but no controlled trials
exist. RA might also have value in lesions refractory to high-pressure
balloon angioplasty. However, the use of mechanical atheroablative
technologies within stents poses risks of device entrapment, and some
suggest reserving mechanical atherectomy for bailout use. Excimer
laser has similarly shown no special bene?ts.
61,64,67
DCBs. Preliminary clinical studies using sirolimus-based DCBs showed
promisingpreliminaryresults; however, randomizedtrials are neededto
demonstrate ef?cacy with DES in ISR. Most data are with paclitaxel
DCBs. Several trials and meta-analyses have demonstrated similar
outcomes of DCB compared with DES in the management of
ISR
44,45,70,71–83
and are summarized in Table 5. Although coronary
DCBs are not available in the United States, the European Society of
Cardiology/European Association for Cardio-Thoracic Surgery Guide-
lines
65
give DCBs a class I indication for the treatment of ISR. DCB
outcomes may be optimized with in?ation time >60 seconds and a
balloon: artery ratio >0.91. Neointimal modi?cation with RA improves
Figure 2.
SCAI algorithmic approach to in-stent restenosis. DES, drug-eluting stents; ISR, in-stent restenosis;
acute luminal improvement over DCB therapy alone, with lower late
lumen loss; however, there are similar clinical outcomes at 6 months.
50
VBT. Vascular brachytherapy inhibits neointimal formation within the
stent by delivering radioactive Strontium-90 β-radiation locally,
decreasing proliferation. This treatment modality was commonly
employed for bare metal ISR 2 decades ago, with minimal long-term
bene?t demonstrated. The use of VBT has undergone resurgence in
use for DES ISR.
86,84,87
The more overlapping stent layers there are, the
less effective brachytherapy is for ISR. With 3 or more stent layers, the
3-yeartargetlesionfailurerateexceeds50%.Accordingly,manycenters
considerrecurrentISRafterfailureof 2DESlayers tobeanindicationfor
intraventricular block.
IVL. Intravascular lithotripsy is a promising new approach in calci?ed
lesions and has been evaluated in nonrandomized series as a treatment
forhighlycalci?edneoatherosclerosiscausingISR.
45,51,88
Themechanism
of action is emission of an electrical charge from a pair of lithotripters
resulting in generation and collapse of vapor bubbles within a pressur-
ized, ?uid-?lled semicompliant balloon. This results in acoustic shock-
waves that exert an instantaneous ?eld force of up to 50 atm creating
fractures within intimal and medial calcium, facilitating subsequent stent
expansion as assessed by IVUS and OCT. Whether this device provides a
long-term bene?t, alone or in combination, in this dif?cult morphologic
subset will require RCTs. IVL has also been combined with VBT.
50
Management of recurrent ISR. Patients with recurrent ISR are re-
fractory to usual treatment modalities.
60
The rates of repeat revascu-
larization have been reported to exceed 50% within 2 years. For this
PCI, percutaneous coronary intervention.
balloons (24-26 atm). Subsequent IVUS imag-
artery.
L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx 7
reason, new approaches are often tried in these cases, but typically
published results are anecdotal reports and uncontrolled series, rather
than controlled trials.
Drug-coated balloons may have a bene?cial effect in recurrent
ISR, but more investigation is needed. Adverse events are signi?-
cantly higher in patients treated with DCBs with >2 stent layers
versus no signi?cant differences in patients with 1 or 2 prior stents.
Atheroablative modalities are often employed, but published reports
are anecdotal. Multilayer (>2 stents) underexpanded ISR is particu-
larly recalcitrant to standard treatment. VBT is often reserved for
refractory ISR and might be considered when multiple layers of stent
are present.
50,84,87
Surgical revascularization should be considered in discussion with
the patient after several interventional procedures have failed.
Although no studies have supported a speci?c approach as to when
repeat procedures should be avoided, Table 6 lists key considerations
to assist in deciding which patients might be better treated with coro-
nary artery bypass graft surgery or optimal medical therapy. A heart
team approach may be advisable to consider all of the relevant factors
in an individual case.
