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STATE-OF-THE-ART REVIEW

Stent Thrombosis

A Clinical Perspective

Bimmer E. Claessen, MD, PHD,* José P.S. Henriques, MD, PHD,* Farouc A. Jaffer, MD, PHD,yRoxana Mehran, MD,zx Jan J. Piek, MD, PHD,* George D. Dangas, MD, PHDzx

JACC: CARDIOVASCULAR INTERVENTIONS CME

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at http://interventions.onlinejacc.org/ by selecting the CME tab on the

top navigation bar.

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the Accreditation Council for Continuing Medical Education (ACCME) to

provide continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum

of 1 AMA PRA Category 1 Credit(s)�. Physicians should only claim credit

commensurate with the extent of their participation in the activity.

Method of Participation and Receipt of CME Certificate

To obtain credit for this CME activity, you must:

1. Be an ACC member or JACC: Cardiovascular Interventions subscriber.

2. Carefully read the CME-designated article available online and in this

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CME Objective for This Article: At the completion of this article, the

learner should be able to: 1) define stent thrombosis; 2) compare

From the *Academic Medical Center, University of Amsterdam, Amsterdam, t

General Hospital, Boston, Massachusetts; zCardiovascular Research Found

Center, New York, New York. Dr. Jaffer has received research grants from M

institutional research grant support from The Medicines Company, Bristol

Regado Biosciences, and STENTYS; is a consultant for Abbott Vascular, Ast

Janssen Pharmaceuticals, Merck, and Sanofi-Aventis; and has equity in and i

Advisory Board of Abbott Vascular; and is a consultant for Miracor. Dr. Dang

Company; is on the Advisory Board of AstraZeneca; has received institution

Company; his spouse is on the Advisory Board of Boston Scientific, Abbott Va

other authors have reported that they have no relationships relevant to the

Manuscript received April 8, 2014; revised manuscript received May 12, 201

antithrombotic therapies and strategies in patients receiving coronary

artery stents to decrease the risk of stent thrombosis; and 3) assess the

risk of the development of stent thrombosis in a patient undergoing

percutaneous coronary intervention.

CME Editor Disclosure: JACC: Cardiovascular Interventions CME Editor

Olivia Hung, MD, PhD, has received research grant support from NIH T32,

Gilead Sciences, and Medtronic Inc.

Author Disclosures: Dr. Jaffer has received research grants from Merck,

Kowa, and Siemens. Dr. Mehran has received institutional research

grant support from The Medicines Company, Bristol-Myers Squibb/

Sanofi-Aventis, Lilly/Daichi Sankyo, Regado Biosciences, and STENTYS;

is a consultant for Abbot Vascular, AstraZeneca, Boston Scientific,

Covidien, CSL Behring, Janssen Pharmaceuticals, Merck, and Sanofi-

Aventis; and has equity in and is a shareholder of Endothelix, Inc.

Dr. Piek is on the Advisory Board of Abbott Vascular; and is a consultant

for Miracor. Dr. Dangas is a consultant for Medtronic and The

Medicines Company; is on the Advisory Board of AstraZeneca; has

received institutional research grants from Eli Lilly and The Medicines

Company; his spouse is on the Advisory Board of Boston Scientific,

Abbott Vascular, and Bristol-Myers Squibb/Sanofi-Aventis. All other

authors have reported that they have no relationships relevant to the

contents of this paper to disclose.

CME Term of Approval

Issue Date: October 2014

Expiration Date: September 30, 2015

he Netherlands; yCardiology Division, Massachusetts

ation, New York, New York; xMount Sinai Medical

erck, Kowa, and Siemens. Dr. Mehran has received

-Myers Squibb/Sanofi-Aventis, Lilly/Daiichi Sankyo,

raZeneca, Boston Scientific, Covidien, CSL Behring,

s a shareholder of Endothelix, Inc. Dr. Piek is on the

as is a consultant for Medtronic and The Medicines

al research grants from Eli Lilly and The Medicines

scular, and Bristol-Myers Squibb/Sanofi-Aventis. All

contents of this paper to disclose.

4, accepted May 14, 2014.

Claessen et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 7 , N O . 1 0 , 2 0 1 4

Stent Thrombosis: A Clinical Perspective O C T O B E R 2 0 1 4 : 1 0 8 1 – 9 2

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Stent Thrombosis

A Clinical Perspective

ABSTRACT

The invention of intracoronary stents greatly increased the safety and applicability of percutaneous coronary inter-

ventions. At this time, >1 million coronary stent implantations are performed each year in the United States. But

together with the growing use of stents, stent thrombosis, the most feared complication after stent implantation,

has emerged as an important entity to understand and prevent. Adjunct pharmacological therapy, stent design,

and deployment technique have been adjusted ever since to reduce its occurrence. The current clinical overview

of stent thrombosis ranges from its pathophysiology to current state-of-the-art technical and pharmacological

recommendations to avoid this complication. (J Am Coll Cardiol Intv 2014;7:1081–92) © 2014 by the American

College of Cardiology Foundation.

