University of Groningen Antiplatelet therapy in myocardial ... · Predictors of coronary stent...

University of Groningen

Antiplatelet therapy in myocardial infarction and coronary stent thrombosisHeestermans, Antonius Adrianus Cornelius Maria

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Predictors of coronary stent thrombosis:

the Dutch Stent Thrombosis Registry

J.W. van Werkum, A.A.C.M. Heestermans, A.C. Zomer, J.C. Kelder, M.J Suttorp,

B.J. Rensing, J.J. Koolen, B.R.G. Brueren, J-H.E. Dambrink, R.W. Hautvast,

F.W. Verheugt and J.M. ten Berg

J Am Coll Cardiol. 2009;53:1399-409

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ABSTRACT

Objectives: This study sought to comprehensively identify predictors of stent thrombosis

(ST).

Background: Given the devastating consequences of ST, great efforts should be directed

towards risk stratification to identify those at highest risk for ST.

Methods: Consecutive patients with angiographic ST between January 2004 - February

2007 were enrolled. Patients who did not suffer from a ST were randomly selected in a

2:1 ratio and were matched for: 1) PCI-indication, 2) same date of index PCI and 3) same

interventional center.

Results: Of 21.009 patients treated with either a BMS or DES, 437 patients (2.1%)

presented with a definite ST. One-hundred-forty were acute ST, 180 were subacute ST,

58 were late ST and 59 were very late. Undersizing of the coronary stent, TIMI flow

<3, malignant disease, the presence of intermediate coronary artery disease proximal

and distal to the culprit lesion, uncovered dissection, lack of aspirin therapy, bifurcation

stenting, left ventricular ejection fraction (LVEF) <30% and younger age were associated

with the occurrence of ST. As compared to patients on clopidogrel therapy, the lack of

clopidogrel therapy at the time of ST in the first 30 days after the index PCI (HR 36.5,

95% CI: 8.0-167.8), between 30 days and 6 months after the index PCI (HR 4.6, 95% CI:

1.4-15.3) as well as beyond 6 months (HR 5.9, 95% CI: 1.7-19.8) after the index PCI was

strongly associated with ST.

Conclusions: Several important correlates of ST in the contemporary era of mixed

DES and BMS use were identified. Discontinuation of clopidogrel, undersizing of the

coronary stent, present malignant disease and the presence of intermediate (≥50% to

<70% stenosis) coronary artery disease proximal to the culprit lesion were the strongest

predictors of ST.

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Coronary stent thrombosis

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INTRODUCTION

Despite improved stent implantation technologies and more effective antiplatelet

regimens, stent thrombosis (ST) continues to occur with an estimated incidence

varying between 1 and 5% [1-6]. This wide variability in the estimated incidence strongly

indicates the multifactorial nature of the phenomenon of ST.

Several observational studies have identified a number of clinical, angiographic and

procedural determinants of ST. These studies are however hampered by a small sample

size, the retrospective character of the study-design and a variation in the definition

of ST [1-5, 7]. Consequently, less-frequent but clinically meaningful risk-factors could

not be explored and the multivariate analysis model was overfitted in the majority of

studies. Furthermore, these studies did not focus on possible differences in underlying

pathophysiological mechanisms between 1) different indications of stent implantation

(stable angina versus acute coronary syndromes (ACS) and 2) early versus late ST.

Since recognition of risk-factors attributable to ST may help to improve prognosis by

the development of a risk stratification-model, we sought to identify predictors of early

and late ST and to determine predictors of ST in different populations (stable angina

and ACS (NSTEMI and STEMI) in a “real world” of mixed bare-metal stent (BMS) and

drug-eluting stent (DES) use. Given the detailed character of our study, we were also

able to study the impact of the clopidogrel discontinuation on the occurrence of ST at

the different time-points after the index-procedure.

METHODS

Study Design and Population

The Dutch stent thrombosis registry is a large-scale, multi-centre study conducted

in three high-volume centers in the Netherlands (>2500 interventions per center per

year). All consecutive patients with an angiographically confirmed ST presenting to

the participating centers from January 2004 to February 2007 were enrolled. ST was

defined according to the ARC criteria for ‘definite’ ST [8]. Clinical criteria consisted of

a new episode of chest pain and/or ischemic EKG-changes and/or increase of cardiac

biomarkers release. Angiographic criteria consisted of partial or complete occlusion

within the previously implanted stent with evidence of fresh thrombus. Based on the

elapsed time since stent implantation, ST was classified as acute (intraprocedural or

within 24 hours of the procedure), subacute (from 24 hours to 30 days), late (>30 days

to 1 year) or very late (>1 year). Acute and subacute ST were also defined as early ST.