Stent thrombosis
ST is an acute or subacute thrombotic occlusion that usually pre-
sents as an acute MI or acute coronary syndrome and is associated with
high rates of morbidity and mortality. These thrombi can be notoriously
dif?cult to treat with traditional interventional techniques because they
tend to be large, friable, and adherent.
89
Incidence and clinical presentation
The overall incidence of ST is 0.5% to 1.0% in the ?rst year and 0.2%
to 0.6% in every subsequent year.
90–92
The rate is lower for elective
stent placement (0.3%-0.5%) but higher in acute coronary syndrome
(3.4%) and MI. In contemporary practice, the observed mortality rate
(~30%) is high, although recent clinical trials and studies requiring au-
topsy con?rmation suggest a better survival, with an average rate of
<10%.
90–92
The ST rate is higher in ST-elevation myocardial infarction
presentations treated with primary stenting.
93–95
Stent thrombosis causes abrupt closure of the stented artery, and
therefore carries a high risk of MI and death. As with any acute vessel
closure, the clinical rami?cations of ST are in?uenced by the amount of
ing (D, distal to proximal) reveals both calci?ed
and noncalci?ed tissue within an appropriately
sized stent, likely representing neo-
atherosclerosis. Despite successful rotational
atherectomy (E: 1.5 mm burr, 160-170,000 rpm
C2 8 passes), non-compliant balloon dilation still
revealed a focal waist (F). Complete expansion
of a 2.5 C2 12 mm Shockwave C2 IVL balloon
was achieved after 80 pulses at 6 atm (G) and
con?rmed with IVUS. A 2.75 C2 26 mm drug-
eluting stent was implanted at 20 atm with
excellent angiographic (G) and IVUS results.
IVL, intravascular lithotripsy; IVUS, intravascular
ultrasound; LAD, left anterior descending
Figure 3.
Stepwise, imaging-guided treatment of a
calci?ed ISR lesion. In-stent restenosis of a
?rst-generation drug-eluting stent (Taxus, Bos-
ton Scienti?c) in the mid LAD, implanted 18
years prior and con?rmed patent several years
afterward. Intrastent (type II) restenosis (A, inset
with orthogonal view) was noted on angiog-
raphy with multiple unsuccessful attempts
made at dilatation (B, C) using noncompliant
threatened myocardium, the degree of myocardial viability, the pres-
ence and adequacy of collaterals, and the speed and success of
revascularization. Approximately 20% of patients with a ?rst ST expe-
rience a recurrent ST episode within 2 years.
92
Classi?cation
Stentthrombosis isclassi?ed bytheAcademicResearchConsortium
criteria
96
based on the presenting clinical scenario and timing after
initial stent placement. Timing is classi?ed as acute, subacute, early,
late, and very late. SToccurring within 24 hours is acute; 24 hours to 30
daysissubacute;from30daysto1yearislate;and>1yearisde?nedas
very late. Early ST is de?ned as occurring within 30 days (ie, acute plus
subacute).Theclinicalpresentationde?neswhetherthelikelihoodofST
is de?nite, probable, or possible. This categorization accurately por-
trays ST and is important in investigating its pathophysiologic
associations.
97
Pathogenesis
Numerous clinical and technical risk factors have been associated
with ST, as summarized in Table 7.
98–105
Prevention of ST is dependent
on optimal stent implantation and the duration and compliance with
DAPT. Premature or patient-initiated termination of DAPT, sometimes
because of bleeding or perioperative concerns, is responsible for most
cases of ST.
