Late and Very Late Thrombosis of Drug-Eluting Stents

Journal of the American College of Cardiology © 2007 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 50, No. 2, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2007.04.031

FOCUS ISSUE: DRUG-ELUTING STENTS

State-of-the-Art Paper

Late and Very Late Thrombosis of Drug-Eluting Stents Evolving Concepts and Perspectives Ronen Jaffe, MD, Bradley H. Strauss, MD, PHD, FACC Toronto, Canada Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention is an uncommon and potentially catastrophic event that might manifest as myocardial infarction and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in ⬍1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased long-term thrombosis risk with DES; however, the clinical significance of these events remains under debate. The degree of protection achieved by dual antiplatelet therapy and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood. (J Am Coll Cardiol 2007;50:119–27) © 2007 by the American College of Cardiology Foundation

Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention (PCI) is an uncommon and potentially catastrophic event that might manifest as myocardial infarction (MI) and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in ⬍1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased longterm thrombosis risk with DES (1,2); however, the clinical significance of these events remains under debate (3). The degree of protection achieved by dual antiplatelet therapy From the Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. Dr. Jaffe is a Research Fellow of the Heart and Stroke Foundation of Canada. Manuscript received February 12, 2007; revised manuscript received March 30, 2007, accepted April 2, 2007.

and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood. Definition and Clinical Manifestations Historically, diagnosis of ST has been based on angiographic and clinical criteria. Angiographic definition— coronary Thrombolysis In Myocardial Infarction flow grade 0 to 1 in the stented vessel in the presence of thrombus— likely underestimates the true incidence of ST, because patients who are asymptomatic or who sustain cardiac arrest might not undergo coronary angiography. Clinical definitions—target vessel MI or urgent target lesion revascularization and unexplained sudden death when the stent was not known to be patent—might overestimate the actual occurrence of ST. The recently proposed “Academic Research Consortium” definitions (4) were designed to standardize ST diagnosis and provide consistency in the reporting of future trials (Table 1). Stent thrombosis is also classified according to the time elapsed since implantation. Acute ST occurs during the stenting procedure or within the subsequent 24 h, subacute ST between 1 and 30 days after implant, late ST between 1

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month and 1 year, and very late ST occurs more than 1 year after the procedure. In the BMS era, BMS ⴝ bare-metal stent(s) ST usually presented acutely or DES ⴝ drug-eluting stent(s) subacutely, before neointimal MI ⴝ myocardial infarction formation. In randomized trials PCI ⴝ percutaneous that compared BMS with DES, coronary intervention rates of acute and subacute ST PES ⴝ paclitaxel-eluting among patients receiving dual antistent(s) platelet therapy were similar for SES ⴝ sirolimus-eluting both stent types (⬍1%) (3,5). Restent(s) cent attention has focused on deST ⴝ stent thrombosis layed occurrence of DES thrombosis beyond 30 days, which might be categorized according to the intensity of antiplatelet therapy administered at the time of the event, while the patient is still receiving dual antiplatelet therapy or after cessation of 1 or both antiplatelet drugs. Acute and subacute thrombosis of both BMS and DES have adverse clinical consequences (6,7). In a registry of patients who underwent DES implantation with 9-month follow-up (8), 24% of ST cases presented as death, 60% as nonfatal MI, and 7% as unstable angina. The case fatality rate for ST in this registry was 45%. In a series of patients who presented with acute coronary syndrome and had angiographically or autopsy proven ST after DES implantation, 6-month mortality was 31% (9). However, in recent meta-analyses of DES trials, modest increases in rates of late and very late ST compared with BMS did not translate into a worse clinical outcome (3,10). These differences might reflect selection bias stemming from different diagnostic criteria for ST or possibly from implantation of DES in small vessels subtending limited myocardial territory. Percutaneous coronary intervention for emergent ST is often suboptimal, and ST recurs in 12% of these patients (11). Abbreviations and Acronyms