Likewise, late and very late stent thrombosis were defined as late ST.

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Matched control group

Patients who underwent a PCI with stent implantation but with no evidence of ST during

follow-up were recruited and served as controls in a 2:1 ratio. Control subjects were

individually matched to case subjects by the following criteria: 1) similar indication

(either stable angina or ACS (NSTEMI, STEMI) for the index-PCI procedure 2) same date

of the index PCI procedure (± 3days) and 3) same performing institution.

Procedural Details and Adjunctive Medical Therapy.

PCI was performed by standard techniques via the femoral approach in most cases.

During PCI, patients were anticoagulated with 70 IU/kg of unfractionated heparin.

All patients were treated with aspirin (80-100 mg) prior to PCI and were loaded

with clopidogrel 300–600 mg if they were not on maintenance therapy. Aspirin was

continued indefinitely. The recommended duration of clopidogrel therapy after the

index PCI varied from 4 weeks following bare-metal stent implantation during elective

angioplasty to 3-12 months with drug-eluting stents (DES). For patients presenting with

ACS, 12 months clopidogrel therapy was recommended regardless of the stent type

used. The use of adjunctive devices (e.g. thrombus aspiration catheter) or glycoprotein

IIb/IIIa therapy was at the operators’ discretion.

Data collection

Detailed data on patient-, angiographic- and procedural characteristics for both the

cases and controls were collected. Comprehensive information about the use of

antithrombotic therapy (i.e. aspirin, clopidogrel, coumadin) at the time of the index PCI

were also collected. The duration of clopidogrel use as well as aspirin compliance after

patient discharge was assessed using telephonic patient interview as well as data from

pharmacy records (the date of clopidogrel dispensed and the number of days supplied

for each dispense).

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Angiographic analysis

Angiograms of both the cases and the controls were reviewed by two experienced

interventional cardiologists who were blinded to the objectives of this study and

outcome data. Calcification was identified as readily apparent radio-opacities within the

vascular wall. Angiographic thrombus was defined as a filling defect seen in multiple

projections surrounded by contrast in the absence of calcification. Angiographically

visible uncovered dissections were graded according to the modified classification of

the Heart, Lung, and Blood institute [9]. Given the relatively low incidence of coronary

dissections, the patient population was analyzed on the basis of the presence or absence

of any dissection type. The sizing of the implanted coronary stent(s) was evaluated

by visual estimate. It is important to note that the stent deployment was judged on

the basis of angiographic appearance and not by quantitative coronary analysis or

intravascular ultrasound analysis. Undersizing of the coronary stent(s) was considered

significant as one of the following criteria was met: i) the stent to the reference segment

diameter ratio was < than 1, ii) inappropriate alignment of the coronary stent with the

coronary vessel wall, iii) mismatch in post-deployment stent dimensions in relation to

the proximal and distal segments of the target vessel.

The presence of intermediate coronary artery disease, defined as a visually estimated

percentage of coronary stenosis of ≥50% but ≤70%, proximal and distal to the stented

segment(s) of the target vessel were also scored.

Statistical analysis

Continuous variables were presented as mean ± SD and were compared using

Student’s t test or Mann-Whitney U test. Chi-square test or Fisher’s exact test was used

to analyze differences in categorical variables. Conditional logistic regression analysis

was performed to determine independent predictors of ST. Selected variables were

first entered into the univariate analysis. Variables with P < 0.05 by univariate analysis

were then entered in the conditional logistic regression analysis for identification of

predictors of ST.

To study the impact of the determinant “lack of clopidogrel therapy at different time

points after the index PCI (<24h, 1 to ≤30 days, >30 days to 6 months and beyond)” a

multivariable Cox proportional hazards model was created with “lack of clopidogrel

therapy at the time of ST” as time varying covariates. For this analysis, it was assumed

that the time-interval between index PCI and the “virtual ST” of the control patients

was exactly the same as that for its matched case. All patients with ST and their

matched controls were also further subdivided into three groups: 1) those who were on

clopidogrel at the (“virtual”) time of ST, 2) those who had discontinued the clopidogrel

within 14 days prior to the ST and 3) those who had discontinued the clopidogrel longer

than 14 days prior to the ST.