100,101,106–112
Congenital or acquired hyporesponder DAPT
status seen with clopidogrel is uncommon with prasugrel or
Table 5. Selected Trials Evaluating Management Strategies for In-stent Restenosis
Trial, publication year Investigation
Time
No. of lesions
centers, region
Design Drug-coated balloon, carrier
agent, commercial name
Control device Restenotic
stent
Endpoint(s) Follow-up
(mo)
Principal ?ndings P-value
PCB vs Uncoated
balloon
PACCOCATH ISR
I&II, 2012
75
Dec 2003 - Dec
2005
54/54
Multicenter, Germany
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, PACCOCATH
Uncoated balloon BMS, DES LLL (mm) 6 0.11 C6 0.44 vs 0.80
C6 0.79
.001
TLR (%) 12/60 4 vs 37 / 9 vs 39 .001/
.004
MACE (%) 12/60 9 vs 44 / 28 vs 59 .001/
.009
Habara et al, 2011
86
Sep 2008 - Nov
2009
25/25
1, Japan
— Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
Uncoated balloon SES LLL (mm) 6 0.18 C6 0.45 vs
0.72 C6 0.55
<.01
TLR (%) 6 4 vs 42 <.01
MACE (%) 6 4 vs 40 <.01
PEPCAD-DES,
2012
72,76
Nov 2009 - Apr
2011
72/38
Multicenter, Germany
Core lab Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
Uncoated balloon DES LLL (mm) 6 0.43 C6 0.61 vs.
1.03 C6 0.77
<.01
TLR (%) 6/36 15 vs 37 / 19 vs 37 <.01/
<.01
MACE (%) 6/36 17 vs 50.0 / 21 vs 53 <.01/
<.01
PCB vs DES
PEPCAD II, 2009
70,77
Jan 2006 - Dec
2006
66/65
10, Germany
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
PES, durable polymer,
stainless steel (132 μm)
BMS LLL (mm) 6 0.17 C6 0.42 vs
0.38 C6 0.6
.03
TLR (%) 12 6 vs 15 .15
MACE (%) 12/36 9 vs 22 / 35 vs 42 .08/–
SEDUCE, 2014
74
Jun 2009 - Oct
2011
24/25
2, Belgium
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
EES, durable polymer, CoCr
(81 μm)
BMS LLL (mm) 9 0.28 vs 0.07 .1
TLR (%) 12 4.2 vs 8 .576
RIBS V, 2014
73
Jan 2010 - Jan
2012
95/94
25, Spain
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
EES, durable polymer, CoCr
(81 μm)
BMS LLL (mm) 6 to 9 0.14C60.5 vs 0.04C6
0.5
.14
TLR (%) 12/36 6 vs 1 / 8 vs. 2 .09/.04
MACE (%) 12/36 8 vs 6 / 12 vs 10 .60/.64
TIS, 2016
78
Jan 2012 - Aug
2014
74/74
1, Czech Rep.
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
EES, durable polymer, CoCr
(81 μm)
BMS LLL (mm) 12 0.02 vs 0.19 <.01
TVR (%) 12 7.4 vs 16.2 .110
MACE (%) 12 10.3 vs 19.1 .213
ISAR-DESIRE3,
2013
71,79
Aug 2009 - Oct
2011
137/131/134
3, Germany
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
1) PES, durable polymer,
stainless steel (132 μm)
2) Common balloon
DES ISR diameter
(%)
6 to 8 38% vs 37.4% vs
54.1%
<.01
a
TLR (%) 12/36 22 vs 14 vs 44 / 33
vs 24 vs 51
.09/.11
b
MACE (%) 12/36 24 vs 19 vs 46 / 38
vs 38 vs 56
.5/.91
b
PEPCAD China ISR,
2014
80
Mar 2011 - Apr
2012
113/108
17, China
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
PES, durable polymer,
stainless steel (132 μm)
DES LLL (mm) 9 0.46 C6 0.51 vs
0.55 C6 0.61
.0005
a
TLR (%) 12/24 15.6 vs 12.3 / 15.9
vs 13.7
.48/.66
TLF (%) 12/24 16.5 vs 16 / 16.8 vs
18.6
.92/.73
RIBS IV, 2018
44
Jan 2010 - Aug
2013
154/155
23, Spain
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
EES, durable polymer, CoCr
(81 μm)
DES Binary
restenosis
6 to 9 19% vs 11% .27
TLR (%) 12 16.2 vs 21.8 .26
MACE (%) 12 18.4 vs 23.3 .35
RESTORE, 2018
81
Apr 2013 - Oct
2016
86/86
10, South Korea
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
EES, durable polymer, CoCr
(81 μm)
DES LLL (mm) 9 0.15 C6 0.49 vs 0.19
C6 0.41
.54
TLR (%) 12 7 vs 5 .51
MACE (%) 12 6 vs 1 .10
DARE, 2018
47
BMS, DES MLD (mm) 6 <.01
a
(continued on next page)
8
L.W
.