Incidence of Late and Very Late Stent Thrombosis Late BMS thrombosis is an uncommon event (12). In an initial report of very late DES thrombosis, the events were associated with cessation of antiplatelet therapy (13). Sub-

sequently, studies of patients who underwent DES implantation for off-label indications in complex anatomical subsets, with prolonged follow-up periods, have documented higher ST rates than previously reported (14 –16). Recently reported registries, randomized trials, and metaanalyses have investigated the relative risk for late ST with either DES or BMS over varying follow-up periods and reported conflicting results. Some studies identified thrombosis-related clinical events, whereas others focused on angiographically proven ST. In a registry of 6,906 patients who received BMS or DES, there was no difference in clinical outcomes or ST rate over 1 year of follow-up (17). In another registry of 8,146 patients who received DES between 2002 and 2005, a persistent excess ST risk of 0.6%/year was found compared with historical control subjects who received BMS (2). A meta-analysis of 8 trials in which 4,545 patients were randomized to sirolimuseluting stent (SES) or paclitaxel-eluting stent (PES) versus BMS revealed no difference in rates of ST over 4 years of follow-up (5). Conversely, another meta-analysis of 14 randomized clinical trials, in which a total of 6,675 patients were randomized to either SES or PES versus BMS, confirmed a 0.5% excess risk of very late ST with DES (1). Several recent studies have highlighted the potential adverse clinical significance of late thrombotic events. In a Swedish registry of DES and BMS patients, the adjusted relative risk for death associated with DES implantation from 6 months to 3 years after PCI was 1.32 (95% confidence interval 1.11 to 1.57) (18). The authors hypothesized that ST caused the increased mortality. In the BASKET-LATE (Basel Stent Kosten Effektivitäts Trial– Late Thrombotic Events) study, 746 patients who had been randomized to DES or BMS and were free of major cardiac adverse events after 6 months (when clopidogrel was stopped) were followed for an additional 12 months (19). During this follow-up period, rates of cardiac death and nonfatal MI were higher in the DES than the BMS group (4.9% vs. 1.3%, respectively). However, this increase in major cardiac events in the DES group was much higher than the actual difference in the rates of definite or possible ST (2.6% DES group vs. 1.3% BMS group). Timing of thrombotic events was evenly distributed across the 12

Stent Thrombosis Definitions and Classification Table 1

Stent Thrombosis Definitions and Classification

“Academic Research Consortium” definitions (4) Definite ST

Acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion

Probable ST

1. Unexplained deaths within 30 days following PCI 2. Acute myocardial infarction involving the target-vessel territory without angiographic confirmation

Possible stent thrombosis

All unexplained deaths occurring at least 30 days following PCI

Temporal classification Acute ST

During PCI or within the following 24 h

Subacute ST

Between 1 and 30 days following PCI

Late ST

Between 1 month and 1 yr following PCI

Very late ST

More than 1 yr following PCI

PCI ⫽ percutaneous coronary intervention; ST ⫽ stent thrombosis.

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months after clopidogrel discontinuation. Camenzind et al. (20) reported a meta-analysis of randomized trials comparing DES with BMS that included 5,108 patients, with follow-up over 9 months to 3 years; SES were associated with a 60% relative increase in death or MI (p ⫽ 0.03), whereas PES were associated with a nonsignificant increase of 15%. Another meta-analysis of 9 trials in which 5,261 patients were randomized to SES, PES, or BMS reached quite different conclusions (3). Over 4 years of follow-up, increased rates of very late ST were found both for both SES (0.6% vs. 0%, p ⫽ 0.025) and PES (0.7% vs. 0.2%, p ⫽ 0.028) compared with BMS. The increased ST rate was confined to the time interval between 1 month and 1 year after PCI and was not associated with adverse clinical outcomes. Similarly, a meta-analysis of 14 trials in which 4,958 patients were randomized to SES or BMS, with follow-up ranging up to 59 months, showed an increased rate of very late ST with SES (0.6% vs. 0.05%, p ⫽ 0.02) without increase in adverse events (10).

