Late Coronary Stent Thrombosis

Late Coronary Stent ThrombosisStephan Windecker, MD; Bernhard Meier, MD

Introduced �20 years ago,1 coronary artery stents haveimproved the safety and particularly the efficacy of percu-

taneous coronary interventions (PCIs).2 Abrupt vessel clo-sure, complicating 6% to 8% of balloon angioplasty proce-dures, was associated with a 5% mortality, 40% rate ofmyocardial infarction (MI), and 40% rate of emergencycoronary artery bypass grafting.3 Stents significantly reducedthese adverse events (Figure 1).4,5 The reduction of restenosisafforded by bare metal stents (BMS) was modest (30% to40%). Repeat revascularization still occurred in 15% to 20%of cases.6 Drug-eluting stents (DES) with antiproliferativedrugs attached via polymers on the stent surface to minimizesmooth muscle proliferation have reduced restenosis andrates of target lesion revascularization by 50% to 70%compared with BMS across nearly all lesion and patientsubsets.7 Initially8 and again more recently,9–16 safety con-cerns were raised about DES, particularly about late stentthrombosis (ST).

Historical PerspectiveST was a bane of stent implantation from the beginning. Theinitial experience with Wallstents in the late 1980s wasovershadowed by ST rates approaching 24%.17 Subsequentseries with Palmaz-Schatz and Gianturco-Roubin stents (stillpredominantly bailout stenting) observed ST in 6% to 12% ofcases.4,18 The postprocedural antithrombotic regimen at thetime consisted of aspirin, often in conjunction with oralanticoagulation. Dual antiplatelet therapy of aspirin and thethienopyridine ticlopidine in conjunction with a shift frombailout to elective stenting resulted in a significant reductionof ST to �2%.5,19 Earlier oral antiplatelet drug loading andglycoprotein IIb/IIIa antagonists further diminished ST. Table1 provides an overview of ST reported in contemporary trialsof BMS and DES, ranging from 0.1% to 3.1%.11,20–38 Thewide range in the incidence of ST across trials with both BMSand DES is explained by differences in definitions, length offollow-up, antithrombotic drug regimens, and complexity ofpatients and lesions.

Definition of STST, typically encountered early postoperatively, generallytranslates into a clinical syndrome consisting of acute onset ofchest pain with ischemic ECG changes in the target vesselterritory. The proof is thrombotic stent occlusion (angiogra-

phy or autopsy). Definitions of ST range from “angiographi-cally proven” to “clinically suspected” ST with the inclusionof MI involving the target vessel to unexplained death (within30 days or anytime). Although the first definition character-izes a well-defined mechanism limited to a select patientpopulation undergoing angiography at the time of ST andhence underestimates the true incidence of ST, the othersinclude events related to disease progression and arrhythmiaand therefore overestimate the true incidence. Accounting forthese limitations, an academic research consortium proposeda new standardized definition of ST (Table 2).39 It is based on2 principles: level of certainty that ST is underlying mecha-nism of adverse event and time of adverse event relative toindex procedure.

Definite ST (highest level of certainty) requires eitherangiographic or postmortem evidence of thrombotic stentocclusion. Probable ST encompasses any unexplained deathwithin 30 days of stent implantation or any MI in the territoryof the implanted stent regardless of time. Possible ST in-cludes any unexplained death beyond 30 days until the end offollow-up. Probable ST and possible ST have been added tothe definition of ST because they provide higher sensitivity indetecting safety signals. Conversely, they are less specificand therefore critically dependent on detailed data collectionabout the cause of death or MI to avoid overreporting of ST.Although it has been suggested that the composite of definiteand probable ST represents a good balance of specificity andsensitivity, reporting of definite and overall rates with carefuladjudication of late unexplained deaths has been encouraged.

The second classification principle is based on the time ofthe adverse event relative to the index procedure (Figure 2).Early ST refers to the first 30 days after stent implantationand is further stratified into acute (�24 hours) and subacute(24 hours to 30 days). Late ST defines the time intervalbetween 1 month and 1 year after stent implantation; very lateST includes any event beyond 1 year. The rationale of thisclassification is to account for different pathophysiologicalmechanisms that may be at work at various times.

An additional level of information is provided by reportingwhether ST occurred in the context of an intercurrent targetlesion revascularization. Thus, censoring of adverse eventsonce intercurrent revascularization procedures occurred maydisadvantage devices with lower (ie, DES) compared withdevices with higher (ie, BMS) reintervention rates. To avoid

From the Department of Cardiology, University Hospital Bern, Bern, Switzerland.Correspondence to Bernhard Meier, MD, Professor and Chairman of Cardiology, Cardiovascular Department, University Hospital Bern, 3010 Bern,

Switzerland. E-mail [email protected](Circulation. 2007;116:1952-1965.)© 2007 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.106.683995

1952

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this form of selective reporting, it is recommended that bothprimary ST rates (without intercurrent target lesion revascu-larization) and secondary ST rates (with intercurrent targetlesion revascularization) be provided. Primary ST rates iden-tify safety signals related to the originally implanted device,whereas secondary ST rates provide information on theoverall treatment strategy, taking into account the impact offrequency of repeat revascularization procedures.

Frequency and Time of STEarly ST (0 to 30 days) is encountered with a similar or evensomewhat lower frequency after DES compared with BMS. A30-day definite ST rate of 1.2% with BMS (506 patients),1.0% with sirolimus-eluting stents (SES; 1017 patients), and1.0% with paclitaxel-eluting stents (PES; 989 patients) wasfound in a sequential cohort comparison.33 A meta-analysis of6 studies comparing BMS with SES in 2963 patients reported

4.9

40.2 40.2

1.34.0

1.00.0

10.0

20.0

30.0

40.0

50.0

Death MI Emergency CABG

Balloon Angioplasty Bare Metal Stent

%

Figure 1. Outcome of 112 patients with abruptvessel closure in the prestent balloon angio-plasty experience of a registry (1985 to 1986;total, 1801 patients)3 and 339 patients withabrupt vessel closure during balloon angioplastytreated with BMS (Palmaz-Schatz) (total, 4596patients).5 CABG indicates coronary arterybypass grafting.