Klein
et
al.
/
Jour
nal
of
the
Society
for
Cardiovascular
Angiography
&
Interv
entions
xxx
(xxxx)
xxx
Table 5 (continued)
Trial, publication year Investigation
Time
No. of lesions
centers, region
Design Drug-coated balloon, carrier
agent, commercial name
Control device Restenotic
stent
Endpoint(s) Follow-up
(mo)
Principal ?ndings P-value
May 2010 - Jun
2015
137/141
8, Netherlands
Core lab,
CEC
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
EES, durable polymer, CoCr
(81 μm)
1.71 C6 0.51 vs 1.74
C6 0.61
TVR (%) 12 7.1 vs 8.8 .65
MACE (%) 12 10.9 vs 9.2 .66
BIOLUX-RCT,
2018
82
Aug 2012 - Jan
2015
163/80
14, Germany, Latvia
Core lab,
CEC
Paclitaxel, BTHC 3 μg/mm
2
,
Pantera Lux
DES, bioresorbable polymer,
CoCr (60–80 μm)
BMS, DES LLL (mm) 6 0.03 C6 0.40 vs 0.20
C6 0.70
.40
TLR (%) 12 12.5 vs 10.1 .82
TLF (%) 12 16.9 vs 14.2 .65
DAEDALUS, 2020
83
Pooled analysis of 10
RCT
c
Core lab,
CEC
Paclitaxel, iopromide/BTHC 3
μg/mm
2
DES BMS, DES TLR (%) 36 16 vs 12, HR 1.27
(0.90-1.79)
.17
Safety
endpoint
d
36 9 vs 11, HR 0.79
(0.58-1.10)
.16
SCB vs PCB
FIM LIMUS DCB,
2019
84
Dec 2015 - Jan
2017
25/25
5, Malaysia
Core lab,
CEC
Sirolimus, crystalline coating 4
μg/mm
2
, SeQuent SCB
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
DES LLL (mm) 6 0.21 C6 0.54 vs 0.17
C6 0.55
.794
TLR (%) 12 16 vs 12 >.99
MACE (%) 12 16 vs 12 >.99
Scheller et al. 2022
85
Dec 2015 - Feb
2020
50/51
10, Malaysia,
Germany, Switzerland
Core lab,
CEC
Sirolimus, crystalline coating 4
μg/mm
2
, SeQuent SCB
Paclitaxel, iopromide 3 μg/
mm
2
, SeQuent Please
DES LLL (mm) 6 0.25 C6 0.57 vs 0.26
C6 0.60
<.35
a
TLR (%) 12 16 vs 10 .39
MACE (%) 12 18 vs 14 .60
BMS, bare metal stent; BTHC, butyryl-tri-hexyl citrate; CEC, clinical events committee; CoCr, cobalt-chromium; DES, drug-eluting stent; EES, everolimus-eluting stent; ISR, in-stent restenosis; LLL, late lumen loss; MACE,
majoradversecardiovascular events;MLD, minimallumendiameter; PCB,paclitaxel-cboatedballoon; PES,paclitaxel-eluting stent;SCB, sirolimus-coated balloon;TLF,target lesion failure;TLR,target lesion revascularization;
TVR, target vessel revascularization;
a
Non-inferiority.
b
PCB vs PES.
c
PEPCAD II, ISAR-DESIRE 3, PEPCAD China ISR, RIBS V, SEDUCE, RIBS IV, TIS, DARE, RESTORE, BIOLUX-RCT.
d
All-cause death, myocardial infarction, or target lesion thrombosis.
L.W
.
Klein
et
al.
/
Jour
nal
of
the
Society
for
Cardiovascular
Angiography
&
Interv
entions
xxx
(xxxx)
xxx
9
proliferative drug and generation, demonstrate delayed endothelial
maturation as compared with BMS.
