Stent Thrombosis

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 7, NO. 10, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

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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,y Roxana Mehran, MD,zx Jan J. Piek, MD, PHD,* George D. Dangas, MD, PHDzx

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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.

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From the *Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; yCardiology Division, Massachusetts General Hospital, Boston, Massachusetts; zCardiovascular Research Foundation, New York, New York; xMount Sinai Medical Center, New York, New York. 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/Daiichi Sankyo, Regado Biosciences, and STENTYS; is a consultant for Abbott 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. Manuscript received April 8, 2014; revised manuscript received May 12, 2014, accepted May 14, 2014.

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Stent Thrombosis: A Clinical Perspective

Stent Thrombosis A Clinical Perspective ABSTRACT The invention of intracoronary stents greatly increased the safety and applicability of percutaneous coronary interventions. 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-

a gradation of certainty (definite, probable, and

nary intervention (PCI) improved dramati-

possible ST), and standardized the timing of ST

cally after the introduction of the coronary

(acute, subacute, late, and very late ST), which may

artery stent. A severe and common early complica-

have different pathophysiological mechanisms and

tion

clinical implications.

of

balloon

angioplasty

alone

was

abrupt

vessel closure, which was associated with significant morbidity and mortality and the need for

SCOPE OF THE PROBLEM

emergency coronary artery bypass surgery (1). Coronary artery stents significantly reduced the inci-

At the very beginning of intracoronary stenting, with

dence of abrupt vessel closure and also reduced

low-pressure inflation and single-antiplatelet therapy,

restenosis by essentially eliminating arterial re-

bare-metal stents (BMS) were associated with high

coil and negative remodeling after angioplasty (2).

rates of ST, ranging from 20% in early reports (4–6)

From the very beginning, thrombosis of the metal

to around 3% to 5% (2,7) with the use of aggressive

endoprosthesis, or stent thrombosis (ST), was recog-

anticoagulation therapy, which in turn was associated

nized as an important complication and adjunct

with hemorrhagic complications. Colombo et al. (8)

pharmacological therapy, and stent technique and

first

technology

therapy (DAPT) instead of warfarin, accomplished

have

been

adjusted

to

reduce

its

occurrence.

by

introduced attaining

stenting

adequate

with stent

dual-antiplatelet expansion

using

high-pressure balloon inflation. This implantation

DEFINITION OF STENT THROMBOSIS

technique achieved an acceptable 1.6% rate of angiographically documented ST at 6-month follow-up and

The sensitivity and specificity of the definition of

was universally accepted from then on (9,10).

ST depends on the level of certainty required (a better

The incidence of ST up to 1 year follow-up seems

judgment can be made in the presence of angiography

similar for DES and BMS and ranges from 0.6% to

or autopsy studies), but also on the accuracy of data

3.2% for BMS and 0.6% to 3.4% for DES, depending

available during adjudication (e.g., events occurring

on patient and lesion characteristics (11–14). Before

in remote locations and long after the index pro-

the introduction of DES, ST was perceived as a com-

cedure cannot be easily adjudicated due to many

plication occurring early after stent implantation. In

coinciding factors, interval interventions, and other

2004, McFadden et al. (15) described 4 cases of late

clinical conditions treated by unrelated medical

and very late ST in first-generation DES (sirolimus-

teams). Until 2007, a large variety of ST definitions

eluting stent, Cypher, Cordis, Warren, New Jersey,

were in use, limiting the possibility to consistently

and paclitaxel-eluting stent, Taxus, Boston Scientific,

evaluate ST rates among studies. A standardized

Natick, Massachusetts). Subsequently, data from a

definition of ST was proposed by the Academic

large all-comers registry suggested that very late ST

Research Consortium (ARC) (Table 1) (3). The ARC

may occur steadily at an annual rate of 0.4% to 0.6%

definition acknowledges these issues by establishing

after first-generation DES implantation (16). These

Claessen et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 10, 2014 OCTOBER 2014:1081–92

T A B L E 1 Definition of Stent Thrombosis According to the Valve

Academic Research Consortium

Table 2 shows published data on mortality after ST (16,18–21,24–34). There is considerable variation in mortality after ST between