Table 1. Coronary ST

Study YearStentType

TotalPopulation, n

ST,n (%) Definition of ST Thienopyridine (%) Time

BMS

Karrillon et al20 1996 BMS 2900 51 (1.8) Definite and probable Ticlopidine Early

Moussa et al21 1997 BMS 1001 19 (1.9) Definite and probable None (25) Early

Ticlopidine (75)

Schühlen et al22 1998 BMS 2833 65 (2.3) Definite Ticlopidine (80) Early

Ticlopidine (75)

None (2)

De Servi et al23 1999 BMS 939 14 (1.5) Definite Ticlopidine Early

Cutlip et al24 2001 BMS 6186 53 (0.9) Definite and probable Ticlopidine Early

Serruys et al25 2001 BMS 600 17 (2.8) Definite Ticlopidine Early

Heller et al26 2001 BMS 1855 34 (1.8) Definite Ticlopidine Early and late

Orford et al27 2002 BMS 4509 23 (0.5) Definite and probable Ticlopidine, clopidogrel Early

Wang et al28 2002 BMS 1191 20 (1.7) Definite Ticlopidine Early and late

Wenaweser et al29 2005 BMS 6058 95 (1.6) Definite Ticlopidine, clopidogrel Early and late

Lee et al30 2005 BMS 1597 9 (0.5) Definite Clopidogrel Early

Lee et al30 2005 BMS 1415 1 (0.1) Definite Clopidogrel and cilostazol Early

DES

Serruys et al31 1998 Hepacoat 414 1 (0.2) Definite Ticlopidine Early

Mehran et al32 2003 Hepacoat 200 2 (1) Definite and probable None Early

Ong et al33 2005 SES, PES 2006 20 (1.0) Definite Clopidogrel Early

31 (1.6) Definite and probable Clopidogrel Early

Iakovou et al34 2005 SES, PES 2229 29 (1.3) Definite, probable, and possible Clopidogrel, ticlopidine Early and late

Kuchulakanti et al35 2006 SES, PES 2974 38 (1.3) Definite Clopidogrel Early and late

Rodriguez et al36 2006 SES, PES 225 5 (2.2) Definite Clopidogrel Early, late, and very late

7 (3.1) Definite and probable Clopidogrel

Urban et al37 2006 SES 15 157 126 (0.9) Definite and probable Clopidogrel Early and late

Park et al38 2006 SES, PES 1911 15 (0.8) Definite, probable, and possible Clopidogrel Early, late, and very late

Daemen et al11 2007 SES, PES 8146 152 (1.9) Definite Clopidogrel Early, late, and very late

Windecker and Meier Late Stent Thrombosis 1953



ST rates at 30 days of 0.5% with SES and 0.6% with BMS,respectively (relative risk [RR], 0.76; 95% confidence inter-val [CI], 0.30 to 1.88; P�0.55).40 A pooled analysis of 5 trialsusing PES in 3513 patients showed early ST rates of 0.5%with PES compared with 0.6% with BMS (RR, 0.74; 95% CI,0.31 to 1.80; P�0.51).41 Finally, a recent analysis of variousdefinitions of ST observed no difference between SES, PES,and BMS in the propensity for early ST.16

Although late ST (�1 month to �1 year) had already beenobserved during the BMS era, it was largely ignored. Fourregistries comprising 9465 BMS patients reported rates oflate ST ranging from 0% to 1% (average, 0.5%) and repre-senting nearly one third of overall ST events (average, 1.6%)(Figure 3).26,28,29,42 Confirmation of this observation camefrom necropsy findings in a series of 13 patients succumbingto late ST after BMS implantation.43 Stenting across ostia,plaque disruption in the peristent region, extensive plaqueprolapse caused by very lipid rich plaque, and in-stent

restenosis were pathological correlates of late ST. In ameta-analysis, no differences existed in the overall (0.6%versus 0.5%; odds ratio, 1.05; 95% CI, 0.51 to 2.15; P�1.00)and late (0.2% versus 0.3%; odds ratio, 99; 95% CI, 0.35 to2.84; P�1.00) incidence of ST between DES (2602 patients)and BMS (2428 patients).44 Similarly, no significant differ-ences existed in the incidence of late ST between SES, PES,and BMS according to various definitions as proposed by theacademic research consortium.16 Whether the 2 US Food andDrug Administration–approved DES differ with respect toearly and late ST has been scrutinized in several randomizedtrials directly comparing SES and PES and in a meta-analy-sis.45 No significant differences were detected for up to 1 yearof follow-up (Figure 4). Taken together, BMS and DES (SESor PES) show similar rates of ST for up to 1 year after theindex procedure. ST occurred within the expected range in abroad spectrum of patients and lesions, but average dualantiplatelet therapy was longer after DES than BMS.