107
When there is an intense neo-
on an inadequate procedural result. The adequacy of stent expansion
and the presence of an occult intimal dissection should be speci?cally
evaluated when the etiology is unclear.
Acute ST. The incidence is 0.2% to 0.6%.
Subacute ST. The incidence is 1.0% to 1.3%.
Late ST. The incidence is 0.4% to 0.6%. The unifying morphologic
?nding is impaired neointimal healing, de?ned as delayed develop-
ment of an endothelialized layer of smooth muscle cells and extracel-
lular matrix that completely covers the stent.
123
Several morphologic substrates have been associated with late ST.
stent. Low-?ow velocity increases ?brin and platelet deposition. Intimal
dissection and plaque disruption in the arterial segments adjacent to
Table 6. Considerations for CABG in refractory/recurrent in-stent restenosis
C15 Multivessel CAD especially LM or proximal LAD involvement
C15 Prior CABG
C15 Suitability of distal vessel for grafting (including diffuseness of CAD, extent of
“metal jacket,” and size of vessel)
C15 Global and regional LV function including viability (especially the segment
subtended by the involved vessel)
C15 Comorbid conditions (including age, frailty, life expectancy, and activity level)
C15 Anticipated completeness of revascularization
C15 Response to optimal medical therapy
CABG, coronary artery bypass grafting; CAD, coronary artery disease; LAD, left
anterior descending coronary artery; LM, left main coronary artery; LV, left
ventricular.
10 L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
intimal growth reaction to the stent, which is an exaggerated response
to arterial healing that peaks at 30 days to 6 months after implantation,
vascular narrowing, which can precipitate ST, may occur. Neointimal
thickness at stent strut sites is increased when there has been damage
to the tunica media. Drug elution and coating polymers may delay this
time frame.
98,103,105,121,122
Correlates of timing of ST and mechanism
The incidence of Academic Research Consortium de?nite or prob-
able ST within 2 years is 4.4% and is distributed among the acute,
subacute,late,andverylatetimeperiods.Eachtimeframeisassociated
with somewhat different mechanistic circumstances.
99–103,105,121–124
Early ST. The strongest predictor of early ST is premature discontinu-
ation of DAPT in the ?rst 30 days following stent implantation.
122
Me-
chanical predictors of early ST are similar to those associated with
ISR—underexpansion and in?ow-out?ow problems, including
geographic miss, signi?cant residual dissections, and especially occult
intramural hematomas—especially at the distal stent edge. Early-stent
occlusion is usually the consequence of platelet-rich thrombi forming
ticagrelor.
107,108
Prior generation stents were susceptible to ST with
discontinuation of DAPTout to 5 years and longer in anecdotal cases.
With the newest generation of stents, the duration of treatment can be
decreased safely to 3 months
113
or 1 month.
114
Circumstances that abet stasis and turbulence, such as under-
expanded stents, stents in small vessels, or long lesions, are associated
withST.
115–121
ThesecommonmechanicaletiologiesofSTareassociated
with stent underexpansion in both early and late ST. A second concern is
injury or endothelial disruption caused by edge dissection. The delayed
healing and endothelial in-growth observed with early-generation DES
are now less common. Early, late, or very late STcan beassociated with a
calci?ed nodule, perhaps because of consequent underexpansion.
Neointima containing smooth muscle cells develops beginning 2
weeks after BMS.
106,121
However, DES, depending on the anti-
Table 7. Risk factors for stent thrombosis
98–105
Clinical risk factors Procedure related Lesion related
C15 ACS (STEMI/NSTEMI)
C15 Left ventricular dysfunction
C15 Chronic kidney disease
C15 Diabetes mellitus
C15 COVID-19
C15 Stent length
C15 Stent underexpansion
C15 No re?ow
C15 Residual stenosis
C15 Dissection
C15 Multiple stents
C15 Bifurcation stenting
C15 Necrotic core
C15 Bifurcation lesions
C15 Prior brachytherapy
C15 Multivessel disease
C15 In?ow and out?ow obstructio
ACS, acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; STEMI,
stents can progress and cause ?ow obstruction. Stenting of lipid-rich
plaques with plaque prolapse also increases risk of ST. Lipid-rich pla-
ques with signi?cant necrosis are prone to stent struts penetrating
deeply into the lipid core, thus losing contact with the vessel wall. Also,
stents placed in a stenosis with large lipid core might delay the devel-
opment of a fully endothelialized neointima because of scarcity of
migrating and proliferating smooth muscle cells in proximity to the
stent. Finally, diffuse ISR with thrombosis can occur because of over-
production of intimal hyperplasia and neoatherosclerosis.