T he safety and efficacy of percutaneous coro-nary intervention (PCI) improved dramati-cally after the introduction of the coronary

artery stent. A severe and common early complica-tion of balloon angioplasty alone was abruptvessel closure, which was associated with signifi-cant morbidity and mortality and the need foremergency coronary artery bypass surgery (1). Coro-nary artery stents significantly reduced the inci-dence of abrupt vessel closure and also reducedrestenosis by essentially eliminating arterial re-coil and negative remodeling after angioplasty (2).From the very beginning, thrombosis of the metalendoprosthesis, or stent thrombosis (ST), was recog-nized as an important complication and adjunctpharmacological therapy, and stent technique andtechnology have been adjusted to reduce itsoccurrence.

DEFINITION OF STENT THROMBOSIS

The sensitivity and specificity of the definition ofST depends on the level of certainty required (a betterjudgment can be made in the presence of angiographyor autopsy studies), but also on the accuracy of dataavailable during adjudication (e.g., events occurringin remote locations and long after the index pro-cedure cannot be easily adjudicated due to manycoinciding factors, interval interventions, and otherclinical conditions treated by unrelated medicalteams). Until 2007, a large variety of ST definitionswere in use, limiting the possibility to consistentlyevaluate ST rates among studies. A standardizeddefinition of ST was proposed by the AcademicResearch Consortium (ARC) (Table 1) (3). The ARCdefinition acknowledges these issues by establishing

a gradation of certainty (definite, probable, andpossible ST), and standardized the timing of ST(acute, subacute, late, and very late ST), which mayhave different pathophysiological mechanisms andclinical implications.

SCOPE OF THE PROBLEM

At the very beginning of intracoronary stenting, withlow-pressure inflation and single-antiplatelet therapy,bare-metal stents (BMS) were associated with highrates of ST, ranging from 20% in early reports (4–6)to around 3% to 5% (2,7) with the use of aggressiveanticoagulation therapy, which in turn was associatedwith hemorrhagic complications. Colombo et al. (8)first introduced stenting with dual-antiplatelettherapy (DAPT) instead of warfarin, accomplishedby attaining adequate stent expansion usinghigh-pressure balloon inflation. This implantationtechnique achieved an acceptable 1.6% rate of angio-graphically documented ST at 6-month follow-up andwas universally accepted from then on (9,10).

The incidence of ST up to 1 year follow-up seemssimilar for DES and BMS and ranges from 0.6% to3.2% for BMS and 0.6% to 3.4% for DES, dependingon patient and lesion characteristics (11–14). Beforethe introduction of DES, ST was perceived as a com-plication occurring early after stent implantation. In2004, McFadden et al. (15) described 4 cases of lateand very late ST in first-generation DES (sirolimus-eluting stent, Cypher, Cordis, Warren, New Jersey,and paclitaxel-eluting stent, Taxus, Boston Scientific,Natick, Massachusetts). Subsequently, data from alarge all-comers registry suggested that very late STmay occur steadily at an annual rate of 0.4% to 0.6%after first-generation DES implantation (16). These

TABLE 1 Definition of Stent Thrombosis According to the Valve

Academic Research Consortium

Level of Certainty Timing

Definite Early

Angiographic or pathological confirmation ofpartial or total thrombotic occlusionwithin the peri-stent region

Acute (<24 h)

AND at least 1 of the following additionalcriteria:

Subacute (24 hto 30 days)

Acute ischemic symptoms

Ischemic electrocardiogram changes

Elevated cardiac biomarkers

Probable Late

Any unexplained death <30 days of stentimplantation

31 days to 1 yr

Any myocardial infarction related todocumented acute ischemia in theterritory of the implanted stentwithout angiographic confirmation ofstent thrombosis and in the absenceof any other obvious cause

Possible Very Late

Any unexplained death beyond 30 days >1 yr

AB BR E V I A T I O N S

AND ACRONYM S

ACS = acute coronary

syndrome(s)

ARC = Academic Research

Consortium

BMS = bare-metal stent(s)

DAPT = dual-antiplatelet

therapy

DES = drug-eluting stent(s)

GPI = glycoprotein IIb/IIIa

inhibitor

IVUS = intravascular

ultrasound

OCT = optical coherence

tomography

PCI = percutaneous coronary

intervention

ST = stent thrombosis

STEMI = ST-segment elevation

ardial infarction

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reports also led to the recognition of the possibility oflate or very late ST with BMS when the randomizedtrial results were systematically reviewed for bothstent types (17). Of note, all studies planned beforethe adoption of the ARC ST definitions in 2007 didnot include any prospective mechanism for identifi-cation, tracking, and reporting late and very late STevents and used diverse ST definitions. In recentyears, a new problem of recurrent ST has beenrecognized. High rates of recurrent ST have beenpublished ranging from 5.9% to 18.8% (18–21).