Case reports, observational studies, extended follow-up oftrials comparing DES with BMS, and meta-analyses ofrandomized trials have corroborated that very late ST (�1year) is more common with DES than BMS. The predispo-sition to ST of DES �1 year after implantation has beenanticipated as design inherent.8 It was first documented in 4patients who discontinued antiplatelet therapy or underwent asurgical procedure.46 Follow-up results in 826 patients as-signed on a random daily basis to treatment with either BMS(n�281) or DES (n�546) indicated an increased risk ofcardiac death (1.2% versus 0%; P�0.09) and MI (4.1%versus 1.3%; P�0.04) with DES during the time period of 7to 18 months (a time when clopidogrel treatment had beendiscontinued),10 although overall rates of cardiac death (2.8%versus 2.5%; P�NS) and MI (6.1% versus 5.3%; P�NS)were similar at 18 months. The frequency and timing ofdefinite ST encountered with first-generation DES have beenexamined in 8146 patients treated at 2 academic centers that

Table 2. Definition of ST as Proposed by the Academic Research Consortium39

Definite ST

Definite stent thrombosis is diagnosed when either angiographic or pathological confirmation is present

Angiographic confirmation of ST*

The presence of a thrombus originating in the stent or in the segment 5 mm proximal or distal to the stented region and at least one of the followingcriteria within a 48-h time window:

Acute onset of ischemic symptoms at rest (typical chest pain �20 min)

New ischemic ECG changes suggestive of acute ischemia

Typical rise and fall in cardiac biomarkers

Pathological confirmation of stent thrombosis

Evidence of recent thrombus within the stent determined at autopsy

Probable ST

Clinical definition of probable ST is diagnosed after intracoronary stenting in the following cases

Any unexplained death within the first 30 d

Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent withoutangiographic confirmation of ST and in the absence of any other obvious cause

Possible ST

Clinical definition of possible ST is diagnosed with any unexplained death from 30 d after intracoronary stenting until the end of trial follow-up

*The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms (silent occlusion) is (for this purpose) not considereda confirmed stent thrombosis.

Time Frame of Stent Thrombosis

1 month 1 year

Acute1 day

Late >1 month - 1year

Subacute>1 day to 1 month

Early <1 month Very late >1year

1 day Acute stent thrombosis>1 day to 1 month Subacute stent thrombosis>1 month to 1 year Late stent thrombosis>1 year Very late stent thrombosis

Figure 2. Timing of ST. Early ST refers to �30 days; late ST,to 1 month to 1 year; and very late ST, to �1 year after stentimplantation.

1954 Circulation October 23, 2007



adopted default DES use in routine clinical practice in 2002.11

Whereas the incidence of early ST (1.1%) was similar toprevious reports, the incidence of late ST continued at asteady rate of 0.6% per year for up to 3 years of follow-up(Figure 5). Pooled analysis of 4 randomized trials (1748patients) comparing SES and of 5 randomized trials (3513patients) comparing PES with BMS revealed similar rates ofprotocol-defined ST up to 1 year but significantly more verylate ST (SES versus BMS: 0.6% versus 0%, P�0.03; PESversus BMS: 0.7% versus 0.2%, P�0.03).12 After readjudi-cation of all ST events in these trials according to each of thenewly proposed academic research consortium categories,differences in the incidence of very late ST diminished butwere still apparent.16 Another systematic review of 14 trialscomparing SES with PES revealed no difference in theoverall incidence of protocol-defined ST (SES, 1.5% versusBMS, 1.3%; P�0.75), but very late ST was more frequentwith SES (0.3% versus 0.04%; P�0.02).14 Finally, a meta-analysis of 6675 patients with follow-up ranging from 8 to 48months reported no difference in the overall incidence of STbetween BMS and DES (0.10% versus 0.07%; RR, 1.03; 95%CI, 0.63 to 1.68; P�0.91) but a significantly higher rate ofvery late ST in disfavor of DES (0.5% versus 0%; RR, 5.02;

95% CI, 1.29 to 19.52; P�0.02).9 Accordingly, very late STis a distinct clinical entity complicating the use of first-generation DES while being exceedingly rare after BMS. Itremains to be determined whether the yearly rate of 0.2% to0.6% persists beyond 3 years, whether DES in off-labelsettings is associated with higher rates of very late DES, andwhether newer-generation DES have a more favorable riskprofile.

Clinical Sequelae of STST results in abrupt closure of the stented artery with theassociated risk of MI and death.24 The impact of ST isinfluenced by the myocardial area at risk, its viability, thedegree of instantly recruitable collaterals, and rapid reperfu-sion therapy. Moreover, ST may be responsible for latecomplications of MI, including heart failure, arrhythmias, ormechanical complications.

Mortality after ST is high. A pooled analysis of multicenterBMS trials24 and a single-center registry of 6058 BMSpatients29 both observed a mortality of 7% at 30 days afterdefinite ST. Mortality at 30 days after definite ST in DESamounted to 9% in a registry of 8146 patients11 and to 19%in a series of 2974 patients.35 A recent report of definite or

1.7 1.8

0.8

1.6

0.80.6

0

0.4

0

1

2

3

Wang Heller Calver Wenaweser

Overall ST Late ST

N=1,191 N=1,855 N=361 N=6,058

%

Figure 3. Overall and late ST in 4 observationalstudies with BMS investigating ST beyond 30days.26,28,29,42

0.04 0.1 0.5 1 2 10 25

Risk ratioFavors SES Favors PES

TAXI 2.94 ( 0.12, 71.37) 2.9ISAR-DIABETES 0.33 ( 0.01, 8.10) 2.9SIRTAX 1.12 ( 0.46, 2.74) 36.5CORPAL 4.85 ( 0.23, 100.62) 3.2

REALITY 0.38 ( 0.13, 1.05) 27.6BASKET 1.06 ( 0.22, 5.23) 11.5Zhang et al 0.55 ( 0.09, 3.28) 9.2Long DES II 5.15 ( 0.25, 106.59) 3.2PROSIT 0.20 ( 0.01, 4.09) 3.2

Overall 0.80 ( 0.47, 1.37), I2=0%

Risk ratio(95% CI) % Weight

Figure 4. Risk of ST in 9 trials directly comparing SES and PES with follow-up to 1 year. Updated from Reference 45.




probable ST in randomized clinical trials of DES versus BMSrevealed similar rates of mortality for both stent types (SESversus BMS, 31% versus 33%; PES versus BMS, 32% versus28%).16 Case fatality rates may vary across studies, depend-ing on the definition of ST (Figure 6). Thus, rates of MI arequite similar in series of definite only and definite/possible/probable ST, whereas mortality ranges between 11% (definiteST) and 45% (definite, probable, and possible ST) at 6 to 9months of follow-up.11,34,35 The difference in case fatality ofST is related to the broader and therefore less specificinclusion of probable and possible as opposed to only definiteST cases.