Level of Certainty

1083

Stent Thrombosis: A Clinical Perspective

Timing

Definite

Early

Angiographic or pathological confirmation of partial or total thrombotic occlusion within the peri-stent region

Acute (<24 h)

AND at least 1 of the following additional criteria:

Subacute (24 h to 30 days)

different studies, ranging from 11% to 42%. A number of mechanisms may explain the high

ABBREVIATIONS AND ACRONYMS ACS = acute coronary syndrome(s)

ARC = Academic Research

mortality observed after ST. For example, in

Consortium

patients who underwent stent implantation

BMS = bare-metal stent(s)

for

acute

coronary

syndrome

(ACS)

in-

DAPT = dual-antiplatelet

dications in whom preexisting ischemic pre-

therapy

Ischemic electrocardiogram changes

conditioning is undone by restoration of

DES = drug-eluting stent(s)

Elevated cardiac biomarkers

adequate antegrade flow, early ST may be

GPI = glycoprotein IIb/IIIa

particularly

inhibitor

Acute ischemic symptoms

Probable

Late

Any unexplained death <30 days of stent implantation

31 days to 1 yr

Any myocardial infarction related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause Possible

Any unexplained death beyond 30 days

comparing

harmful. patients

Moreover, undergoing

a

study

primary

ultrasound

infarction (STEMI) due to de novo coronary

OCT = optical coherence

thrombosis with ST reported lower rates of successful reperfusion in the ST group (93.9% vs. 80.4%, p < 0.0001) (26). Very Late

>1 yr

IVUS = intravascular

PCI for ST-segment elevation myocardial

tomography

PCI = percutaneous coronary intervention

ST = stent thrombosis

PATHOPHYSIOLOGY OF ST. A multitude of

STEMI = ST-segment elevation

mechanisms lead to the occurrence of ST.

myocardial infarction

Many patient-related, lesion-related, procedural, and post-procedural reports also led to the recognition of the possibility of late or very late ST with BMS when the randomized trial results were systematically reviewed for both stent types (17). Of note, all studies planned before the adoption of the ARC ST definitions in 2007 did not include any prospective mechanism for identification, tracking, and reporting late and very late ST events and used diverse ST definitions. In recent years, a new problem of recurrent ST has been recognized. High rates of recurrent ST have been published 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 of chest pain and ischemic electrocardiographic changes

factors

are

associated

with

ST

(Table 3) (19,21,22,29,30,32,35–37). These predispose to ST by one of the following pathophysiological mechanisms:

1)

exposure

of

blood

before

re-

endothelialization to prothrombotic subendothelial constituents, stent struts, and/or polymer material leading to activation of the extrinsic pathway of the coagulation cascade; 2) persistent slow coronary blood flow and low shear stress leading to activation of the intrinsic pathway; 3) inadequate pharmacological suppression of platelet activation (e.g., after premature discontinuation of DAPT); and 4) the presence of a systemic prothrombotic state (e.g., due to ACS or malignancy). A large-scale meta-analysis including 221,066 patients and 4,276 ST events found that the most consistently reported predictors are early DAPT discontinuation, the extent of coronary artery disease, and total stent length (36).

in the target vessel territory. However, ST can also

EARLY ST. Early ST occurs within 30 days after stent

present as sudden death, or it can be asymptomatic

implantation, when technical and procedural factors

in the setting of collateral vessels. The cornerstone

are important. A suboptimal procedural result (e.g.

of the angiographic detection of thrombus is the

slow flow, inadequate post-procedural lumen di-

presence of a filling defect. When a filling defect is

mensions, residual dissection, and tissue prolapse) is

detected angiographically, intravascular ultrasound

associated with the incidence of early ST (19,37,38).