CLINICAL PRESENTATION, DIAGNOSIS, AND

CLINICAL OUTCOME OF STENT THROMBOSIS

The typical clinical presentation of ST consists ofchest pain and ischemic electrocardiographic changesin the target vessel territory. However, ST can alsopresent as sudden death, or it can be asymptomaticin the setting of collateral vessels. The cornerstoneof the angiographic detection of thrombus is thepresence of a filling defect. When a filling defect isdetected angiographically, intravascular ultrasound(IVUS) may be used to detect the underlying me-chanism of ST (e.g., underexpansion, malapposition,edge dissection) (22). Moreover, optical coherencetomography (OCT) is very suitable for visualizationof the stent surface thanks to its high resolution(10 mm), and its ability to detect the presence of(sub) clinical thrombus has been experimentallyconfirmed (23).

Table 2 shows published data on mortalityafter ST (16,18–21,24–34). There is consider-able variation in mortality after ST betweendifferent studies, ranging from 11% to 42%. Anumber of mechanisms may explain the highmortality observed after ST. For example, inpatients who underwent stent implantationfor acute coronary syndrome (ACS) in-dications in whom preexisting ischemic pre-conditioning is undone by restoration ofadequate antegrade flow, early ST may beparticularly harmful. Moreover, a studycomparing patients undergoing primaryPCI for ST-segment elevation myocardialinfarction (STEMI) due to de novo coronarythrombosis with ST reported lower rates ofsuccessful reperfusion in the ST group (93.9%vs. 80.4%, p < 0.0001) (26).

PATHOPHYSIOLOGY OF ST. A multitude ofmechanisms lead to the occurrence of ST.

Many patient-related, lesion-related, procedural, andpost-procedural factors are associated with ST(Table 3) (19,21,22,29,30,32,35–37). These predisposeto ST by one of the following pathophysiologicalmechanisms: 1) exposure of blood before re-endothelialization to prothrombotic subendothelialconstituents, stent struts, and/or polymer materialleading to activation of the extrinsic pathway of thecoagulation cascade; 2) persistent slow coronaryblood flow and low shear stress leading to activationof the intrinsic pathway; 3) inadequate pharmaco-logical suppression of platelet activation (e.g., afterpremature discontinuation of DAPT); and 4) thepresence of a systemic prothrombotic state (e.g., dueto ACS or malignancy). A large-scale meta-analysisincluding 221,066 patients and 4,276 ST events foundthat the most consistently reported predictors areearly DAPT discontinuation, the extent of coronaryartery disease, and total stent length (36).

EARLY ST. Early ST occurs within 30 days after stentimplantation, when technical and procedural factorsare important. A suboptimal procedural result (e.g.slow flow, inadequate post-procedural lumen di-mensions, residual dissection, and tissue prolapse) isassociated with the incidence of early ST (19,37,38).Because the arterial segment receiving the endo-prosthesis has not yet re-endothelialized, inhibitionof platelet activation is a key factor: discontinuationof DAPT during this time frame can be catastrophicand provoke ST. Stenting in prothrombotic conditionsin patients with ACS is also strongly associated withearly ST (36). Due to its fast elimination at a timethat antiplatelet drugs may not yet have become

myoc

TABLE 2 Mortality After Stent Thrombosis

First Author (Ref. #) Year N Stent Type VARC Defined? Timing of ST Follow-Up Mortality, %

Cutlip et al. (30) 2001 53 BMS No Early 6 months 20.8

Wenaweser et al. (20) 2005 95 BMS No Early and late 6 months 11.0

Iakovou et al. (29) 2005 49 DES, BMS No Early and late Not specified 45.0

Ong et al. (27) 2005 26 DES No Early 30 days 12.0

Kuchulakanti et al. (28) 2006 38 DES No Early and late 6 months 29.0

Daemen et al. (16) 2007 152 DES No Early and (very) late 6 months 11.0

de la Torre-Hernandezet al. (32)

2008 301 DES, BMS No Early and (very) late Median 11.8 months 16.0

Aoki et al. (33) 2009 48 DES Yes, definite/probable Early 30 days 27.1

Chechi et al. (26) 2008 82 BMS Yes, definite Early and (very) late 6 months 20.9

van Werkum et al. (19) 2009 431 DES Yes, definite Early and (very) late Median 27.1 months 15.4

Lasala et al. (25) 2009 184 PES Yes, definite/probable Early and (very) late 7 days 23.4

Acute (n ¼ 17) 29.4

Subacute (n ¼ 60) 41.7

Late (n ¼ 51) 11.8

Very late (n ¼ 56) 12.5

Kimura et al. (31) 2009 71 SES Yes, definite Early and (very) late 30 days 20.4

Early (n ¼ 36) 11.0

Late (n ¼ 21) 38.0

Very late (n ¼ 14) 18.0

Kimura et al. (21) 2010 611 SES Yes, definite Early and (very) late 1 yr 25.0

Early (n ¼ 322) 25.0

Late (n ¼ 105) 27.8

Very late (n ¼ 184) 23.3

Moon et al. (18) 2010 31 DES, BMS Yes, definite Early and (very) late Median 34.9 months 14.3