Most ST patients develop MI (66% to 100% with DES11,16,35

and 60% to 87% with BMS) with no differences between DESand BMS.16,24,29 The consequences of ST may be grave inpatients in whom multiple stents in different vessels occludesimultaneously, as has been observed in 7 of 152 patients (5%)with DES ST.11 Patients with suspected ST may show a

thrombus without flow impairment resulting from spontaneousor drug-facilitated lysis and may suffer minimal or no myocar-dial injury. Patients suffering from ST are at significant risk ofrecurrent thrombotic stent occlusion; 11 of 95 patients (12%)with BMS ST and 3 of 152 patients (2%) with DES ST hadrecurrent ST after a first event.11,29 Impaired collateral flow afterimplantation of DES compared with BMS (collateral flow index,0.15�0.10 versus 0.22�0.14; P�0.01) during 6 months offollow-up was suggested,47 but the clinical significance of thisobservation in patients with ST remains unclear. Definite earlyor late ST after DES implantation in 152 patients had compara-ble rates of death (13.2% versus 8.2%; P�0.24) and majoradverse cardiac events (77% versus 75%; P�0.99).11

The US Food and Drug Administration convened a meet-ing of its Circulatory System Devices Advisory Panel onDecember 7 and 8, 2006, to address the concern of whetherthe slight excess of very late ST with DES compared withBMS might be associated with increased rates of death or MI

Days after DES Implantation

Num

berS

T

0 3 6 9 13 18 24 31 46 85 146

192

224

260

336

356

381

441

464

491

551

568

606

670

762

822

925

1074

0

5

10

15

20

Cum

ulat

ive

num

bero

feve

nts

(%)

0.5

1.0

1.5

2.0Early stent thrombosis Late stent thrombosis Cumulative number ST

Figure 5. Frequency distribution over time of ST in 152 of 8146 consecutive DES patients. Early ST cases are gray (91 patients); lateST cases (61 patients) are black. The line shows the cumulative number of events over time. Reproduced from Daemen et al,11 copy-right © 2007, with permission from Elsevier.

Figure 6. Levels of certainty in the diagno-sis of ST in DES and impact on mortalityand MI. A, Definite ST in 152 of 8146 con-secutive patients.11 B, Definite ST in 38 of2974 consecutive patients.35 C, Definite,probable, or possible ST in 29 of 2229 con-secutive patients.34




during long-term follow-up. The clinical outcomes of ran-domized clinical trials comparing SES and PES with BMSwere analyzed in several systematic reviews and revealed nosignificant differences relative to death (PES, 6.1% versusBMS, 6.6%; hazard ratio [HR], 0.94; 95% CI, 0.70 to 1.26;P�0.6812; SES, 6.0% versus BMS, 5.9%; HR, 1.03; 95% CI,0.80 to 1.30)14 or MI (PES, 7.0% versus BMS, 6.3%; HR,1.06; 95% CI, 0.81 to 1.39; P�0.6612; SES, 9.7% versusBMS, 10.2%; HR, 0.97; 95% CI, 0.81 to 1.16)14 duringlong-term follow-up to 4 to 5 years.13 It was hypothesized thatthe small increase in very late ST with DES was balanced bya somewhat smaller early ST rate, less frequent need forrepeat revascularization procedures, and fewer associatedcomplications compared with BMS. This notion is supportedby the observation of a higher rate of late and very late STafter readjudication of previously censored ST cases inpatients allocated to treatment with BMS after intercurrentrevascularization procedures.16 Yet a large-scale registry of6033 DES and 13 738 BMS patients in Sweden reportedsimilar rates of mortality (propensity score–adjusted Coxregression analysis: RR, 0.94; 95% CI, 0.83 to 1.06) and MI(RR, 0.94; 95% CI, 0.77 to 1.03) for up to 6 months, followedby an excess risk of death (RR, 1.20; 95% CI, 1.05 to 1.37)and MI (RR, 1.12; 95% CI, 0.95 to 1.32), using landmarkanalyses during follow-up to 3 years.15 Although groups ofDES and BMS differed widely with respect to cardiovascularrisk factors such as diabetes (DES, 24% versus BMS, 16%),number of stents, stent diameter, stent length, and targetlesion location, limiting the value of adjustments made bypropensity score analysis, concerns persist that the use ofDES in more complex patient and lesion subsets not repre-sented in the randomized clinical trials may be associatedwith higher adverse event rates.