(IVUS) may be used to detect the underlying me-

Because the arterial segment receiving the endo-

chanism of ST (e.g., underexpansion, malapposition,

prosthesis has not yet re-endothelialized, inhibition

edge dissection) (22). Moreover, optical coherence

of platelet activation is a key factor: discontinuation

tomography (OCT) is very suitable for visualization

of DAPT during this time frame can be catastrophic

of the stent surface thanks to its high resolution

and provoke ST. Stenting in prothrombotic conditions

(10 m m), and its ability to detect the presence of

in patients with ACS is also strongly associated with

(sub) clinical thrombus has been experimentally

early ST (36). Due to its fast elimination at a time

confirmed (23).

that antiplatelet drugs may not yet have become

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Stent Thrombosis: A Clinical Perspective

T A B L E 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

Wenaweser et al. (20)

2005

95

BMS

No

Early and late

6 months

20.8

Iakovou et al. (29)

2005

49

DES, BMS

No

Early and late

Not specified

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

11.0 45.0

Daemen et al. (16)

2007

152

DES

No

Early and (very) late

6 months

11.0

de la Torre-Hernandez et 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

Kimura et al. (31)

2009

71

SES

Yes, definite

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

Early and (very) late

30 days

11.0

Late (n ¼ 21)

38.0

Very late (n ¼ 14) Kimura et al. (21)

2010

611

SES

Yes, definite

20.4

Early (n ¼ 36)

Early and (very) late

18.0 1 yr

Early (n ¼ 322)

25.0 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

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

Armstrong et al. (87)

2012

1,391

BMS, DES

No

14.3

In-hospital

27.8

Out-of-hospital

10.8

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.

effective, bivalirudin use in primary PCI may predis-

compared with BMS, and has been associated with

pose to acute ST compared with heparin plus optional

(very) late ST (Figure 1) (42). Finally, neoathero-

glycoprotein IIb/IIIa inhibitors (GPIs) (39,40).

sclerotic plaques can develop in neointima within

LATE

AND

VERY

LATE

ST. Delayed

endothelial

coverage, persistent fibrin deposition, and ongoing vessel inflammation are associated with ST >30 days after stent implantation. Re-endothelialization after stent implantation is significantly delayed in DES compared with BMS and is likely responsible for the higher rates of very late ST with first-generation

previously stented areas, which may rupture, causing ST (Figure 2) (43). Neoatherosclerotic plaques have been observed in both BMS and DES. However, pathological evidence suggests that neoatherosclerosis may develop earlier in DES (44,45). Its development appears to be similar in first- and second-generation DES (46).

DES (41). Stent malapposition is defined as lack of contact between stent struts and the underlying

PHARMACOPREVENTION

arterial wall intima (despite full stent expansion at its nominal diameter). Late stent malapposition is

P2Y 1 2 INHIBITORS. The ISAR (Intracoronary Stenting

typically the result of positive vessel wall remodeling

and Antithrombotic Regimen) and STARS (STent An-

(i.e., outward arterial wall expansion “away” from

ticoagulation RestenosiS) trials established DAPT

the stent struts that were well apposed at the time

with aspirin and a thienopyridine as the stan-

of implantation), appears more commonly in DES

dard of care after coronary stenting (9,10). In the

Claessen et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 10, 2014 OCTOBER 2014:1081–92

Stent Thrombosis: A Clinical Perspective

T A B L E 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-antiplatelet therapy, genetic polymorphisms, thrombocytosis

End-stage renal disease, smoking, STEMI, nonadherence to dual-antiplatelet therapy (unknown for very late 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 polymer DES (compared with bioresorbable polymer DES), overlapping DES

Post-procedural

Discontinuation of antiplatelet therapy

Discontinuation of antiplatelet therapy (unknown for very late ST), late acquired stent malapposition

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

STARS trial, treatment with aspirin and ticlopidine

bleeding risk, and prasugel is particularly contra-

compared with aspirin alone or a combination of

indicated (54). In contrast, subgroups with pro-

aspirin and warfarin reduced ST at 30 days (0.5% vs.

thrombotic potential such as patients with diabetes

3.6% vs. 2.7%, p < 0.01). Subsequent clinical trials

or acute myocardial infarction undergoing PCI may

showed that clopidogrel compared with ticlopidine

derive greater net benefit with prasugrel (58,59). The

resulted in similar 30-day ST rates (47–49). Clopi-

significant benefit in cardiovascular survival docu-

dogrel, which was better tolerated and offered once-

mented with ticagrelor in addition to lower ST has

daily dosing, subsequently replaced ticlopidine in

raised the possibility of pleiotropic effects (55).