Ergelen et al. (24) 2010 118 DES, BMS Yes, definite Early and (very) late Mean 22 months 17.4

Dangas et al. (34) 2012 156 DES Yes, definite/probable Early and (very) late 3 yrs 16.7

In-hospital 27.8

Out-of-hospital 10.8

Armstrong et al. (87) 2012 1,391 BMS, DES No Early In-hospital 7.9

1,370 Late In-hospital 3.8

4,318 Very late In-hospital 3.6

BMS ¼ bare-metal stent(s); DES ¼ drug-eluting stent(s); PES ¼ paclitaxel-eluting stent(s); ST ¼ stent thrombosis; VARC ¼ Valve Academic Research Consortium.

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effective, bivalirudin use in primary PCI may predis-pose to acute ST compared with heparin plus optionalglycoprotein IIb/IIIa inhibitors (GPIs) (39,40).

LATE AND VERY LATE ST. Delayed endothelialcoverage, persistent fibrin deposition, and ongoingvessel inflammation are associated with ST >30 daysafter stent implantation. Re-endothelialization afterstent implantation is significantly delayed in DEScompared with BMS and is likely responsible forthe higher rates of very late ST with first-generationDES (41). Stent malapposition is defined as lack ofcontact between stent struts and the underlyingarterial wall intima (despite full stent expansion atits nominal diameter). Late stent malapposition istypically the result of positive vessel wall remodeling(i.e., outward arterial wall expansion “away” fromthe stent struts that were well apposed at the timeof implantation), appears more commonly in DES

compared with BMS, and has been associated with(very) late ST (Figure 1) (42). Finally, neoathero-sclerotic plaques can develop in neointima withinpreviously stented areas, which may rupture, causingST (Figure 2) (43). Neoatherosclerotic plaques havebeen observed in both BMS and DES. However, path-ological evidence suggests that neoatherosclerosismay develop earlier in DES (44,45). Its developmentappears to be similar in first- and second-generationDES (46).

PHARMACOPREVENTION

P2Y12 INHIBITORS. The ISAR (Intracoronary Stentingand Antithrombotic Regimen) and STARS (STent An-ticoagulation RestenosiS) trials established DAPTwith aspirin and a thienopyridine as the stan-dard of care after coronary stenting (9,10). In the

TABLE 3 Predictors of Early and (Very) Late Stent Thrombosis

Early Stent Thrombosis (Very) Late Stent Thrombosis

Patient Malignancy, heart failure, peripheral artery disease, diabetes mellitus,acute coronary syndromes, nonadherence to dual-antiplatelettherapy, genetic polymorphisms, thrombocytosis

End-stage renal disease, smoking, STEMI, nonadherenceto dual-antiplatelet therapy (unknown for verylate ST)

Lesion Bifurcation lesion, LAD, vessel size, lesion length, thrombus,saphenous vein grafts

LAD, incomplete endothelialization, delayed healing,previous brachytherapy, vein graft stenting

Procedural Stent undersizing, stent underexpansion, stent malapposition,dissection, no pre-procedural thienopyridine administration,bivalirudin as anticoagulant in STEMI patients, stent length

DES (compared with BMS), permanent polymerDES (compared with bioresorbable polymer DES),overlapping DES

Post-procedural Discontinuation of antiplatelet therapy Discontinuation of antiplatelet therapy (unknown forvery late ST), late acquired stent malapposition

LAD ¼ left anterior descending; STEMI ¼ ST-segment elevation myocardial infarction; other abbreviations as in Table 2.

FIGURE 1 Stent Malapposition Detected by Intracoronary OCT Imaging

(Top) The axial image shows an OCT catheter in the center of the right cor-

onary artery. At the 2-o’clock position, bright, reflective stent struts are

visualized and are not in contact with the intima of the artery (blue dotted

arrow). There is a gap ofw0.6 mm between these stent struts and the artery.

This finding indicates stent malapposition, a mechanical, stent-based risk

factor for late stent thrombosis. (Bottom) The axial cross section was ob-

tained at w22 mm into an automated OCT pullback during contrast injection

to displace obscuring blood. OCT ¼ optical coherence tomography.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 7 , N O . 1 0 , 2 0 1 4 Claessen et al.O C T O B E R 2 0 1 4 : 1 0 8 1 – 9 2 Stent Thrombosis: A Clinical Perspective

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STARS trial, treatment with aspirin and ticlopidinecompared with aspirin alone or a combination ofaspirin and warfarin reduced ST at 30 days (0.5% vs.3.6% vs. 2.7%, p < 0.01). Subsequent clinical trialsshowed that clopidogrel compared with ticlopidineresulted in similar 30-day ST rates (47–49). Clopi-dogrel, which was better tolerated and offered once-daily dosing, subsequently replaced ticlopidine inclinical practice.