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The independent “baseline” predictors of ST from conditional logistic regression

analysis were also included in this model. All tests were 2 tailed and used a P-value

< 0.05 to characterize statistical significance.

Role of the funding source

The supporting pharmaceutical company Sanofi-Aventis had no role in study design,

data collection, data analysis, data interpretation, or writing of the report. Van Werkum,

Heestermans and ten Berg had full access to all data and had final responsibility for the

decision to submit for publication.

RESULTS

During the study period, a total of 21.009 patients underwent stent implantation in the

participating hospitals. A total number of 31.065 stents were implanted (19.840 BMS

and 11.225 DES). As expected, there were significant differences in age, prevalence of

cardiovascular risk-factors, lesion characteristics and the prevalence of other clinical co-

morbidities between patients who received a BMS and DES (Table 1). During a median

follow-up of 30.9 months (25th -75th percentiles: 23.6-41.9 months), 437 patients (2.1%)

presented with an angiographic confirmed ST. According to the different categories of

ST, 140 (32.0%) were acute ST, 180 (41.2%) were subacute ST, 58 (13.3%) were late ST (36

within 6 months) and 59 were very late (13.5%). Two-hundred-seventy stent thromboses

were related to a BMS (cumulative incidence 2.2%), 152 stent thromboses were related

to a DES (cumulative incidence 2.0%) and 15 were related to both a BMS and a DES

stent (mixed use: cumulative incidence 1.8%). The cumulative incidence of ST was not

significantly different between the two different types of coronary stents: p=0.38).

We were able to match 866 controls to the case subjects (99.0%). Detailed clinical,

procedural and angiographic features of the patients with ST and the matched controls

are described in Table 2.

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Comprehensive risk-factor identification: all cases versus all matched controls

Independent clinical, procedural and angiographic predictors of ST when comparing

all cases with all matched controls in multivariate analysis are depicted in figure 1.

Cessation of clopidogrel at various time points, undersizing, present malignant disease,

the presence of intermediate coronary artery disease proximal to the culprit lesion,

suboptimal procedural result (TIMI flow post-PCI<3), uncovered dissection, bifurcation

stenting, left ventricular ejection fraction (LVEF) <30%, peripheral artery disease, the

presence of intermediate coronary artery disease distal to the culprit lesion, no aspirin

therapy, diabetes mellitus, use of any DES and younger age were associated with the

occurrence of ST.

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Table 1: Bare-metal versus drug-eluting stents

CharacteristicsDES & mixed stents

( n = 418)BMS

( n = 885) P-value

Clinical FactorsFemale – no./total no. (%) 123/416 (29.6) 220/883 (24.9) 0.0797Age - yr 60.2 ± 12.0 62.7 ± 11.7 0.0004Body Mass Index 27.0 ± 4.1 27.2 ± 3.9 0.5379Current smoking – no./total no. (%) 259/418 (62.0) 546/885 (61.7) 0.9513History – no./total no. (%) Hypertension 189/418 (45.2) 377/885 (42.6) 0.4020 DM 93/418 (22.3) 120/885 (13.6) 0.0001 Hypercholesterolemia 219/418 (52.4) 392/885 (44.3) 0.0074 Prior MI 123/418 (29.4) 181/885 (20.5) 0.0004 Prior PCI 106/418 (25.4) 143/885 (16.2) 0.0001 Prior CABG 28/411 (6.8) 45/869 (5.2) 0.2468 Malignancy 28/418 (6.7) 59/885 (6.7) 1.0000 Family History of CAD 219/418 (52.4) 389/885 (44.0) 0.0051 Peripheral artery disease (PAD) 30/418 (7.2) 74/885 (8.4) 0.5119 MDRDeGFR < 60 68/368 (18.5) 143/754 (19.0) 0.8710LVEF – no./total no. (%) > 45 % 351/418 (84.0) 708/885 (80.0) 0.0225 30-45 % 37/418 (8.9) 124/885 (14.0) < 30 % 30/418 (7.2) 53/885 (6.0)Indication – no./total no. (%) Stable Angina 168/417 (40.3) 186/884 (21.0) <0.0001 UAP / NSTEMI 73/417 (17.5) 122/884 (13.8) STEMI 176/417 (42.2) 576/884 (65.2)Lesion Characteristics – no./total no. (%)ACC/AHA B2 or C 281/418 (67.2) 569/885 (64.3) 0.3189Severe Calcification 55/418 (13.2) 94/885 (10.6) 0.1919Bifurcation-lesion 171/418 (40.9) 265/885 (29.9) 0.0001Lesion in coronary ostium 10/410 (2.4) 25/871 (2.9) 0.7174Excentric lesion 46/410 (11.2) 102/869 (11.7) 0.8516Chronic total occlusion 17/407 (4.2) 10/861 (1.2) 0.0012Visible Thrombus 179/411 (43.6) 576/868 (66.4) <0.0001Tortuosity 9/418 (2.2) 24/885 (2.7) 0.7060Multivessel disease 122/418 (29.2) 261/885 (29.5) 0.9481Coronary Vessel LAD 252/418 (60.3) 396/885 (44.8) <0.0001 RCA 124/418 (29.7) 352/885 (39.8) 0.0004 RCX 70/418 (16,8) 143/885 (16.2) 0.8099 Venegraft 8/418 (1.9) 18/885 (2.0) 1.0000Procedural Characteristics – no./total no. (%)TIMI flow 3 pre-PCI 219/418 (52.4) 376/885 (42.5) 0.0009TIMI flow 3 post-PCI 377/418 (90.2) 788/885 (89.0) 0.5638Rescue PCI 15/417 (3.6) 80/885 (9.0) 0.0003