Risk Factors of STST is a multifactorial problem related to patient, lesion, andprocedural factors and to the coagulation system and responseto antiplatelet therapy (Table 3). Early ST has been viewed asa problem originating from the procedure itself. Schühlen etal,22 using a classification and regression tree, identifiedresidual dissections, followed by length of the stented seg-ment, as the most important predictors of ST within 30 dayswith BMS. The importance of residual dissections in the DESera has been reiterated when observing an increased risk ofST (6.3% versus 1.3%; P�0.01) and major adverse cardiacevents (18.5% versus 11.2%; P�0.07) at 6 months in patientswith or without residual dissections.48

ST is mediated predominantly by platelet-rich thrombi andhence platelet aggregation. ADP-induced (65�3% versus51�2%; P�0.001) and shear-induced (40.9�12.2% versus18.2�18%; P�0.013) platelet aggregation has been found tobe increased in patients with ST compared with controlsubjects, suggesting increased intrinsic platelet reactivity.49,50

Moreover, impaired response to antiplatelet therapy withaspirin, not correctable by the addition of clopidogrel, wasdocumented in patients suffering from ST.51 Whether differ-ences in platelet reactivity and response to antiplatelet ther-apy affect late and very late ST is unknown.

Discontinuation of antiplatelet therapy has emerged as oneof the most important predictors of ST. Aspirin withdrawalwas responsible for admission with an acute coronary syn-drome in 51 of 1236 patients (4%) with a mean delay betweenaspirin cessation and hospitalization of 10�2 days.52 Nota-bly, 10 of 51 patients (19%) presented with late and very lateST at a mean of 16�7 months after BMS implantation.Discontinuation of antiplatelet therapy was related in de-scending order to patient noncompliance, dental procedures,surgical procedures, and bleeding. Predictors of the compos-ite of definite, probable, and possible ST up to 9 months afterDES implantation were identified in a cohort study of 2229patients.34 The strongest predictor of early (HR, 161; 95% CI,26 to 998; P�0.001), late (HR, 57; 95% CI, 15 to 220;P�0.001), and overall ST (HR, 90; 95% CI, 30 to 270;P�0.001) was premature discontinuation of antiplatelet ther-apy: both aspirin and thienopyridine in 4 patients and thien-opyridine alone in 1 patient. Similarly, discontinuation ofthienopyridines was more prevalent in patients suffering fromST after DES implantation compared with control subjects(37% versus 11%; P�0.0001) and emerged as an indepen-dent predictor of overall ST in a population of 2974 pa-tients.35 It is noteworthy that most of these data are based ononly a few events, that compliance with antiplatelet therapy isdifficult to assess, and that even continued dual antiplatelettherapy provides but an imperfect safety net.53 Patients maystill develop early and late ST despite adherence to theprescribed antiplatelet regimen. Dual antiplatelet therapy was

Table 3. Multifactorial Origin of ST

Patient factors

Thickness and robustness of neointimal stent coverage

Drug response/interactions

Gene polymorphism

Left ventricular function

Acute coronary syndrome

Renal failure

Diabetes mellitus

Antithrombotic and anticoagulation therapy

Coagulation activity

Inhibition of platelet aggregation

Procedural factors

Dissection

Incomplete stent apposition

Stent expansion

Lesion factors

Vessel size

Lesion length

Thrombus

Plaque characteristics

Bifurcation

Device factors

Stent surface

Drugs

Polymer




taken by 14 of 61 patients (23%) suffering from late ST afterDES implantation, whereas only 16 (26%) were off antiplate-let therapy at the time of late ST (Figure 7).11 ST occurred latein 31 patients while on aspirin monotherapy, and most ofthem (30 of 31; 97%) experienced the event well after therecommended period of clopidogrel. Taken together, thesedata indicate that dual antiplatelet therapy is important butis no panacea for the prevention of ST with both BMS andDES, that discontinuation of either aspirin or clopidogrelshould be avoided (particularly during the first 6 to 12months after the index procedure), and that cessation ofantiplatelet therapy is related mostly to noncompliance andsurgical procedures.54,55

Similar to previous the experience with BMS, ST compli-cating DES implantation is influenced by several additionalpatient, lesion, and procedural factors. In a series of 15 157patients treated with SES and followed up prospectively for 1year, ST occurred in 126 patients (0.9%: early, 0.7%; late,0.2%), and multivariate analysis identified impaired postpro-cedural flow impairment, insulin-dependent diabetes, calcifi-cation, total occlusions, acute coronary syndrome, and num-ber of treated lesions as predictors of overall ST.37 Renalfailure, bifurcation lesions, total stent length, and diminishedleft ventricular function were additional clinical predictors ofST with DES in subsequent reports.34,35 Intravascular ultra-sound in 15 patients with ST compared with 45 controlsubjects revealed smaller minimal stent area (4.3�1.6 versus6.2�1.9 mm2; P�0.001), reduced stent expansion (65�18%versus 85�14%; P�0.001), and residual edge stenosis (67%versus 9%; P�0.001) to be more common in the ST patientsthan the control subjects.56

Pathogenesis of STVirmani and colleagues57 first described a case of localhypersensitivity reaction with extensive vasculitis of intima,

media, and adventitia consisting predominantly of lympho-cytes and eosinophils in a patient suffering very late DESthrombosis. Histopathological analysis revealed aneurysmaldilatation of the vessel wall within the stented segment withevidence of stent malapposition and thick fibrin thrombusbetween the stent and the arterial wall. Clinical evidence ofhypersensitivity reactions stems from a registry,58 with 17 of5783 patients reporting hypersensitivity symptoms probablyor certainly related to DES.