clinical practice. CLOPIDOGREL. Clopidogrel is a prodrug; its active

metabolite irreversibly inhibits the P2Y12-type platelet adenosine diphosphate receptor (50). Genetic variations in the activity of cytochrome enzymes involved in metabolizing clopidogrel are associated with lower plasma concentrations of active metabolites and poor responder status. High on-treatment platelet reactivity in patients receiving DAPT consisting of aspirin and clopidogrel has been linked to the occurrence of ST (51). New P2Y 12 inhibitors have been developed to address these limitations. NEW P2Y 1 2 INHIBITORS. Prasugrel, a thienopyridine,

inhibits platelet activation more rapidly, more consistently, and to a greater intensity than clopidogrel (52). Ticagrelor and cangrelor are nonthienopyridine direct-acting, reversible, P2Y 12 inhibitors. Of note, cangrelor is an intravenous agent developed to be used during PCI and reduces intraprocedural ST compared with clopidogrel (53). Table 4 summarizes trials investigating novel P2Y 12 inhibitors compared with clopidogrel and another trial that investigated

F I G U R E 1 Stent Malapposition Detected by Intracoronary OCT Imaging

double-dose (150 mg) compared with standard-dose

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

(75 mg) clopidogrel in patients undergoing PCI for

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

ACS (53–57). Table 4 illustrates that double-dose clo-

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

pidogrel and novel P2Y12 inhibitors are associated with lower rates of ST, but also with increased bleeding

arrow). There is a gap of w0.6 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-

rates. Specific subgroups including patients with

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

active pathological bleeding and previous stroke or

to displace obscuring blood. OCT ¼ optical coherence tomography.

transient ischemic accident sustain an increased

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Stent Thrombosis: A Clinical Perspective

terms of bleeding and all-cause mortality at 1-year follow-up. No difference in the incidence of ST was noted between the study groups. DURATION OF DAPT. Current American College of

Cardiology/American Heart Association guidelines state a Class I, Level of Evidence: B recommendation to continue DAPT for 12 months in patients receiving a stent (BMS or DES) (61). DAPT for patients who receive a stent for ACS indications may include prasugrel 10 mg/day (a 5-mg daily dose may be given to patients at high risk of bleeding), ticagrelor 90 mg twice daily, or clopidogrel 75 mg/day in addition to aspirin (Class I, Level of Evidence: B) (61). For patients receiving a DES for a non-ACS indication, clopidogrel 75 mg/day is indicated. The recently updated European Society of Cardiology guidelines are slightly different for patients with stable coronary artery disease and recommend 1 month of DAPT after BMS implantation, and 6 months of DAPT with aspirin and clopidogrel after DES implantation (62). In patients receiving a stent (BMS or DES) after ACS the recommendation is 12 months of DAPT with aspirin and ticagrelor or prasugrel (or clopidogrel when ticagrelor and prasugrel are contraindicated) (63). Ongoing large-scale trials are investigating the safety and efficacy of shorter or longer DAPT duraF I G U R E 2 Neoatherosclerosis as a Cause of Very Late Stent Thrombosis

tions. Recently, several trials showed better out-

of a DES Placed in an SVG

comes with a 3- to 6-month DAPT duration in rather

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

low-risk patients due to similar ischemic endpoint

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

but significantly lower bleeding rates (64–66) Two

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

modestly sized trials, one comparing 12-month with

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

24-month DAPT duration and another comparing

magnified images (dotted white box regions). (Top) OCT of the stent reveals mild neointima within the stent, but at the 4-o’clock position, there is evidence of cap disruption

6-month with 24-month DAPT duration, found no

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

differences in composite endpoints of adverse events,

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

with similar rates of stent thrombosis (66,67). An

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

even longer DAPT duration is under investigation in

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

the >20,000-patient DAPT Study (Dual Antiplatelet

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

Therapy study) that will determine whether DAPT

graft.

for 30 months compared with only 12 months may protect against ST.