CLOPIDOGREL. Clopidogrel is a prodrug; its activemetabolite irreversibly inhibits the P2Y12-type plate-let adenosine diphosphate receptor (50). Geneticvariations in the activity of cytochrome enzymesinvolved in metabolizing clopidogrel are associatedwith lower plasma concentrations of active metabo-lites and poor responder status. High on-treatmentplatelet reactivity in patients receiving DAPT con-sisting of aspirin and clopidogrel has been linked tothe occurrence of ST (51). New P2Y12 inhibitors havebeen developed to address these limitations.

NEW P2Y12 INHIBITORS. Prasugrel, a thienopyridine,inhibits platelet activation more rapidly, more con-sistently, and to a greater intensity than clopidogrel(52). Ticagrelor and cangrelor are nonthienopyridinedirect-acting, reversible, P2Y12 inhibitors. Of note,cangrelor is an intravenous agent developed to beused during PCI and reduces intraprocedural STcompared with clopidogrel (53). Table 4 summarizestrials investigating novel P2Y12 inhibitors comparedwith clopidogrel and another trial that investigateddouble-dose (150 mg) compared with standard-dose(75 mg) clopidogrel in patients undergoing PCI forACS (53–57). Table 4 illustrates that double-dose clo-pidogrel and novel P2Y12 inhibitors are associatedwith lower rates of ST, but also with increased bleedingrates. Specific subgroups including patients withactive pathological bleeding and previous stroke ortransient ischemic accident sustain an increased

bleeding risk, and prasugel is particularly contra-indicated (54). In contrast, subgroups with pro-thrombotic potential such as patients with diabetesor acute myocardial infarction undergoing PCI mayderive greater net benefit with prasugrel (58,59). Thesignificant benefit in cardiovascular survival docu-mented with ticagrelor in addition to lower ST hasraised the possibility of pleiotropic effects (55).

FIGURE 2 Neoatherosclerosis as a Cause of Very Late Stent Thrombosis

of a DES Placed in an SVG

Three years after DES placement to the distal body of an SVG to the right coronary artery,

this patient presented with unstable angina. SVG angiography revealed a severe, hazy-

filling defect in the SVG stent. He was placed on intravenous heparin. The following day,

OCT of the SVG was performed. Two sequential OCT frames are presented with full and

magnified images (dotted white box regions). (Top) OCT of the stent reveals mild neo-

intima within the stent, but at the 4-o’clock position, there is evidence of cap disruption

and a residual crater (white arrowhead, magnified image). (Bottom) In the adjacent OCT

frame, the same region at the 4-o’clock position demonstrates an irregular contour

consistent with thrombus within the stent. Stent struts are noted covered by neointima

(small arrowheads at the 2-o’clock position). These findings indicate plaque rupture of

neoatherosclerosis within a stent, a recently appreciated mechanism of stent thrombosis.

DES ¼ drug-eluting stent(s); OCT ¼ optical coherence tomography; SVG ¼ saphenous vein

graft.

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ANTIPLATELET THERAPY IN PATIENTS ON ORAL

ANTICOAGULANTS. The WOEST (What is the OptimalantiplatElet & Anticoagulant Therapy in Patientswith Oral Anticoagulation and Coronary StenTing)study recently reported on the optimal antiplateletstrategy after elective PCI with stent implantation inpatients with an indication for long-term treatmentwith oral anticoagulants (60). A regimen consisting of12 months of double therapy (oral anticoagulantsplus clopidogrel) was superior to triple therapy (oralanticoagulants plus aspirin and clopidogrel) in

terms of bleeding and all-cause mortality at 1-yearfollow-up. No difference in the incidence of ST wasnoted between the study groups.

DURATION OF DAPT. Current American College ofCardiology/American Heart Association guidelinesstate a Class I, Level of Evidence: B recommendationto continue DAPT for 12 months in patients receivinga stent (BMS or DES) (61). DAPT for patients whoreceive a stent for ACS indications may include pra-sugrel 10 mg/day (a 5-mg daily dose may be given topatients at high risk of bleeding), ticagrelor 90 mgtwice daily, or clopidogrel 75 mg/day in additionto aspirin (Class I, Level of Evidence: B) (61). Forpatients receiving a DES for a non-ACS indication,clopidogrel 75 mg/day is indicated. The recentlyupdated European Society of Cardiology guidelinesare slightly different for patients with stable coronaryartery disease and recommend 1 month of DAPT afterBMS implantation, and 6 months of DAPT with aspirinand clopidogrel after DES implantation (62). Inpatients receiving a stent (BMS or DES) after ACS therecommendation is 12 months of DAPT with aspirinand ticagrelor or prasugrel (or clopidogrel whenticagrelor and prasugrel are contraindicated) (63).