103,118–121
Residual stent edge dissection has been associated with target
lesion revascularization.
101,123,124
Edge dissections are de?ned as
beingmajorbyOCTwhentheyextendinanarcof>60
C14
andare>3mm
in length. Intimal dissection and plaque disruption in the arterial seg-
ments adjacent to stents can progress and cause ?ow obstruction.
Very late ST. The incidencehas been reported between0.4% to 0.8%.
Very late ST (VLST) occurs 1 to 5 years after stent implantation at a rate
of 2% per year. The most commonly identi?ed causes of VLST are
malapposition, uncovered struts, neoatherosclerosis, and stent under-
expansion. The degree and extent of malapposition and uncovered
stent struts are the most important correlates of thrombus formation in
VLST.
101,124
Intravascular imaging can identify suboptimal stent
deployment.
Diagnostic imaging modalities
Intravascular imaging is crucial to developing rational individual
case strategy because the causative mechanism is highly in?uential in
selecting treatment strategy to manage the thrombus and prevent its
recurrence. Although no imaging modality is rated in the class I
Stent related Antiplatelet related
n
C15 Bio-compatible polymers
C15 Polymer/stent thickness
C15 Drug dosage
C15 Adherence
C15 CYP2C19 polymorphisms
C15 High on-treatment platelet reactivity
C15 Antiplatelet type
C15 Dual antiplatelet therapy duration
ST-elevation myocardial infarction
Stenting across major arterial side branches is well recognized. Over-
lapping and bifurcation stenting
125
are prone to underexpansion and
malapposition; careful technique and close attention to adjunct imag-
ing are essential. Stent struts that are not apposed to the vessel wall,
which can be because of malapposition or late remodeling, produce
increased blood ?ow turbulence and low-?ow foci at the margins of the
O
Figure 4.
L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx 11
Stent Thrombosis
Stent Under-expansion Uncovered Struts Neoatherosclerosis
Minimum Stent Area 4.2 mm
2
Neointima Lumen AreaLipidic NeoatherosclerosisWhite Thrombus
ABC
Ac Bc Cc
Acc Bcc Ccc
Coronary
Angiogram
OCT
Mechanism of
Stent Failure
Stent Under-expansion Uncovered Struts Neoatherosclerosis
A CB
Coronary
Angiogram
Top
Bottom
category by existing guidelines because of an absence of randomized
trials, angiography alone is clearly inadequate because of its intrinsic
inadequacy to assess stent expansion, neoatherosclerosis, calci?cation,
and remodeling. IVUS and OCT provide detailed assessment of the
stented segment and accurately identify the underlying mechanisms.
For these reasons, SCAI recommends that imaging be strongly
considered when the etiology of ST is uncertain from clinical and
angiographic information.
Angiographic factors. The extent of coronary artery disease is an
independent predictor of ST.
105,122
The Dutch Stent Thrombosis
Registry included 21,009 consecutive patients and showed that
multivessel disease, long lesions, and multiple lesions (total stent
length) are independent determinants of ST.
117
The volume of
thrombus burden is important in appraising the risk of distal
embolization, as is the degree of residual ?ow, presence of collat-
erals, and status of the microvasculature.
53–55
The size of the jeop-
ardized myocardial segment and the residual left ventricular function
are also critical factors.
Intravascular imaging. There is substantial data suggesting that
intravascular imaging improves outcomes (see Figures 4A, B and 5).
IVUS has been considered the standard imaging modality for
ST.