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Trombosuction / Aspiration 8/406 (2.0) 31/849 (3.7) 0.1198PCI for restenosis 33/418 (7.9) 13/885 (1.5) <0.0001GP IIb/IIIa therapy 107/405 (26.4) 319/850 (37.5) 0.0001Clopidogrel 416/418 (99.5) 883/884 (99.9) 0.2428Aspirin 384/418 (91.9) 822/884 (93.0) 0.4960Coumadin 35/417 (8.4) 62/883 (7.0) 0.4286No-reflow 9/418 (2.2) 28/885 (3.2) 0.3733Dissection 40/418 (9.6) 87/885 (9.8) 0.9206Undersizing 44/418 (10.5) 55/885 (6.2) 0.0072Non-culprit stenosis distal of the stented segment which is left untreated (>50%)

30/418 (7.2) 78/885 (8.8) 0.335

Non-culprit stenosis proximal of the stented segment which is left untreated (>50%)

4/418 (1.0) 18/885 (2.0) 0.248

Total stent length – mm. 28.9 ± 18.1 23.3 ± 12.3 <0.0001Minimal stent diameter – mm. 2.93 ± 0.4 3.16 ± 0.4 <0.0001Maximal balloon pressure – atm. 14.2 ± 2.5 13.7 ± 2.5 0.0005

DES=drug-eluting stent; BMS=bare-metal stent; DM=diabetes mellitus ; MI=myocardial infarction; PCI=percutaneous coronary intervention; CABG=coronary artery bypass-grafting; CAD=coronary artery disease; PAD=peripheral artery disease; MDRDeGFR= Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate; LVEF=left ventricular ejection fraction; UAP=unstable angina pectoris; NSTEMI=non-ST elevated myocardial infarction; STEMI=ST-elevated myocardial infarction; LAD= left anterior descending artery; RCA=right coronary artery; RCX= right circumflex artery; TIMI-Thrombolysis in myocardial infarction.

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Table 2: Baseline clinical, lesion and procedural characteristicsCasesn=437

Matched controlsn=866 P-value

Clinical Characteristics– no./total no. (%)Female – no./total no. (%) 108/437 (24.7) 235/862 (27.3) 0.3512Age - yr 61.0 ± 11.8 62.3 ± 11.7 0.0616Body Mass Index 27.2 ± 4.1 27.0 ± 3.8 0.5541Current smoking – no./total no. (%) 285/437 (65.2) 520/866 (60.1) 0.0705History – no./total no. (%) Hypertension 205/437 (46.9) 361/866 (41.7) 0.0759 DM 102/437 (23.3) 111/866 (12.8) <0.0001 Hypercholesterolemia 233/437 (53.3) 378/866 (43.7) 0.0010 Prior MI 132/437 (30.2) 172/866 (19.9) <0.0001 Prior PCI 104/437 (23.8) 145/866 (16.7) 0.0028 Prior CABG 22/436 (5.1) 51/844 (6.0) 0.5259 Malignancy 46/437 (10.5) 41/866 (4.7) 0.0001 Family History of CAD 216/437 (49.4) 392/866 (45.3) 0.1586 Peripheral artery disease (PAD) 48/437 (11.0) 56/866 (6.5) 0.0065 MDRDeGFR < 60 73/407 (17.9) 138/715 (19.3) 0.6336LVEF – no./total no. (%) > 45 % 318/437 (72.8) 741/866 (85.6) 30-45 % 73/437 (16.7) 88/866 (10.2) < 30 % 46/437 (10.5) 37/866 (4.3) <0.0001Indication – no./total no. (%) Stable Angina 113/437 (25.9) 242/866 (27.9) Matched