Ongoing large-scale trials are investigating thesafety and efficacy of shorter or longer DAPT dura-tions. Recently, several trials showed better out-comes with a 3- to 6-month DAPT duration in ratherlow-risk patients due to similar ischemic endpointbut significantly lower bleeding rates (64–66) Twomodestly sized trials, one comparing 12-month with24-month DAPT duration and another comparing6-month with 24-month DAPT duration, found nodifferences in composite endpoints of adverse events,with similar rates of stent thrombosis (66,67). Aneven longer DAPT duration is under investigation inthe >20,000-patient DAPT Study (Dual AntiplateletTherapy study) that will determine whether DAPTfor 30 months compared with only 12 months mayprotect against ST.

ADJUNCTIVE ANTITHROMBOTIC STRATEGIES

The role of the intravenous GPIs abciximab, tirofiban,and eptifibatide in the current era of oral DAPT isunclear. In general, treatment with GPIs in ACS re-duces acute ST compared with heparin alone (40,68).In the HORIZONS-AMI trial (Harmonizing outcomeswith revascularization and stents in acute myocardialinfarction), which randomized 3,602 STEMI patientsundergoing primary PCI to treatment with bivalirudinmonotherapy or heparin plus a GPI, the use of biva-lirudin was associated with an increased rate of acute

TABLE 4 Stent Thrombosis and Bleeding Rates in Trials Comparing Clopidogrel With Novel P2Y12 Inhibitors and Single-Dose

Versus Double-Dose Clopidogrel

Study (Ref. #) Year Follow-Up ComparisonDefinite/ProbableStent Thrombosis p Value

TIMI MajorBleeding p Value

TRITON (53) 2007 15 months Clopidogrel 2.4 (142/6,422) <0.001 1.8 (111/6716) 0.03

Prasugrel 1.1 (68/6,422) 2.4 (146/6741)

PLATO (54) 2009 12 months Clopidogrel 2.9 (158/5,649) 0.009 7.7 (638/9186) 0.57

Ticagrelor 2.2 (118/5,640) 7.9 (657/9235)

CHAMPION (56) 2009 48 h Clopidogrel 0.3 (11/3,865) 0.34 0.3 (14/4365) 0.39

Cangrelor 0.2 (7/3,889) 0.4 (19/4374)

CHAMPION PHOENIX (52) 2009 48 h Clopidogrel 1.4 (74/5,469) 0.01 0.1 (5/5527) 0.99

Cangrelor 0.8 (46/5,470) 0.1 (5/5529)

CURRENT-OASIS 7 (55) 2010 30 days Clopidogrel 2.3* <0.001 0.7 (60/8703) 0.074

Double-dose clopidogrel 1.6* 1.0 (80/8560)

Values shown are % (n/N). *Number not reported.

TIMI ¼ Thrombolysis In Myocardial Infarction.

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ST (1.3% vs. 0.3%, p < 0.01) (40). Nonetheless, 30-dayand 1-year ST rates were similar in both treatmentarms, and bivalirudin reduced major bleeding andmortality rates (40,69). The recent EUROMAX (Euro-pean Ambulance Acute Coronary Syndrome Angiog-raphy) trial randomized 2,218 STEMI patients whowere being transported for primary PCI to pre-hospital administration of either bivalirudin orunfractionated or low molecular weight heparin withoptional GPIs (39). Bivalirudin reduced majorbleeding (2.6% vs. 6.0%, p < 0.001) but still showedhigher acute ST (1.1% vs. 0.2%, p ¼ 0.007) than thecontrol arm.

TREATMENT FOR ST AND THE ROLE OF

INTRAVASCULAR IMAGING

The preferred treatment for ST is emergency PCI,including the possibility of thrombus aspiration re-storing antegrade blood flow. Additional stent im-plantation is not absolutely necessary and is advisedfor treatment of significant residual dissections.

Intravascular imaging with IVUS or OCT can providesignificant insight into underlying mechanismscausing this complication. Imaging can be safely per-formed after initial stabilization of the patient. IVUS/OCT can interrogate the entire arterial segment aroundthe stent and can identify several conditions thatcan be largely undetectable by angiography. Addi-tionally, OCT can visualize thrombus and stentstruts at a higher resolution than IVUS; however, fewerclinical studies have used OCT, which requires addi-tional intracoronary contrast injection to displaceblood and enable visualization, which may not beaswell tolerated in hemodynamically compromised STpatients.