ADJUNCTIVE ANTITHROMBOTIC STRATEGIES ANTIPLATELET THERAPY IN PATIENTS ON ORAL ANTICOAGULANTS. The WOEST (What is the Optimal

The role of the intravenous GPIs abciximab, tirofiban,

antiplatElet & Anticoagulant Therapy in Patients

and eptifibatide in the current era of oral DAPT is

with Oral Anticoagulation and Coronary StenTing)

unclear. In general, treatment with GPIs in ACS re-

study recently reported on the optimal antiplatelet

duces acute ST compared with heparin alone (40,68).

strategy after elective PCI with stent implantation in

In the HORIZONS-AMI trial (Harmonizing outcomes

patients with an indication for long-term treatment

with revascularization and stents in acute myocardial

with oral anticoagulants (60). A regimen consisting of

infarction), which randomized 3,602 STEMI patients

12 months of double therapy (oral anticoagulants

undergoing primary PCI to treatment with bivalirudin

plus clopidogrel) was superior to triple therapy (oral

monotherapy or heparin plus a GPI, the use of biva-

anticoagulants

lirudin was associated with an increased rate of acute

plus

aspirin

and

clopidogrel)

in

Claessen et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 10, 2014 OCTOBER 2014:1081–92

Stent Thrombosis: A Clinical Perspective

T A B L E 4 Stent Thrombosis and Bleeding Rates in Trials Comparing Clopidogrel With Novel P2Y 12 Inhibitors and Single-Dose

Versus Double-Dose Clopidogrel

Study (Ref. #)

TRITON (53) PLATO (54)

Year

Follow-Up

2007

15 months

2009

CHAMPION (56)

2009

CHAMPION PHOENIX (52) CURRENT-OASIS 7 (55)

2009 2010

12 months 48 h 48 h 30 days

Definite/Probable Stent Thrombosis

p Value

TIMI Major Bleeding

Clopidogrel

2.4 (142/6,422)

<0.001

1.8 (111/6716)

Prasugrel

1.1 (68/6,422)

Comparison

Clopidogrel

2.9 (158/5,649)

Ticagrelor

2.2 (118/5,640)

Clopidogrel

0.3 (11/3,865)

Cangrelor

0.2 (7/3,889)

Clopidogrel

1.4 (74/5,469)

Cangrelor

0.8 (46/5,470)

Clopidogrel

2.3*

Double-dose clopidogrel

1.6*

p Value

0.03

2.4 (146/6741) 0.009

7.7 (638/9186)

0.57

7.9 (657/9235) 0.34

0.3 (14/4365)

0.39

0.4 (19/4374) 0.01

0.1 (5/5527)

0.99

0.1 (5/5529) <0.001

0.7 (60/8703)

0.074

1.0 (80/8560)

Values shown are % (n/N). *Number not reported. TIMI ¼ Thrombolysis In Myocardial Infarction.

ST (1.3% vs. 0.3%, p < 0.01) (40). Nonetheless, 30-day

STENT UNDEREXPANSION. This is a common mech-

and 1-year ST rates were similar in both treatment

anism underlying ST. A rigid arterial segment has

arms, and bivalirudin reduced major bleeding and

severely restricted the expansion of the initially

mortality rates (40,69). The recent EUROMAX (Euro-

implanted stent, or an undersized stent may have

pean Ambulance Acute Coronary Syndrome Angiog-

been selected initially (Figure 3). If confirmed by

raphy) trial randomized 2,218 STEMI patients who

IVUS/OCT, high-pressure balloon angioplasty with

were being transported for primary PCI to pre-

noncompliant balloons sized according to the normal

hospital administration of either bivalirudin or

adjacent reference segment can be attempted. A new

unfractionated or low molecular weight heparin with

stent can be particularly deleterious in treating stent

optional

underexpansion if the reason is due to a highly rigid

GPIs

(39).

Bivalirudin

reduced

major

bleeding (2.6% vs. 6.0%, p < 0.001) but still showed

(e.g., calcified) segment because multiple layers of

higher acute ST (1.1% vs. 0.2%, p ¼ 0.007) than the

stent metal will be present in an underexpanded

control arm.

lesion. If balloon expansion is ineffective, then the patient should be temporarily treated with balloon

TREATMENT FOR ST AND THE ROLE OF

angioplasty and return for definite therapy after the

INTRAVASCULAR IMAGING

acute ST presentation has passed. Subsequent treat-

The preferred treatment for ST is emergency PCI,

stent, the neighboring anatomy, and the experience

including the possibility of thrombus aspiration re-

of the operator: 1) rotational atherectomy can ablate

ment options may depend on the exact location of the

storing antegrade blood flow. Additional stent im-

the stent struts and the underlying calcific plaque

plantation is not absolutely necessary and is advised

(26,70); 2) excimer laser aiming at the unexpanded

for treatment of significant residual dissections.