item

IAP / NSTEMI 72/437 (16.5) 124/866 (14.3) Matched item

STEMI 252/437 (57.7) 500/866 (57.7) Matched item

Lesion Characteristics – no./total no. (%)ACC/AHA B2 or C 334/437 (76.4) 516/866 (59.6) <0.0001Severe Calcification 85/437 (19.5) 64/866 (7.4) <0.0001Bifurcation-lesion 228/437 (51.7) 210/866 (24.3) <0.0001Lesion in coroary ostium 10/420 (2.4) 25/861 (2.9) 0.7159Excentric lesion 56/419 (13.4) 92/860 (10.7) 0.1636Chronic total occlusion 11/417 (2.6) 16/851 (1.9) 0.4098Visible Thrombus 260/418 (62.2) 495/861 (57.5) 0.1152Tortuosity 11/437 (2.5) 22/866 (2.5) 1.0000Multivessel disease 181/437 (41.4) 202/866 (23.3) <0.0001Coronary vessel LAD 273/437 (62.5) 375/866 (43.3) <0.0001 RCA 128/437 (29.3) 348/866 (40.2) <0.0001 RCX 65/437 (14.9) 148/866 (17.1) 0.3411 Veingraft 5/437 (1.1) 21/866 (2.4) 0.1435

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Procedural Characteristics–no./total no. (%)Bare-metal stent(s) 270 (61.8%) 614 (70.9%) 0.0015Drug-eluting stent(s) 152 (34.8%) 238 (27.5%)Mixed stent(s) 15 (34.3%) 14 (1.6%)TIMI flow 3 pre-PCI 178/437 (40.7) 417/866 (48.2) 0.0114TIMI flow 3 post-PCI 346/437 (79.2) 819/866 (94.6) <0.0001Rescue PCI 35/436 (8.0) 60/866 (6.9) 0.4986Trombosuction / Aspiration 14/417 (3.4) 25/836 (3.0) 0.7315PCI for restenosis 20/437 (4.6) 26/866 (3.0) 0.1543No-reflow 17/437 (3.9) 20/866 (2.3) 0.1135Dissection 75/437 (17.2) 52/866 (6.0) <0.0001Undersizing 79/437 (18.1) 20/866 (2.3) <0.0001Non-culprit stenosis distal of the stented segment which is left untreated (>50%)

62/437 (14.2) 46/866 (5.3) <0.0001

Non-culprit stenosis proximal of the stented segment which is left untreated (>50%)

14/437 (3.2) 8/866 (0.9) <0.0001

Total stent length – mm. 27.8 ± 15.2 23.7 ± 14.2 <0.0001Total number of stents 1.54 ± 0.82 1.34 ± 0.67 <0.0001Minimal stent diameter – mm. 3.0 ± 0.4 3.13 ± 0.4 <0.0001Maximal balloon pressure – atm. 13.7 ± 2.5 13.9 ± 2.5 0.1823Antithrombotic medication at the time of the index PCI

GP IIb/IIIa therapy 136/429 (31.7) 290/826 (35.1) 0.2331Clopidogrel 428/437 (97.9) 861/866 (99.4) 0.97Aspirin 379/436 (86.9) 827/866 (95.5) <0.0001Coumadin 48/435 (11.0) 49/865 (5.7) 0.0007

DM=diabetes mellitus ; MI=myocardial infarction; PCI=percutaneous coronary intervention; CABG=coronary artery bypass-grafting; CAD=coronary artery disease; PAD=peripheral artery disease; MDRDeGFR= Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate; LVEF=left ventricular ejection fraction; UAP=unstable angina pectoris; NSTEMI=non-ST elevated myocardial infarction; STEMI=ST-elevated myocardial infarction; LAD= left anterior descending artery; RCA=right coronary artery; RCX= right circumflex artery; TIMI-Thrombolysis in myocardial infarction.

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Figure 1: Independent risk-factors for ST when comparing the total group of patients with ST

with all matched-controls.