Mechanisms Contributing to ST: Are There Differences Between BMS and DES? After both BMS and DES implantation, procedural and technical factors play a major role in determining the occurrence of acute and subacute ST, whereas delayed thrombotic events seem to be influenced largely by the degree of endothelial coverage and intensity of antiplatelet therapy (21). Incomplete endothelization and presence of thrombus were frequent angioscopic findings in a study performed 3 to 6 months after DES implantation but were not found in BMS (22). Presence of lipid-rich plaques abundant in tissue factor within the vessel wall might predispose to late ST (12). Data regarding risk factors for DES thrombosis are derived from selected case reports, non-randomized registries (Table 2), and randomized clinical trials (23–27) (Table 3). Evidence for increased long-term ST risk with DES is primarily from patient registries and not from randomized clinical trials, suggesting that part of the incremental risk is associated with treatment of complex coronary lesions in real-world patients (Table 4). Patient variables. Angioplasty in the setting of acute coronary syndromes could theoretically predispose to ST owing to the large thrombotic burden already present, suboptimal stent expansion to avoid the risk of no-reflow, or DES implantation on a thrombus that eventually disappears leading to malapposition. An SES registry reported increased risk of ST in patients who presented with acute coronary syndromes (28). However, 3 randomized trials comparing BMS and DES for primary angioplasty in acute MI found no difference in ST rate between the stent types (29 –31). Some registry reports have suggested increased ST rates in diabetic patients and patients with renal failure (8,9,28).

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Procedural variables. Small vessel size, long stents, suboptimal stent expansion, residual dissections and thrombus, and slow coronary flow are associated with DES thrombosis (9,28,32,33), similar to BMS. A 1.03-fold greater ST risk for every 1-mm increase in stent length has been calculated (34). Reports of higher ST rates in bypass grafts treated with DES compared with BMS (19) were not confirmed in a randomized trial (35). Drug-eluting stents have permitted an aggressive approach to angioplasty of bifurcation lesions, which is associated with higher rates of ST (36). In a registry of patients undergoing stenting with BMS or DES, bifurcation stenting in the setting of acute MI was an independent risk factor for ST (odds ratio 13) (7). In another DES registry, bifurcation stenting was associated with a 3.6% to 3.9% ST rate, depending on whether 1 or 2 stents were implanted (8). A registry of “crush” bifurcation stenting with DES reported that 4.3% of the patients had an event consistent with possible ST over 9 months of follow-up (16). In a randomized trial that compared implantation of 1 versus 2 SES in coronary bifurcations, 3.5% of the patients had ST and another patient died suddenly, all of whom had undergone implantation of 2 stents (14). Antiplatelet therapy. Cessation of antiplatelet therapy is a major risk factor for late BMS thrombosis. In a series of angiographically documented cases of late DES thrombosis, no cases occurred in patients who were receiving dual antiplatelet therapy (37). In another study of DES thrombosis within 9 months of stenting (14 subacute ST, 15 late ST), the most important independent predictor of ST was premature antiplatelet therapy discontinuation (hazard ratio 90) (8). In a registry of bifurcation “crush” stenting with DES, premature discontinuation of dual antiplatelet therapy was associated with occurrence of subacute and late ST (odds ratio 17) (15). In a registry of 4,666 patients who underwent PCI, prolonged use of clopidogrel was associated with decreased risk of death or MI after implantation of DES but not BMS (38). Premature discontinuation of antiplatelet agents might be relatively common: among 500 patients who received DES after MI, 13.6% stopped thienopyridine therapy within 30 days (39). Patients who prematurely stopped thienopyridine therapy had more comorbidities, lower socioeconomic status, and were less informed about the importance of long-term therapy than patients continuing therapy. These patients were also more likely to die during the next 11 months (7.5% vs. 0.7%) and be rehospitalized (23% vs. 14%). Inadequate response to antiplatelet therapy might be caused by patient non-compliance, underdosing, drug interactions, comorbidities that affect the drug-response, genetic polymorphisms at the receptor level, or upregulation of other platelet activation pathways (40,41). Several studies have suggested a role for clopidogrel resistance in the pathogenesis of subacute ST in BMS (42,43). In a cohort of patients undergoing non-emergent PCI (75% DES), high preprocedural platelet aggregation was associated with an increased risk for postpro-

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Rates of Stent Thrombosis in Patient Registries

Reference

Rates of Stent Thrombosis in Patient Registries

No. of Patients

Study Design

Stent Type

Antiplatelet Medication

Duration of Dual Antiplatelet Therapy

Follow-Up Duration

ST Definition

ST Rate

Suggested Risk Factors

2,229

SES registry

SES 48% PES 52%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

9 months

ACS ⫹ angio, SCD or MI after successful PCI not clearly due to another coronary lesion