STENT UNDEREXPANSION. This is a common mech-anism underlying ST. A rigid arterial segment hasseverely restricted the expansion of the initiallyimplanted stent, or an undersized stent may havebeen selected initially (Figure 3). If confirmed byIVUS/OCT, high-pressure balloon angioplasty withnoncompliant balloons sized according to the normaladjacent reference segment can be attempted. A newstent can be particularly deleterious in treating stentunderexpansion if the reason is due to a highly rigid(e.g., calcified) segment because multiple layers ofstent metal will be present in an underexpandedlesion. If balloon expansion is ineffective, then thepatient should be temporarily treated with balloonangioplasty and return for definite therapy after theacute ST presentation has passed. Subsequent treat-ment options may depend on the exact location of thestent, the neighboring anatomy, and the experienceof the operator: 1) rotational atherectomy can ablatethe stent struts and the underlying calcific plaque(26,70); 2) excimer laser aiming at the unexpandedarea in combination with contrast dye infusion cancreate local conditions that may ablate the problem-atic strut as noted above (26,71); and 3) aortocoronarybypass surgery can provide flow distal to the stentarea, although it may not prevent recurrent throm-bosis at the underexpanded area.

STENT MALAPPOSITION. This can be verified by theexistence of a space filled with blood between thestent struts and the vessel wall (Figure 1). The extentof this low-flow area has been associated with ST(42). Angioplasty with an appropriately sized balloonas determined by the IVUS/OCT-derived measure-ment of the arterial wall diameter at the culpritcross sections typically suffices to ameliorate thisproblem.

FIGURE 3 Stent Underexpansion in a Patient Presenting With Late Stent Thrombosis of a Drug-Eluting Stent Placed in the LAD

Approximately 1 year after stent placement, this patient presented with an acute anterior ST-segment elevation myocardial infarction.

Emergency coronary angiography revealed a 90% hazy lesion within the LAD stent consistent with late stent thrombosis. (Left) Intracoronary

OCT revealed a large burden of irregularly contoured thrombus within the middle of the stent, also seen on the longitudinal OCT reconstruction

below at the 22-mm mark of the OCT pullback (arrowhead). As the stent struts are in contact with arterial wall, the stent is not malapposed in

this area. (Right) However, the OCT image of the immediate proximal flanking artery at 26 mm demonstrates that the reference artery area and

diameter are substantially larger than within stented segment. This finding demonstrates stent underexpansion, which is a risk factor for stent

thrombosis. The patient was treated with OCT-guided appropriately sized percutaneous transluminal coronary angioplasty. LAD ¼ left anterior

descending artery; OCT ¼ optical coherence tomography.

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DISSECTIONS. Stent edge dissections can provoke STand are easily detectable by IVUS/OCT, despite beingsometimes dubious angiographically (72). A newstent can typically cover them and restore adequateflow.

NEW PLAQUE RUPTURE. This condition essentiallymeans the absence of ST per se and supports theextension of thrombosis within the stent after initia-tion at the adjacent plaque disruption area. A newstent may be needed to treat the culprit new lesionarea.

STENT FRACTURE. Right coronary artery lesions,excessive tortuosity or angulation of the vessel,overlapping stents, and longer stents have beenassociated with an increased risk of stent fracture(73). A stent fracture may cause mechanical damageto the endothelium that could subsequently lead toST and can be treated with implantation of a shortstent to cover the area of the stent fracture.

NEGATIVE REMODELING AT THE STENT EDGE.

This can explain abrupt lumen compromise distal to astent that might have predisposed to flow reduction.

NEOATHEROSCLEROSIS. The development of an ACScaused by rupture or erosion of a neoatheroscleroticplaque in a previously stented lesion has beenacknowledged as a potential culprit in very late ST

(Figure 2) (74). Intracoronary imaging, particularlyOCT, is critical in detecting neoatherosclerosisin vivo (75).

ST RISK ASSESSMENT AND PREVENTION

PATIENT, LESION, AND STENT SELECTION. As thereare a number of modifiable risk factors for thedevelopment of ST, several preventive strategies maydecrease the risk of ST. Adequate patient and lesionselection is a first priority. Physicians may prefer touse BMS in lesions with a low risk of restenosis andin patients at increased risk of bleeding, scheduledfor surgery, allergic to thienopyridines, and/or inwhom compliance is questionable. After awarenessof very late ST was raised, novel DES types weredesigned to provide superior safety and efficacycompared with first-generation DES. As the durablepolymer on first-generation DES was considered tobe associated with ST, newer DES designs include,among others, the following: bioresorbable poly-mers; biomimetic polymers; polymer coating on theabluminal surface of stent struts only; and fullybiodegradable DES (76). A large-scale network meta-analysis of 49 randomized trials revealed signifi-cantly lower ST rates with the “second-generation”everolimus-eluting stent containing a fluoropolymercompared with other durable polymer DES as well as

TABLE 5 Integer-Based Risk Score for 1-Year Definite/Probable Stent Thrombosis in Patients With Acute Coronary Syndromes

Variable Integer Assignment for Stent Thrombosis Risk Score Calculation Add to Score

Type of acute coronary syndrome NSTE-ACS w/o ST changes þ1 NSTE-ACS with ST deviation þ2 STEMIþ4

Current smoking Yes: þ1 No: þ0

Insulin-treated diabetes mellitus Yes: þ2 No: þ0

History of PCI Yes: þ1 No: þ0

Baseline platelet count <250 K/ml: þ0 250 K/ml–400 K/ml: þ1 >400 K/ml: þ2

Absence of early (pre-PCI) Heparin* Yes: þ1 No: 0

Aneurysm or ulceration Yes: þ2 No: 0

Baseline TIMI flow grade 0/1 Yes: þ1 No: 0

Final TIMI flow grade <3 Yes: þ1 No: 0

No. of vessels treated 1 vessel: þ0 2 vessels: þ1 3 vessels: þ2

ST Risk Score

*Includes parenteral heparin or low molecular weight heparin.