Influence of the indication for the index PCI on ST rate and determinants of ST

With regard to the different indications for stent implantation, the cumulative incidence

of ST in patients who underwent an elective PCI for the indication stable angina pectoris

was low 113/11.207 patients (cumulative incidence:1.00%). However, the cumulative

incidence of ST was higher when the indication for index stent implantation was

unstable angina/NSTEMI (72/3960 patients, cumulative incidence: 1.8%) and for STEMI

(252/5842 cumulative incidence: 4.3%). Determinants of ST for the different indications

of index stent implantation are depicted in figure 2. Independent factors that predispose

to the development of ST in patients undergoing elective PCI with stent implantation for

the indication stable angina were undersizing, the presence of intermediate coronary

artery disease proximal to the culprit lesion, malignant disease, suboptimal procedural

result (TIMI flow post-PCI<3), LVEF<30%, uncovered dissection, multivessel disease,

LAD stenting and long total stent length. Predictors of ST in the setting of ACS (including

STEMI) as the indication for index PCI were undersizing, suboptimal procedural result

(TIMI flow post-PCI<3), uncovered dissection, the presence of intermediate coronary

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143

artery disease proximal to the culprit lesion, bifurcation lesion, any DES, no aspirin

therapy, LVEF<30%, the presence of intermediate coronary artery disease distal to the

culprit lesion and multivessel disease. Of note, peri-procedural use of glycoprotein (GP)

IIb/IIIa therapy for the indication ACS (including STEMI) was associated with a reduction

of ST. It is important to note that the time-varying covariable “cessation of clopidogrel”

was not included in these multivariate models.

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Total stent length (10mm)

LAD stenting

Multivessel disease

Dissection

LVEF <30%

TIMI flow post-PCI <3

Malignancy

50% proximal of culprit≥CAD

Undersizing 57.72

14.21

13.08

9.71

8.44

5.64

3.30

2.55

1.88

[6.26-223.9]

[3.82-52.87]

[1.99-85.93]

[1.84-50.0]

[2.21-32.17]

[1.88-16.94]

[1.30-8.40]

[1.07-6.09]

[1.18-2.50]

OR 95%-CI

P=0.0003

P<0.0001

P=0.0074

P=0.0073

P=0.0018

P=0.0021

P=0.0122

P=0.035

P=0.0042

P-value

Predictors of Stent thrombosisCases and matched controls with Stable Angina as indication for index PCI

>

>

OR0 4 8 12 16 20

GP IIb/IIIa therapy

Multivessel disease

50% distal of culprit≥CAD

LVEF <30

no ASA

Any DES

Bifurcation lesion


Dissection


Undersizing 12.28

4.31

3.93

3.72

2.74

2.64

2.27

1.83

1.82

1.63

0.50

[4.72-31.93]

[2.24-8.33]

[2.06-7.48]

[2.14-6.47]

[1.81-4.16]

[1.63-4.29]

[1.09-4.74]

[1.14-2.95]

[1.14-2.90]

[1.04-2.56]

[0.33-0.75]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.028

P=0.013

P=0.0117

P=0.033

P=0.001

P-value

Predictors of Stent thrombosisCases and matched controls with ACS as indication for index PCI

>

OR

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Figure 2: Independent risk-factors for ST for the different indications of index stent

implantation (stable angina versus ACS)

Risk-factors for early ST (≤30 days) and late ST (>30 days)

Almost 75% of the STs occurred within 30 days after stent implantation. Figure 3 displays

the independent predictors of early ST (≤30 days after the index PCI) with associated

odds ratios (OR) and 95% CI and the independent predictors of late ST (>30 days after

the index PCI). Early predictors of ST included undersizing, uncovered dissection,

suboptimal procedural result (TIMI flow post-PCI<3), the presence of intermediate

coronary artery disease proximal to the culprit lesion, present malignant disease, no

aspirin, LVEF<30%, bifurcation lesion, the presence of intermediate coronary artery

disease distal to the culprit lesion, any DES, total number of stents. GP IIb/IIIa was

protective for the occurrence of early ST.

The following determinants were independently associated with the occurrence of late

ST: undersizing, present malignant disease, the presence of intermediate coronary

artery disease proximal to the culprit lesion, peripheral artery disease, diabetes mellitus,

bifurcation lesions, long total stent length and younger age.

Again, it is important to note that the time-varying covariable “cessation of clopidogrel”

was not included in these multivariate models.