SAT: 0.6% LST: 0.7% (median 57 days)

Discontinuation of dual antiplatelet therapy, renal failure, bifurc lesions, diabetes, reduced LVEF

Ong et al. (7)

2,512

Combined BMS & DES registry

BMS 20% SES 40% PES 40%

ASA, thieno

ⱖ1 month

1 month

Definite: angio Possible: SCD or MI not clearly due to another coronary lesion

Definite: BMS 1.2%, SES 1.0%, PES 1.0% Possible: BMS 1.4%, SES 1.5%, PES 1.6%

Bifurc stenting in the setting of acute MI

Williams et al. (17)

6,906

Combined BMS & DES registry

BMS 6% SES 56% PES 38%

ASA, thieno

Unspecified

12 months

Definite: ACS ⫹ angio Probable: unexplained SCD or MI in target vessel territory

Definite ⫹ probable: BMS 0.8%, SES 0.5%, PES 0.8%

Ong et al. (37)

2,006

DES registry of LST and VLST

SES 51% PES 49%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

Mean 1.5 ⫾ 0.5 yrs

ACS ⫹ angio

LST: 0.25% (range 2–11 months), VLST: 0.15% (range 14–26 months)

Kuchulakanti et al. (9)

2,974

DES registry

SES 72% PES 28%

ASA, thieno

ⱖ6 months

12 months

Autopsy or angio (⫹ ACS if ⬎30 days after PCI)

SAT: 0.84% (mean 9 ⫾ 9 days), LST: 0.27% (mean 153 ⫾ 100 days)

Renal failure, bifurc lesion, in-stent restenosis, discontinuation of dual antiplatelet therapy

Urban et al. (28)

15,157

SES registry

SES 100%

ASA, thieno

Unspecified

12 months

Definite: angio or autopsy Likely: target vesselrelated MI or death due to ACS within 30 days of PCI

SAT: 0.56% LST: 0.19%

Insulin-dependent diabetes, ACS at presentation, advanced age, reduced coronary flow after PCI, treatment of multiple lesions, calcified or totally occluded lesion, multivessel disease

Daemen et al. (2)

8,146

DES registry

SES 47% PES 53%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

Mean 20 months

ACS ⫹ angio

SAT: 1.1%, LST: 0.3% VLST: 0.4%

Discontinuation of dual antiplatelet therapy

Ge et al. (15)

181

DES registry of bifurc “crush” stenting

SES 59% PES 41%

ASA, thieno

ⱖ6 months

9 months

ACS ⫹ angio, MI within the stented territory, cardiac death

SAT: 0.6%, LST: 2.2%

Discontinuation of dual antiplatelet therapy, advanced age

Hoye et al. (16)

231

DES registry of bifurc “crush” stenting

SES 57% PES 43%

ASA, thieno

ⱖ6 months

9 months

ACS ⫹ angio, MI within the stented territory, cardiac death

SAT: 1.3% LST: 3%

Discontinuation of dual antiplatelet therapy

ACS ⫽ acute coronary syndrome; Angio ⫽ angiography; ASA ⫽ aspirin; bifurc ⫽ bifurcation; BMS ⫽ bare-metal stents; DES ⫽ drug-eluting stents; FU ⫽ follow-up; LST ⫽ late stent thrombosis; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; PES ⫽ paclitaxel-eluting stents; SAT ⫽ subacute stent thrombosis; SCD ⫽ sudden cardiac death; SES ⫽ sirolimus-eluting stents; ST ⫽ stent thrombosis; thieno ⫽ thienopyridines; VLST ⫽ very late stent thrombosis.