In a recent necropsy comparison of 23 DES cases with 25BMS cases (�30 days after the index procedure), delayedhealing manifested by persistent fibrin deposition and incom-plete reendothelialization emerged as an important discrimi-nator between BMS and DES.59 Endothelialization (27�26%versus 66�25% versus 90�21%) was reduced whereas fibrinscores (3.0�0.9 versus 1.9�1.1 versus 0.9�0.8) were in-creased in DES patients with late ST compared with patientswith both patent DES and BMS. Endothelialization wasnearly complete in BMS specimens examined beyond 6months, whereas incomplete endothelialization in DES spec-imens persisted beyond 40 months (Figure 8). Fourteen of 21DES patients suffered late ST, which was related to delayedhealing in all patients; in addition, the following pathologicalmechanisms were identified: chronic inflammation/hypersen-sitivity reaction, stenting over major side branches or bifur-cation stenting using the crush technique, malappositionrelated to positive arterial remodeling or incomplete stentexpansion, in-stent restenosis with superimposed thrombus,and penetration of necrotic core through stent struts. Theresults of this analysis are confounded by selection biasbecause patients with late DES thrombosis were more likelyto undergo autopsy for suspected late thrombosis, whereaspatients with BMS were more likely to be referred for otherreasons.

8.9

4.4

26.2

23.0

86.750.8

0%

20%

40%

60%

80%

100%

Early stent thrombosis Late stent thrombosis

Dual antiplatelet therapy Single antiplatelet therapy No antiplatelet therapy

Figure 7. Antiplatelet treatment at the time of DES thrombosis in 152 patients. Proportion of patients with early (left column; 91patients) and late (right column; 61 patients) ST, respectively, treated with dual, single, or no antiplatelet therapy. Data fromDaemen et al.11




Several clinical investigations support the notion of re-duced or dysfunctional endothelialization after DES implan-tation. Kotani et al60 compared stent strut coverage betweenBMS (n�22) and SES (n�15) 3 to 6 months after theprocedure using intracoronary angioscopy. Struts of SESwere not (grade 0, 20%) or were minimally (grade 1, 67%)covered, whereas BMS showed complete coverage in allcases (grade 2, 13%; grade 3, 87%). Although angioscopy isunable to provide histological evidence of endothelialization,it is not farfetched to conclude that both neointimal regrowthand reendothelialization were impaired by DES. Physiologi-cal evidence of dysfunctional endothelium comes from stud-ies assessing vasomotion 6 months after DES implanta-tion.61,62 Through the use of bicycle exercise during coronaryangiography, the segment proximal and distal to DES showedparadoxical vasoconstriction, whereas BMS demonstratednormal vasodilatation (Figure 9), suggesting that DES eitherprevent reendothelialization or induce vascular damage withsubsequent endothelial dysfunction and reduced nitric oxideavailability. Using pharmacological evaluation of endothelialfunction 6 months after the index procedure, another studycorroborated paradoxical vasoconstriction distal to the stentwith a maximal decrease in the mean coronary diameter by32% compared with baseline in SES-treated patients with aninsignificant decrease in the BMS control group (2%;P�0.03).63

A pooled analysis of intravascular ultrasound studiesafter SES64 (8.5% versus 0%; P�0.05) and PES65 (8.4%versus 3.5%; P�0.05) implantation revealed a higher

incidence of incomplete stent apposition with DES com-pared with BMS that was not associated with any majoradverse cardiac events at the 1-year follow-up. In contrast,a study of 13 DES patients undergoing intravascularultrasound before emergency PCI at the time of very lateST showed a higher incidence and larger area of incom-plete stent apposition compared with a control group of144 event-free DES patients (frequency, 77% versus 12%;P�0.001; maximum area, 8.3�7.5 versus 4.0�3.8 mm2;P�0.03).66 Although vessel cross-sectional area was com-parable for the reference segment, it was significantlylarger for the in-stent segment in patients with very late STcompared with DES control subjects, suggesting positivearterial remodeling as a potential pathogenetic mechanismof very late ST. A similar observation was reporteddescribing 2 cases of very late ST after DES implantationwith late acquired incomplete stent apposition and pro-nounced positive arterial remodeling within the stentedsegment.67 Finally, drugs released from the drug-polymercombination may exert a thrombogenic effect on their own.Paclitaxel and sirolimus have been reported to enhanceendothelial tissue factor expression, a cell surface receptorfor coagulation factor VII, the principal activator of thecoagulation cascade that activates factors IX and X.68,69

In summary, delayed healing and impaired endotheli-alization are common features of most cases of late and verylate ST, which either alone or in combination with chronicinflammation and hypersensitivity reactions, incomplete stentapposition resulting from positive arterial remodeling or stent

Figure 8. Healing after BMS and DES in humans. Left, Degree of endothelialization of thrombosed DES vs patent DES and BMS asobtained from an autopsy study of 23 DES and 25 BMS. Right, Percentage of endothelialization as a function of time after the indexprocedure. Dashed line indicates BMS; solid line, DES. Reproduced from Joner et al,59 copyright © 2006, with permission fromElsevier.




underexpansion, and penetration of the stent into a necroticcore leads to this adverse event. In contradistinction to thethick layer of neointima after balloon angioplasty or BMSimplantation, the surface coverage on a DES may be thin andbrittle or even absent and thus prone to rupture, not unlike avulnerable plaque. It remains to be explained why SES arenot more susceptible to this problem than PES in light of theirattested thinner neointimal coverage. Inhomogeneity of neo-intimal hyperplasia with PES (thin on struts, thicker betweenstruts) may account for this.

Treatment of STST constitutes an emergency, be it early, late, or very late, justlike any acute MI. Primary PCI is the therapy of choice, thegoal being to mechanically recanalize the thrombosed stent.Procedural success in �90% of patients has been reported.29

Most thrombotic stent occlusions can be treated with balloonangioplasty alone, perhaps aided by thrombus aspiration.Additional stent implantation should be limited to significantresidual dissections. Glycoprotein IIb/IIIa antagonists may beadministered to improve microvascular reperfusion and toovercome increased platelet aggregation. Systemic fibrinoly-sis should be considered in the presence of ongoing signifi-cant ischemia and unavailability of prompt PCI. If plateletaggregation studies reveal insufficient (�50%) inhibition ofplatelet aggregation with standard dual antiplatelet therapy,the sustained administration of 150 mg/d clopidogrel shouldbe considered.70

Prevention of STSeveral preventive strategies may help to limit the risk of STin patients treated with DES.