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Total stent length (10mm)

LAD stenting

Multivessel disease

Dissection

LVEF <30%


Malignancy


Undersizing 57.72

14.21

13.08

9.71

8.44

5.64

3.30

2.55

1.88

[6.26-223.9]

[3.82-52.87]

[1.99-85.93]

[1.84-50.0]

[2.21-32.17]

[1.88-16.94]

[1.30-8.40]

[1.07-6.09]

[1.18-2.50]

OR 95%-CI

P=0.0003

P<0.0001

P=0.0074

P=0.0073

P=0.0018

P=0.0021

P=0.0122

P=0.035

P=0.0042

P-value

Predictors of Stent thrombosisCases and matched controls with Stable Angina as indication for index PCI

>

>

OR0 4 8 12 16 20

GP IIb/IIIa therapy

Multivessel disease


LVEF <30

no ASA

Any DES

Bifurcation lesion


Dissection


Undersizing 12.28

4.31

3.93

3.72

2.74

2.64

2.27

1.83

1.82

1.63

0.50

[4.72-31.93]

[2.24-8.33]

[2.06-7.48]

[2.14-6.47]

[1.81-4.16]

[1.63-4.29]

[1.09-4.74]

[1.14-2.95]

[1.14-2.90]

[1.04-2.56]

[0.33-0.75]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.028

P=0.013

P=0.0117

P=0.033

P=0.001

P-value

Predictors of Stent thrombosisCases and matched controls with ACS as indication for index PCI

>

OR

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145

Figure 3: Independent risk-factors for early (≤30days) ST and late (>30 days) ST.

0 4 8 12 16 20

GP IIb/IIIa therapy

Total No of stents (per stent)

Any DES


Bifurcation

LVEF <30%

no ASA

Malignancy


TIMI flow post-PCI

Dissection

Undersizing 13.46

6.19

5.24

4.15

3.06

2.82

2.71

2.42

2.22

[5.23-34.64]

[3.25-11.79]

[2.75-10.00]

[2.46-7.00]

[1.31-7.14]

[1.24-6.41]

[1.61-4.57]

[1.59-3.70]

[1.39-3.56]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.0097

P=0.0132

P=0.0002

P<0.0001

P=0.0009

P-value

Predictors of Early (≤30 days) Stent thrombosis

>

2.07 [1.25-3.44] P=0.048

1.35 [1.04-1.76] P=0.0276

0.40 [0.25-0.65] P<0.0001

OR0 4 8 12 16 20 24 28 32

age (per 10 yrs)

Total stent length (per 10 mm)

Bifurcation

DM

PAD


Malignancy

Undersizing 28.17

17.45

8.66

5.62

3.14

2.93

1.37

0.54

[4.73-163.90]

[4.67-65.26]

[3.18-23.56]

[1.43-22.09]

[1.33-7.45]

[1.37-6.23]

[1.04-1.79]

[0.39-0.76]

OR 95%-CI

P=0.0002

P<0.0001

P<0.0001

P=0.0133

P=0.0093

P=0.0005

P=0.0233

P=0.0004

P-value

Predictors of Late (>30 days) Stent thrombosis

>

>

OR

0 4 8 12 16 20

GP IIb/IIIa therapy


Any DES


Bifurcation

LVEF <30%

no ASA

Malignancy


TIMI flow post-PCI

Dissection

Undersizing 13.46

6.19

5.24

4.15

3.06

2.82

2.71

2.42

2.22

[5.23-34.64]

[3.25-11.79]

[2.75-10.00]

[2.46-7.00]

[1.31-7.14]

[1.24-6.41]

[1.61-4.57]

[1.59-3.70]

[1.39-3.56]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.0097

P=0.0132

P=0.0002

P<0.0001

P=0.0009

P-value


>

2.07 [1.25-3.44] P=0.048

1.35 [1.04-1.76] P=0.0276

0.40 [0.25-0.65] P<0.0001

OR0 4 8 12 16 20 24 28 32

age (per 10 yrs)


Bifurcation

DM

PAD


Malignancy

Undersizing 28.17

17.45

8.66

5.62

3.14

2.93

1.37

0.54

[4.73-163.90]

[4.67-65.26]

[3.18-23.56]

[1.43-22.09]

[1.33-7.45]

[1.37-6.23]

[1.04-1.79]

[0.39-0.76]

OR 95%-CI

P=0.0002

P<0.0001

P<0.0001

P=0.0133

P=0.0093

P=0.0005

P=0.0233

P=0.0004

P-value


>

>

OR

0 4 8 12 16 20

GP IIb/IIIa therapy


Any DES


Bifurcation

LVEF <30%

no ASA

Malignancy


TIMI flow post-PCI

Dissection

Undersizing 13.46

6.19

5.24

4.15

3.06

2.82

2.71

2.42

2.22

[5.23-34.64]