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Iakovou et al. (8)

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Table 2

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Rates of Stent Thrombosis in Randomized Controlled Trials and Meta-Analyses Table 3

Rates of Stent Thrombosis in Randomized Controlled Trials and Meta-Analyses

Reference

No. of Patients

Study Design

Stent Type

Medication

Duration of Dual Antiplatelet Therapy

Follow-Up Duration

ST Definition

ST Rate

Suggested Risk Factors

Moreno et al. (34)

5,030

Meta-analysis: RCT of BMS vs. DES

BMS 48% SES 17% PES 34%

ASA, thieno

1–6 months

6–12 months

Unspecified

SAT: 0.35% (BMS ⫽ DES) LST: 0.23% (BMS ⫽ DES)

Stent length

Bavry et al. (23)

3,817

Meta-analysis: RCT of BMS vs. PES

BMS 48% PES 52%

ASA, thieno, cilostozal

ASA ⫹ thieno: 0–6 months

6–12 months

ACS ⫹ angio

SAT ⫹ LST: 0.76% (PES ⫽ BMS)

Discontinuation of dual antiplatelet therapy

Morice et al. (REALITY) (24)

1,386

RCT of SES vs. PES

SES 51% PES 49%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

12 months

SAT: cardiac death, MI in stented territory LST: MI in stented territory with angio

SAT: SES 0.4%, PES 1.0% LST: SES 0%, PES 0.3%

Kastrati et al. (25)

3,669

Meta-analysis: RCT of SES vs. PES

SES 50% PES 50%

ASA, thieno

2–12 months

6–13 months

ACS ⫹ angio, unexplained SCD, MI in stented territory

SAT ⫹ LST: 1.0% (PES ⫽ SES)

Colombo et al. (14)

85

RCT of single vs. dual SES for bifurc PCI

SES 100%

ASA, thieno

3 months

6 months

Probable: angio, MI or SCD within 30 dys of PCI Possible: SCD beyond 1 month

Probable: 3.5%, Probable ⫹ possible: 4.5%

Spalding et al. (26)

1,748

Meta-analysis: RCT of BMS vs. SES

BMS 50% SES 50%

ASA, thieno

ⱖ2 months

48 months

ARC: definite ⫹ probable ⫹ possible

SAT: SES 0.5%, BMS 0.5% LST: SES 0.3%, BMS 1.3% (p ⫽ 0.03) VLST: SES 2.8%, PES 1.7%

Mauri et al. (5)

4,545

Meta-analysis: RCT of BMS vs. DES

SES 19% PES 31% BMS 50%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

48 months

ARC: definite ⫹ probable

SES vs. BMS: SAT: SES 0.5%, BMS 0.3% LST: SES 0.1%, BMS 1.0% VLST: SES 0.9%, BMS 0.4% PES vs. BMS: SAT: PES 0.5%, BMS 0.5% LST: PES 0.4%, BMS 0.3% VLST: PES 0.9%, BMS 0.6%

Kastrati et al. (10)

4,958

Meta analysis: RCT of BMS vs. SES

SES 50% BMS 50%

ASA, thieno

1–12 months

12.1–58.9 months

According to definitions in individual trial protocols

SAT ⫹ LST ⫹ VLST: SES 1.4%, BMS 1.26% VLST: SES 0.6%, BMS 0.05% (p ⫽ 0.02)

Dual stenting

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Table 3

Continued

Reference

No. of Patients

Study Design

Stent Type

Medication

Duration of Dual Antiplatelet Therapy

Follow-Up Duration

ST Definition

ST Rate

Suggested Risk Factors

Pfisterer et al. (BASKETLATE) (19)

746

RCT of DES vs. BMS* (analysis of LST and VLST)

SES 34% PES 38% BMS 38%

ASA

None

12 months after initial 6 months follow-up

Definite: ACS ⫹ angio Possible: all SCD and MI attributable to the target vessel

Definite: DES 1.4%, BMS 0.8% Definite ⫹ possible: DES 2.6%, BMS 1.3%

Previous MI, increased need for glycoprotein IIb/IIIa inhibitor, side branch, bypass graft stenting

Ellis et al. (27)

3,445

Meta-analysis: RCT of BMS vs. PES

PES 50% BMS 50%

ASA, thieno

6 months

14–41 months

ACS ⫹ angio, MI in stented territory

SAT: PES: 0.5%, BMS: 0.5% LST ⫹ VLST: PES 0.5%, BMS 0.06% (p ⫽ 0.049)†

LST ⫹ VLST: major adverse cardiac event within 30 days postprocedure

Stone et al. (3)