**-20

-10

0

10

20

30

Bare metal stentPaclitaxel stentSirolimus stent

Exercise

0

20

40

NitroglycerinVasoconstriction

PE

RC

EN

TC

HA

NG

E(%

)Vasodilation

Prox.Ref. Prox. Stent Distal Distal Ref.

Prox.Ref. Prox. Stent Distal Distal Ref.

Bare metal stentPaclitaxel stentSirolimus stent

PE

RC

EN

TC

HA

NG

E(%

)

*P<0.005 vs BMS

60

**

Figure 9. Percent changes of the mean cross-sectional lumen area in SES, PES, and BMS during exercise (top) and after nitroglycerin appli-cation (bottom). Mean�SEM is shown for the proximal reference segment (Prox. Ref.), proximal segment (Prox.), stent segment (Stent), distalsegment (Distal), and distal reference segment (Distal Ref.). The stent segment does not exhibit any vasomotion. SES and PES showexercise-induced vasoconstriction proximal and distal to the stent, whereas BMS maintain exercise-induced vasodilatation of the respectivesegments. Adapted from Togni et al,61 copyright © 2005, and Togni et al,62 copyright © 2007, with permission from Elsevier.




Antiplatelet TherapyThe importance of compliance with dual antiplatelet therapyhas been underscored in a registry of 500 patients with acuteMI treated with DES.71 Among discharged patients, 68 (14%)discontinued thienopyridine therapy within 30 days. Predic-tors of premature thienopyridine discontinuation were olderage, lower socioeconomic status, preexisting cardiovasculardisease, and lack of discharge instructions or cardiac rehabil-itation referral. Mortality (7.5% versus 0.7%; HR, 9.0; 95%CI, 1.3 to 61; P�0.02) and rehospitalization (23% versus14%; HR, 1.5; 95% CI, 0.78 to 3.0; P�0.08) were higher inpatients without than with thienopyridine therapy. The studyhighlights the importance of simple measures to improvecompliance such as careful counseling, patient cards withinformation on the duration and purpose of dual antiplatelettherapy, cardiac rehabilitation programs, attention to eco-nomic issues, and the avoidance of DES in noncompliantpatients.

The optimal duration of dual antiplatelet therapy after DESimplantation is not well established. Prolonged use of thien-opyridines (9 to 12 months) has already been shown to bebeneficial in reducing ischemic cardiovascular events inpatients undergoing PCI with BMS72 and in patients withacute coronary syndromes73,74 and has been advocated as aclass I indication in patients undergoing PCI not at increasedrisk of bleeding in American Heart Association/AmericanCollege of Cardiology guidelines.70 The impact of thienopy-ridine treatment on long-term outcome after DES implanta-tion has been examined in a single-center observational studyof 4666 patients (3165 BMS patients, 1501 DES patients).75

Using landmark analyses of patients event free at 6 and 12months, the investigators assessed the risk of death, MI, andthe composite of death or MI at 2 years of follow-up stratifiedto stent type and self-reported thienopyridine intake at thatpoint in time. Although thienopyridine use inferred no ad-vantage in the 2-year risk of death (3.7% versus 4.5%;P�0.50) and death or MI (5.5% versus 6.0%; P�0.70)among BMS patients event free at 6 months, it significantlypredicted lower adjusted rates of death (2.0% versus 5.3%;P�0.03) and death or MI (3.1% versus 7.2%; P�0.02) inDES patients. This pattern was maintained for patients whowere event free and on or off thienopyridine at 12 months,suggesting an important prognostic benefit of clopidogreltreatment up to 1 year after DES implantation. Importantly,the risk of death or MI was lower in DES compared withBMS patients with thienopyridine use and was similar in DEScompared with BMS patients without thienopyridine use at 6and 12 months, confirming the absence of a negative effect ofDES on overall prognosis. Therefore, it appears reasonable tomaintain patients treated with (first-generation) DES for �1year on dual antiplatelet therapy if they tolerate it and are atlow risk of bleeding. Whether prolonged dual antiplatelettherapy prevents late and very late ST after DES implanta-tion, is associated with a lower rate of ischemic cardiovascu-lar events, and has a favorable net clinical benefit requiresconfirmation in randomized, prospective trials. This appearsparticularly important because of the small but increased riskof bleeding observed with prolonged administration of dualantiplatelet therapy.72–74

Adherence to a 12-month regimen of dual antiplatelettherapy after DES implantation has been endorsed by a recentscience advisory report54 and by a clinical alert issued by theSociety of Cardiac Angiography and Interventions.55 Theformer document also recommends deferring elective surgi-cal procedures with significant risk of bleeding by at least 12months after DES implantation, and surgeons are advised notto automatically discontinue antiplatelet therapy but rather toconsult with the patient’s cardiologist.

Patient and Lesion SelectionSelection of patients suitable for DES implantation is anothermeasure to reduce the risk of ST. Patients at increased risk ofbleeding, those scheduled for elective surgery, patients withgastrointestinal disorders preventing absorption of thienopy-ridines, those requiring oral anticoagulation, patients withunexplained thrombocytopenia or established allergy tothienopyridines, and all those in whom compliance withextended dual antiplatelet therapy cannot be ensured shouldnot receive DES and perhaps not be stented at all if anacceptable balloon angioplasty result is attained.