101,102,122
OCT, which has 10-fold higher axial resolution, has more
Minimum Stent Area 3.6 mm
2
Lumen Area Old Stent Strutsde novo PlaqueWhite Thrombus Lipidic Neoatherosclerosis
Ac Bc Cc
Acc Bcc Ccc
IVUS
Mechanism of
Stent Failure
ld Stent Struts
Mechanisms of stent thrombosis evaluated by intravascular im-
aging. A
0
-C
0
are optical coherence tomography (OCT) or intravas-
cular ultrasound (IVUS) images corresponding to stent thrombosis
seen in the angiographic images A-C (white arrows). A
00
-C
00
are
representative diagrams provided to clarify the intracoronary images
A
0
-C
0
. Top. Mechanisms of stent thrombosis evaluated by OCT (A)
Subacute stent thrombosis in which OCT showed a severely
underexpanded stent occupied by white thrombus in the mid left
anterior descending artery. (B) Very late stent thrombosis occurred 2
hours after noncardiac surgery and after discontinuation of anti-
platelet therapy. OCT showed uncovered stent struts occupied by
white thrombus. (C) Lipidic plaque (strong signal attenuation) within
stent struts indicating neoatherosclerosis resulting in plaque rupture
with thrombus. Bottom. Mechanisms of stent thrombosis evaluated
by IVUS (A) Subacute stent thrombosis in which IVUS showed a
severely underexpanded stent and thrombus in the mid left
circum?ex artery. (B) Very late stent thrombosis in which IVUS
showed a well-expanded stent occupied by thrombus. Because
there is no neointimal hyperplasia, it was speculated that uncovered
stent struts were the cause of stent thrombosis. (C) Lipidic plaque
(strong signal attenuation) appeared within the stent struts indi-
cating neoatherosclerosis resulting in plaque rupture with thrombus.
recently shown great promise.
115,119,126,127
Although the absence of a
multicenter, controlled trial limits a formal level of indication,
24
these
modalities appear to be useful in optimal lesion preparation strategies.
There are several well-de?ned imaging criteria to optimize stenting
(Table 8).
115–120
IVUS can be of great value during stent placement to
assess stent sizing, expansion, and apposition. Several studies suggest
that IVUS-guided stent placement reduces ST, restenosis, and repeat
revascularization.
101,102,116,118,128–130
Stent undersizing occurs
frequently when visual estimation alone is used for size selection, and
this is a majorcontributor to the risk of ST (and ISR). The incidenceof ST
issigni?cantlyreducedwhenIVUSisusedtoguidestentplacementand
optimize expansion.
128
In the Assessment of Dual Antiplatelet Therapy
With Drug-Eluting Stents (ADAPT-DES) study,
129
at 1 year, there was a
signi?cant reduction in de?nite/probable ST (0.52% vs 1.04%, P ?.01)
and MI (2.5% vs 3.7%, P ?.002)
128
when IVUS guidance was employed.
Optical coherence tomography may be superior to IVUS in assess-
ing the cause of ST. In particular, uncovered struts and underexpansion
are seen in acute and subacute ST, and neoatherosclerosis, uncovered
struts, and malapposition are seen in late and very late ST.
126,131,132
OCT has been shown to be highly effective in determining the under-
lying cause of VLST in >98% of cases, and multiple mechanisms are
usually present (55%). OCT demonstrates malapposition, neo-
atherosclerosis, uncovered struts, and stent underexpansion underlying
ST.
127
OCT identi?ed adverse features requiring further intervention in
35% of cases, with signi?cantly lower risk of death and MI at 1 year in
the CLI-OPCI trial.
97
In ULTIMATE,
130
IVUS-guided PCI was associated with important
reductions in target vessel failure (cardiac death, MI, or target vessel
revascularization). At 3 years, target vessel failure occurred in 47 pa-
presentation is acute, although optimal reperfusion is achieved in only
2/3.
89
TheSCAIrecommendedalgorithmtoorganizetheseapproaches
is provided in Figure 6.
Following diagnostic angiography, most ST occlusions can be
treated initially with balloon angioplasty alone, sometimes with
adjunctive thrombus aspiration when the clot burden is large. Addi-
tional stent implantation should ordinarily be limited to signi?cant re-
sidual dissections, especially if recent DAPT has been discontinued.