PCI ¼ percutaneous coronary intervention; NSTE-ACS ¼ non-ST-segment elevation acute coronary syndrome; w/o ¼ without; other abbreviations as in Tables 2 to 4.

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BMS to 2-year follow-up (77). Two even largernetwork meta-analyses, which also included data onbiodegradable polymer DES, one comprising 258,544patients from 126 randomized trials (78) and anothercomprising 63,242 patients from 60 randomizedtrials (79), were recently published. These studiesconfirmed that newer generation durable polymerstents such as the everolimus-eluting stent and theResolute zotarolimus-eluting stent (Medtronic,Santa Rosa, California) provide the best combinationof safety and efficacy even when compared withbiodegradable polymer DES. Fully bioabsorbablecoronary stents may reduce very late stent throm-bosis, but long-term results of large-scale trialsinvestigating the safety and efficacy of these devicesare not yet available.

RISK SCORE CALCULATION. A risk score has beenproposed to personalize risk assessment for the oc-currence of ST in ACS patients (Table 5) (80). This riskscore may be used to identify patients who mightbenefit the most from more aggressive antiplatelettherapy after stent implantation.

TECHNIQUE. An optimal procedural result is impor-tant to minimize the risk of ST. Proper stent expan-sion and apposition over the full length of the stentshould be ascertained, and residual dissectionsshould be avoided. A recent study by Roy et al.(81) reported a strong trend toward reduced STafter IVUS-guided stent implantation compared withangiography only–guided PCI. As the risk of ST in-creases with stent length, excessive use of stents isdiscouraged. However, it is imperative that stentsdo cover the entire lesion because residual plaqueat stent edges can also produce dissections, flowcompromise, and ST. In bifurcation lesions, a

provisional side-branch stenting approach might bepreferable to routine crush and culotte stenting,which have been associated with higher ST rates(82,83). When a 2-stent (DES) approach is imple-mented in a bifurcation, re-endothelialization can beparticularly slow and enhance ST risks.

DAPT COMPLIANCE AND INTERRUPTION. Compli-ance with DAPT is paramount to minimize the risk ofST (29,84), particularly if it occurs within 30 days ofimplantation. Unclear communication of treatmentplans, low levels of patient education, and othersocial factors have been shown to influence DAPTcompliance and should routinely be taken intoaccount.

Several studies suggested that the relationshipbetween ST and nonadherence to DAPT varies overtime. It is strongest in the first month after stentimplantation, remains important until 6 months,but fades afterward (85,86). The 5,031-patient PARIS(Patterns of Non-adherence to Anti-platelet Re-gimens in Stented Patients) registry investigateddifferent categories of DAPT cessation: physician-recommended cessation, interruption (for surgery),and disruption (abrupt, unsupervised nonadherenceor for bleeding) (86). At 2 years after stent implanta-tion, overall DAPT cessation was 57.3%, discontinua-tion occurred in 40.8%, interruption in 10.5%, anddisruption in 14.4% of patients. DAPT disruptionwas associated with an increased risk of ST. Thiseffect was strongest during the first 7 days afterDAPT cessation (hazard ratio: 18.25, p < 0.0001) andweakened overtime.

RECOMMENDATIONS FOR DAPT INTERRUPTION.

When considering an elective invasive diagnostictest or surgery in a patient with coronary stents, it

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may be preferable to postpone the procedure until1 year after stent implantation. If there are pressingreasons to interrupt DAPT before the guideline-recommended period of 6 to 12 months, this shouldbe postponed as long as possible, and aspirin shouldbe continued.

CONCLUSIONS

ST is an uncommon but serious complication of PCI.The incidence of early and late ST is similar in BMSand DES, but very late ST, although uncommon,

occurs more frequently in first-generation DES. Manyrisk factors for ST have been identified by intravas-cular imaging and pathology, some modifiable andsome not. Adequate patient, lesion, and stent selec-tion; a good technical result; and effective DAPTare critical in minimizing the risk of ST.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.George D. Dangas, Cardiovascular Institute, MountSinai Medical Center, One Gustave L. Levy Place, Box1030, New York, New York 10029. E-mail: gdangas@crf.org.

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KEY WORDS coronary artery disease,percutaneous coronary intervention, stentthrombosis

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