area in combination with contrast dye infusion can

Intravascular imaging with IVUS or OCT can provide significant

insight

into

underlying

mechanisms

create local conditions that may ablate the problematic strut as noted above (26,71); and 3) aortocoronary

causing this complication. Imaging can be safely per-

bypass surgery can provide flow distal to the stent

formed after initial stabilization of the patient. IVUS/

area, although it may not prevent recurrent throm-

OCT can interrogate the entire arterial segment around

bosis at the underexpanded area.

the stent and can identify several conditions that

STENT MALAPPOSITION. This can be verified by the

can be largely undetectable by angiography. Addi-

existence of a space filled with blood between the

tionally, OCT can visualize thrombus and stent

stent struts and the vessel wall (Figure 1). The extent

struts at a higher resolution than IVUS; however, fewer

of this low-flow area has been associated with ST

clinical studies have used OCT, which requires addi-

(42). Angioplasty with an appropriately sized balloon

tional intracoronary contrast injection to displace

as determined by the IVUS/OCT-derived measure-

blood and enable visualization, which may not be

ment of the arterial wall diameter at the culprit

as well tolerated in hemodynamically compromised ST

cross sections typically suffices to ameliorate this

patients.

problem.

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Stent Thrombosis: A Clinical Perspective

F I G U R E 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.

DISSECTIONS. Stent edge dissections can provoke ST

(Figure 2) (74). Intracoronary imaging, particularly

and are easily detectable by IVUS/OCT, despite being

OCT,

sometimes dubious angiographically (72). A new

in vivo (75).

is

critical

in

detecting

neoatherosclerosis

stent can typically cover them and restore adequate flow.

ST RISK ASSESSMENT AND PREVENTION

NEW PLAQUE RUPTURE. This condition essentially

means the absence of ST per se and supports the extension of thrombosis within the stent after initiation at the adjacent plaque disruption area. A new stent may be needed to treat the culprit new lesion area.

PATIENT, LESION, AND STENT SELECTION. As there

are a number of modifiable risk factors for the development of ST, several preventive strategies may decrease the risk of ST. Adequate patient and lesion selection is a first priority. Physicians may prefer to use BMS in lesions with a low risk of restenosis and

STENT FRACTURE. Right coronary artery lesions,

in patients at increased risk of bleeding, scheduled

excessive tortuosity or angulation of the vessel,

for surgery, allergic to thienopyridines, and/or in

overlapping stents, and longer stents have been

whom compliance is questionable. After awareness

associated with an increased risk of stent fracture

of very late ST was raised, novel DES types were

(73). A stent fracture may cause mechanical damage

designed to provide superior safety and efficacy

to the endothelium that could subsequently lead to

compared with first-generation DES. As the durable

ST and can be treated with implantation of a short

polymer on first-generation DES was considered to

stent to cover the area of the stent fracture.

be associated with ST, newer DES designs include,

NEGATIVE

REMODELING

AT

THE

STENT

EDGE.

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

among others, the following: bioresorbable polymers; biomimetic polymers; polymer coating on the abluminal surface of stent struts only; and fully biodegradable DES (76). A large-scale network meta-

NEOATHEROSCLEROSIS. The development of an ACS

analysis of 49 randomized trials revealed signifi-

caused by rupture or erosion of a neoatherosclerotic

cantly lower ST rates with the “second-generation”

plaque in a previously stented lesion has been

everolimus-eluting stent containing a fluoropolymer

acknowledged as a potential culprit in very late ST

compared with other durable polymer DES as well as

Claessen et al.

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Stent Thrombosis: A Clinical Perspective

T A B L E 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

Type of acute coronary syndrome

NSTE-ACS w/o ST changes þ1

NSTE-ACS with ST deviation þ2

Current smoking

Yes: þ1

No: þ0

Insulin-treated diabetes mellitus

Yes: þ2

No: þ0 No: þ0

History of PCI

Yes: þ1

Baseline platelet count

<250 K/ml: þ0

250 K/ml–400 K/ml: þ1

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

Add to Score

STEMIþ4

>400 K/ml: þ2

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.