The need for surgical procedures may arise after recentDES implantation. Surgery poses a risk to patients withcoronary artery disease in general but particularly to thosewho underwent stent implantation76 as a result of antiplatelettherapy withdrawal,77 increased platelet aggregation, anddecreased fibrinolysis in the perioperative period. In a studyof 103 stent patients undergoing noncardiac surgery, analarming 5% mortality rate and 45% complication rate werenoted.78 It should be determined whether the surgical proce-dure can be postponed beyond 12 months after stenting orwhether dual antiplatelet therapy can be maintained through-out the perioperative period. If the risk of bleeding is judgedto be unacceptably high, clopidogrel should be discontinuedfor �5 days before the procedure and should be resumedwithin 48 hours with no interruption in aspirin (81 to 100mg/d).70 No evidence exists that the addition of heparin orglycoprotein IIb/IIIa inhibitors is useful for preventing ische-mic events in the perioperative period.

The risk-to-benefit ratio of PCI depends on the eachindividual patient. The benefit of DES is related largely to themore powerful inhibition of neointimal hyperplasia, which isof particular importance in smaller vessels less able toaccommodate neointimal in-growth. A small randomized trial(500 patients) comparing SES with thin-strut BMS showedsimilar rates of binary restenosis (SES, 10% versus BMS,13%; P�0.52) in vessels with a reference vessel diameter�2.8 mm (mean reference vessel diameter, 3.1 mm).79

Similarly, a stratified subgroup analysis of a trial suggested abenefit of DES in terms of cardiac death, MI, and repeatrevascularization in small vessels (stent diameter �3.0 mm)but the potential of harm in larger vessels.80 Accordingly,BMS remain a valuable alternative to DES in large vesselswith discrete lesions. A step further, balloon angioplastyremains a valid option in selected patients.81 A meta-analysiscomparing BMS with balloon angioplasty has shown similaroutcomes in terms of death or MI (odds ratio, 0.90; 95% CI,0.72 to 1.11), and the benefit in reducing repeat revascular-ization in favor of BMS from 16% to 4% was all but




exhausted with provisional stenting in 20% to 40% of cases.6

After balloon angioplasty, late thrombosis is not an issue, andthus thienopyridine therapy is of less importance; therefore,balloon angioplasty with provisional stenting should be thestrategy of choice in patients requiring surgery in the nearfuture or who are at high risk of bleeding.

TechniqueAttention to technical details also may improve results whenPCI is performed with DES. Because both the number ofstents27 and stent length enhance the risk of ST, refrainingfrom excessive overall stent length and from stent overlap isjudicious. Moreover, proper deployment of the DES with caretaken to fully expand it over its entire length, particularly incalcified lesions, should be ensured, and residual dissectionsshould be avoided. For example, because using the multistentcrush technique to treat bifurcations results in considerablestent overlap and has been associated with an excess risk ofST,82 provisional side-branch stenting appears preferable.83

Although DES compared with BMS have shown no excessrisk when implanted in the setting of acute MI,84,85 the benefitof DES in this setting requires further study. The observationperiod is limited to 1 year so far; affected vessels are onaverage larger than in patients with stable coronary arterydisease; and the viability of the underlying myocardium isreduced. This curtails the therapeutic potential of DES orBMS in patients with acute MI but also reduces the risk incase of ST.

Future DevelopmentsThe problem of very late ST may not apply less to second- orlater-generation DES.86 Limited follow-up duration in low-risk patients precludes firm conclusions at this time. Becausedurable polymers used in first-generation DES are suspectedto be responsible for some of the observed pathologicalchanges, efforts concentrate on drug release via biodegrad-able polymers with reduced surface area through the use ofreservoirs or coating of the abluminal surface only87,88 and onpolymer-free drug release.89 However, the fact that early STappears slightly lower in DES compared with BMS inrandomized trials using identical patient management forboth may be a hint that polymers protect from thrombosisduring the phase when all stents are fully exposed to blood.Another approach banks on drugs with improved healingproperties such as antibodies capturing CD34-positive endo-thelial progenitor cells90 or antithrombotic substances32 ap-plied to the stent surface. Fully biodegradable stents based onpolylactic acid or magnesium compounds are in clinicalevaluation. Finally, stent coatings with improved biocompat-ibility such as titanium–nitride oxide have been shown to bemore effective than conventional BMS in reducing restenosisand repeat revascularization, with in-stent late luminal loss(0.55�0.63 mm) comparable to that of zotarolimus-elutingstents (0.61�0.46 mm).91

ConclusionsST is a serious adverse event after PCI, resulting in abruptclosure with risk of MI and death. Although early ST and lateST occur with similar frequency after BMS or DES and

outnumber very late ST by far, very late ST has emerged asa distinct clinical entity more germane to (at least thefirst-generation) DES than BMS. Delayed healing and im-paired endothelialization induced by the drug-polymer com-bination are the prevailing mechanisms of late and very lateST. Immediate reperfusion, preferably by primary PCI, is thetherapy of choice. Preventive measures such as carefulattention to implantation details, uninterrupted dual antiplate-let therapy for �12 months, and alternative revascularizationstrategies in selected patients may curb this adverse event.

DisclosuresDr Windecker is consultant and has received lecture fees fromAbbott, Biotronik, Boston Scientific, and Cordis. He is an unpaidconsultant for Biosensors. He has received grants from Cordis,Boston Scientific, Biosensors, and Medtronic. Dr Meier is consultantand has received lecture fees from Abbott, Biotronik, BostonScientific, Cordis, Biosensors, and Medtronic. He has receivedresearch grants from Cordis, Boston Scientific, Medtronic, andBiosensors.

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KEY WORDS: devices, medical � angioplasty � balloon � infarction� stents � thrombosis




Stephan Windecker and Bernhard MeierLate Coronary Stent Thrombosis

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