5,261

Meta-analysis: RCT of BMS vs. DES

SES 17% PES 33% BMS 50%

ASA, thieno

SES ⱖ2 months PES ⱖ6 months

48 months

According to definitions in individual trial protocols

SES vs. BMS: SAT: SES 0.5%, BMS 0.1% LST: SES 0.1%, BMS 0.5% VLST: SES 0.6%, BMS 0% (p ⫽ 0.025) PES vs. BMS: SAT: PES 0.5%, BMS 0.6% LST: PES 0.2%, BMS 0.1% VLST: PES 0.7%, BMS 0.2% (p ⫽ 0.028)

Bavry et al. (1)

6,675 (14 trials)‡

Meta-analysis: VLST in RCT of BMS vs. DES

SES 24% PES 26% BMS 50%

ASA

None

12–36 months beyond first year after PCI

ACS ⫹ angio

Total cohort: DES 0.5%, BMS 0% (p ⫽ 0.02) SES vs. BMS: SES 0.36%, BMS 0% (p ⫽ 0.22) PES vs. BMS: PES 0.59%, BMS 0% (p ⫽ 0.49)

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*Cohort of patients who survived the initial 6 months without major events were followed for 1 year after stopping thieno; †only p values ⬍ 0.05 specified; ‡only 8 of the trials had more than 1-year follow-up. ARC ⫽ Academic Research Consortium; RCT ⫽ randomized controlled trial; other abbreviations as in Table 2.

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Suggested Risk Factors For Late and Very Late Stent Thrombosis Table 4

Suggested Risk Factors For Late and Very Late Stent Thrombosis

Patient characteristics

Diabetes, acute coronary syndrome, renal failure, advanced age, reduced ejection fraction, major adverse cardiac event within 30 days of the original procedure, previous myocardial infarct

(8,9,15,19,27,28)

Coronary anatomy

Type C lesion, bifurcation, in-stent restenosis, multivessel disease, calcification, total occlusion, stent length, bypass graft

(8,9,19,28,34)

Procedural characteristics

Reduced coronary flow after stenting, stent underexpansion, residual dissection, “crush” technique, side branch occlusion, need for glycoprotein IIb/IIIa inhibitor

(14,16,19,28,32,33)

Discontinuation of dual antiplatelet therapy

(2,8,9,15,35)

Clopidogrel resistance

(44)

Hypersensitivity reaction

(59,61)

Delayed arterial healing

(55)

cedural ischemic events over 1 year of follow-up (44). Crossresistance to aspirin and clopidogrel might be common (45). In a study of elective PCI patients, 12.7% were aspirin-resistant and 24% were clopidogrel-resistant (46). Aspirin-resistant patients were more likely to be women and have diabetes, and 47.4% of them were clopidogrel-resistant. An additional concern regarding antagonism of cytochrome P450 3A4 metabolism of clopidogrel by statins (47) has not been substantiated (48). Response of the vessel to DES. The intact endothelium separates the thrombogenic vessel wall and stent struts from the blood stream and secretes a variety of antithrombotic and vasodilator substances. Drug-eluting stents expose the vessel wall to antiproliferative drugs and drug-eluting platforms, with variable effects on endothelial regeneration and function. Rabbit iliac arterial segments in which overlapping SES and PES were implanted exhibited delayed healing compared with proximal and distal non-overlapping sites and compared with overlapping BMS (49). However, in human studies, overlapping SES were not associated with increased ST risk (50). Studies performed 6 months after PCI have examined endothelium-dependant arterial vasomotion in response to acetylcholine (51) and exercise (52). Arterial segments adjacent to SES but not BMS demonstrated reduced endothelial function, although the clinical significance of this finding is unknown. Malapposition of the stent to the vessel wall might result from suboptimal stent expansion (“procedural”) or develop months after the PCI (“acquired”). Although procedural malapposition is a recognized risk factor for acute and subacute ST (53), the clinical significance of acquired malapposition is controversial. Acquired BMS malapposition, which is related to positive arterial remodeling, is rare and benign (54). Acquired DES malapposition might result from drug-induced inhibition of neointimal formation, delayed reparative events that usually enable the vessel wall to incorporate the stent, and drug-induced positive remodeling of the vessel wall (55). Some randomized studies (56,57) but not others (58) reported an increased rate of acquired malapposition with DES compared with BMS, which was not associated with adverse events. Late hypersensitivity reactions to DES seem to be another mechanism contributing to ST. Virmani et al. (59)