BMS to 2-year follow-up (77). Two even larger

provisional side-branch stenting approach might be

network meta-analyses, which also included data on

preferable to routine crush and culotte stenting,

biodegradable polymer DES, one comprising 258,544

which have been associated with higher ST rates

patients from 126 randomized trials (78) and another

(82,83). When a 2-stent (DES) approach is imple-

comprising 63,242 patients from 60 randomized

mented in a bifurcation, re-endothelialization can be

trials (79), were recently published. These studies

particularly slow and enhance ST risks.

confirmed that newer generation durable polymer stents such as the everolimus-eluting stent and the

DAPT COMPLIANCE AND INTERRUPTION. Compli-

(Medtronic,

ance with DAPT is paramount to minimize the risk of

Santa Rosa, California) provide the best combination

ST (29,84), particularly if it occurs within 30 days of

of safety and efficacy even when compared with

implantation. Unclear communication of treatment

biodegradable polymer DES. Fully bioabsorbable

plans, low levels of patient education, and other

coronary stents may reduce very late stent throm-

social factors have been shown to influence DAPT

bosis, but long-term results of large-scale trials

compliance and should routinely be taken into

investigating the safety and efficacy of these devices

account.

Resolute

zotarolimus-eluting

stent

Several studies suggested that the relationship

are not yet available.

between ST and nonadherence to DAPT varies over RISK SCORE CALCULATION. A risk score has been

time. It is strongest in the first month after stent

proposed to personalize risk assessment for the oc-

implantation, remains important until 6 months,

currence of ST in ACS patients (Table 5) (80). This risk

but fades afterward (85,86). The 5,031-patient PARIS

score may be used to identify patients who might

(Patterns of Non-adherence to Anti-platelet Re-

benefit the most from more aggressive antiplatelet

gimens in Stented Patients) registry investigated

therapy after stent implantation.

different categories of DAPT cessation: physicianrecommended cessation, interruption (for surgery),

TECHNIQUE. An optimal procedural result is impor-

and disruption (abrupt, unsupervised nonadherence

tant to minimize the risk of ST. Proper stent expan-

or for bleeding) (86). At 2 years after stent implanta-

sion and apposition over the full length of the stent

tion, overall DAPT cessation was 57.3%, discontinua-

should be ascertained, and residual dissections

tion occurred in 40.8%, interruption in 10.5%, and

should be avoided. A recent study by Roy et al.

disruption in 14.4% of patients. DAPT disruption

(81) reported a strong trend toward reduced ST

was associated with an increased risk of ST. This

after IVUS-guided stent implantation compared with

effect was strongest during the first 7 days after

angiography only–guided PCI. As the risk of ST in-

DAPT cessation (hazard ratio: 18.25, p < 0.0001) and

creases with stent length, excessive use of stents is

weakened overtime.

discouraged. However, it is imperative that stents do cover the entire lesion because residual plaque

RECOMMENDATIONS

at stent edges can also produce dissections, flow

When considering an elective invasive diagnostic

compromise,

test or surgery in a patient with coronary stents, it

and

ST. In

bifurcation

lesions, a

FOR

DAPT

INTERRUPTION.

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Stent Thrombosis: A Clinical Perspective

may be preferable to postpone the procedure until

occurs more frequently in first-generation DES. Many

1 year after stent implantation. If there are pressing

risk factors for ST have been identified by intravas-

reasons to interrupt DAPT before the guideline-

cular imaging and pathology, some modifiable and

recommended period of 6 to 12 months, this should

some not. Adequate patient, lesion, and stent selec-

be postponed as long as possible, and aspirin should

tion; a good technical result; and effective DAPT

be continued.

are critical in minimizing the risk of ST.

CONCLUSIONS

REPRINT REQUESTS AND CORRESPONDENCE : Dr.

George D. Dangas, Cardiovascular Institute, Mount ST is an uncommon but serious complication of PCI.

Sinai Medical Center, One Gustave L. Levy Place, Box

The incidence of early and late ST is similar in BMS

1030, New York, New York 10029. E-mail: gdangas@

and DES, but very late ST, although uncommon,

crf.org.

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KEY WORDS coronary artery disease, percutaneous coronary intervention, stent thrombosis

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