High-pressure in?ations with noncompliant balloons to assure stent
apposition may be necessary in some cases. At this time, no particular
Index
Event
Figure 5.
Early restenosis due to re-protrusion of a calci?ed nodule. This patient underwent
percutaneous coronary intervention to treat lesions in the distal and mid right coronary ar-
tery. Optical coherence tomography (OCT) showed an eruptive calci?ed nodule (white ar-
rows)inbothlesions.Acalci?ednoduleischaracterizedbyanaccumulationofsmallcalcium
fragmentstypicallywithstrongsignalattenuationduetoaccompanyingandoverlying?brin.
The patient came back for staged procedure of LAD (left anterior descending artery) 6
weeks later. OCTshowed reprotruding calci?ed nodules within the stent.
Table 8. Intravascular imaging correlates of stent thrombosis
103,105,115–120
C15 Small cross-sectional area of <5mm
C15 Underexpansion
C15 Malapposition or incomplete stent apposition
C15 Correct stent sizing
C15 Late positive remodeling or aneurysm formation
C15 In?ow/out?ow lesions proximal or distal to the stented segment
C15 Plaque prolapse or protrusion
C15 Edge dissection
C15 Signi?cant residual stenosis
C15 Stent overlap
C15 Plaque characteristics: lipid content; delayed or absent endothelialization of stent
struts
C15 Hypersensitivity or in?ammatory reactions
C15 Strut fractures
C15 Neoatherosclerosis (very late stent thrombosis)
12 L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx
Mechanical and pharmacologic treatment of ST
Balloon in?ation, aspiration thrombectomy and pharmacologic
treatment with anticoagulants and antiplatelet drugs are the mainstays
of treatment (Table 4).
52–55
Emergent PCI is indicated when the
tients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the
angiography-guided group (P ?.01), driven mainly by the decrease in
clinically driven target vessel revascularization (4.5% vs 6.9%; P ?.05).
Both OPINION
133
and ILUMIEN III
131
compared IVUS and OCT and
concluded that these methods have similar treatment outcomes.
Figure 6.
SCAI algorithmic approach to stent thrombosis.
stent design or polymer coating has been shown to prevent ST more
than others.
Glycoprotein IIb/IIIa antagonists should be considered to improve
microvascular reperfusion because of distal embolization, and pro-
longed infusions up to 72 hours have been successful in anecdotal
cases. Prolonged anticoagulation and antiplatelet therapy may be
bene?cial when residual thrombus is detected following intervention.
Compliance and drug resistance should be evaluated in detail. More
potent antiplatelet therapy should be considered, including aspirin,
prasugrel, or ticagrelor.
107,108,134
If platelet aggregation studies are
available and reveal insuf?cient (<50%) inhibition of platelet aggrega-
tion with standard DAPT, the sustained administration of 150 mg/d
clopidogrel may be considered. Long-term non-vitamin K
proportionately to the stent length; however, treatment of edge dis-
quent approach to these challenging cases.
intervention: an individual patient data pooled analysis of 21 randomized trials
L.W. Klein et al. / Journal of the Society for Cardiovascular Angiography & Interventions xxx (xxxx) xxx 13
This research did not receive any speci?c grant from funding
agencies in the public, commercial, or not-for-pro?t sectors.
Supplementary material
To access the supplementary material accompanying this article,
visit the online version of the Journal of the Society for Cardiovascular
Angiography & Interventions at 10.1016/j.jscai.2023.100971.
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Ziad Ali served on the advisory council and received honoraria and
consulting fees from Boston Scienti?c and Abbott Laboratories. Roxana
Mehran is a primary investigator for Abbott. Gary Mintz received hon-
oraria from Boston Scienti?c. Amir Lot?, Lloyd Klein, John Messenger,
Sunil Rao, Karim Al-Azizi, Yader Sandoval, Sandeep Nathan, Jennifer
Rymer, and Akiko Maehara reported no ?nancial interests.
Funding sources
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