reported autopsy findings after late ST (18 months after receiving 2 SES). Angiographic and intravascular ultrasound (IVUS) results at 8 months had demonstrated vessel enlargement with absence of neointimal formation. Autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils. Because sirolimus is minimally present in the vessel wall after 60 days, these findings likely reflect an effect of the nonerodable polymer (60). A subsequent pathological study revealed that late ST after DES was correlated with delayed healing of the vessel wall, persistent fibrin deposition, and delayed endothelization (55). Nebeker et al. (61) reported 17 cases of hypersensitivity reaction attributable to DES implantation (14 SES and 3 PES) that occurred up to 210 days after the index procedure. Autopsies in 4 patients who died after ST confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. In 1 of these patients, concomitantly placed BMS were not associated with these hypersensitivity findings. Clinical manifestations included urticarial and non-urticarial rash, dyspnea, myalgia/arthralgia, itching, and blisters. All urticarial eruptions began within 10 days of implantation. Laboratory findings included eosinophilia and elevated immunoglobulin E titers 5-fold above normal levels in 3 patients. Clinical or laboratory findings did not abate with discontinuation of antiplatelet medications. Prevention Optimization of stent deployment (62) and dual antiplatelet therapy with aspirin and a thienopyridine (63– 65) have achieved the currently accepted 30-day ST rate of ⬍1%. Reports of late DES thrombosis, often in association with cessation of antiplatelet therapy (9,13,19,37,38,59), suggest that long-term combined antiplatelet therapy might be appropriate. A recent science advisory has recommended lengthening the duration of dual antiplatelet therapy to 1 year after PCI and that elective surgery should be postponed for 1 year (66). The efficacy of increasing the maintenance dose of clopidogrel to 150 mg daily in patients with suspected clopidogrel resistance is unknown (67). Triple antiplatelet therapy with aspirin, a thienopyridine, and

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cilostazol was associated with reduced rate of subacute BMS thrombosis compared with dual antiplatelet therapy (68), although its role in the DES era is unknown. Innovative stent designs that are polymer-free, bioabsorbable, or coated with monoclonal antibodies that bind circulating endothelial progenitor cells have been proposed to decrease ST rates (69). Their role in preventing late DES thrombosis is unclear. Late ST: Is It the Artery or the Stent? Drug-eluting stents, by significantly reducing restenosis rates, have expanded the indications for PCI into new complex anatomic subsets (long lesions, small arteries, bifurcations) in high-risk patients (renal failure, diabetes), who are more susceptible to both restenosis and ST. A recent meeting of a U.S. Food and Drug Administration advisory panel concluded that DES seem to carry a greater risk of late ST than BMS, which might be associated with off-label use of these stents, although the magnitude of the risk is unclear (70). This increased risk might be explained both by the complexity of the atherosclerotic substrate currently being treated as well as by intrinsic properties of the DES themselves. By delaying vessel healing in an artery predisposed to thrombosis and inducing a prolonged inflammatory response, DES effectively lengthen and amplify the window of opportunity for ST to occur. Because of current evidence of the modest increased risk, it is imperative for clinicians to stratify the individual patient’s risk for ST, restenosis, and bleeding when selecting appropriate revascularization strategies. Specifically, if the patient is unlikely to comply with long-term clopidogrel therapy, is likely to require surgery in the near-term, or is at risk of bleeding, alternative treatments are preferred, such as implanting BMS, performing bypass surgery, or managing the patients medically. According to current guidelines, dual antiplatelet therapy should be continued for 1 year (66). Some authorities recommend an even longer duration of dual therapy pending further data (71). Ultimately, innovative pharmacological and device developments to prevent late ST are required to restore full confidence in DES for widespread use. Reprint requests and correspondence: Dr. Bradley H. Strauss, Reichmann Research Chair in Cardiovascular Sciences, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Suite A-253, Toronto, Ontario, Canada M4N 3M5. E-mail: [email protected]. REFERENCES

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