[3.25-11.79]

[2.75-10.00]

[2.46-7.00]

[1.31-7.14]

[1.24-6.41]

[1.61-4.57]

[1.59-3.70]

[1.39-3.56]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.0097

P=0.0132

P=0.0002

P<0.0001

P=0.0009

P-value


>

2.07 [1.25-3.44] P=0.048

1.35 [1.04-1.76] P=0.0276

0.40 [0.25-0.65] P<0.0001

OR0 4 8 12 16 20 24 28 32

age (per 10 yrs)


Bifurcation

DM

PAD


Malignancy

Undersizing 28.17

17.45

8.66

5.62

3.14

2.93

1.37

0.54

[4.73-163.90]

[4.67-65.26]

[3.18-23.56]

[1.43-22.09]

[1.33-7.45]

[1.37-6.23]

[1.04-1.79]

[0.39-0.76]

OR 95%-CI

P=0.0002

P<0.0001

P<0.0001

P=0.0133

P=0.0093

P=0.0005

P=0.0233

P=0.0004

P-value


>

>

OR

0 4 8 12 16 20

GP IIb/IIIa therapy


Any DES


Bifurcation

LVEF <30%

no ASA

Malignancy


TIMI flow post-PCI

Dissection

Undersizing 13.46

6.19

5.24

4.15

3.06

2.82

2.71

2.42

2.22

[5.23-34.64]

[3.25-11.79]

[2.75-10.00]

[2.46-7.00]

[1.31-7.14]

[1.24-6.41]

[1.61-4.57]

[1.59-3.70]

[1.39-3.56]

OR 95%-CI

P<0.0001

P<0.0001

P<0.0001

P<0.0001

P=0.0097

P=0.0132

P=0.0002

P<0.0001

P=0.0009

P-value


>

2.07 [1.25-3.44] P=0.048

1.35 [1.04-1.76] P=0.0276

0.40 [0.25-0.65] P<0.0001

OR0 4 8 12 16 20 24 28 32

age (per 10 yrs)


Bifurcation

DM

PAD


Malignancy

Undersizing 28.17

17.45

8.66

5.62

3.14

2.93

1.37

0.54

[4.73-163.90]

[4.67-65.26]

[3.18-23.56]

[1.43-22.09]

[1.33-7.45]

[1.37-6.23]

[1.04-1.79]

[0.39-0.76]

OR 95%-CI

P=0.0002

P<0.0001

P<0.0001

P=0.0133

P=0.0093

P=0.0005

P=0.0233

P=0.0004

P-value


>

>

OR

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The influence of antiplatelet therapy on the occurrence of ST

The proportion of cases and matched controls that were on clopidogrel therapy for the

time-frames of the different categories ST is presented in figure 4. In detail, a total of

134 (30.7%) cases were not on clopidogrel therapy at the time of the ST. Of these, in

9/140 (6.4%) patients presenting with an acute ST the clopidogrel was erroneously not

initiated, 30/179 (16.7%) patients with a subacute ST had discontinued the clopidogrel for

a median of 5 days [IQR: 3-7days], 39/58 (67.2%) patients with a late ST had discontinued

the clopidogrel for a median of 13 days [IQR: 7-61days] and 56/59 (94.9% ) patients

with a very late ST had discontinued the clopidogrel for a median of 200 days [IQR: 23-

981days].

After applying the exact elapsed time-frame between the index PCI and ST for every

case to their matched controls it is shown that a significant higher proportion of controls

were on clopidogrel therapy at the “virtual time” of occurrence of ST (figure 4). As

compared to patients on clopidogrel therapy, the lack of clopidogrel therapy at the time

of ST in the first 30 days after the index PCI was strongly associated with ST (HR 36.5,

95% CI: 8.0-167.8). Likewise, the lack of clopidogrel therapy at the time of ST between

30 days and 6 months after the index PCI was also linked to the occurrence of ST (HR

4.6, 95% CI: 1.4-15.3). Multivariate Cox proportional hazard analysis also found that

discontinuation of clopidogrel therapy after 6 months from the index stent implantation

was a predictor of ST (HR 5.9, 95% CI: 1.7-19.8).

Alternatively, given the fact that clopidogrel irreversibly inhibits the human platelet

throughout its entire lifespan (10-12 days), we hypothesized that cessation of

clopidogrel <14 days prior to the ST would reveal the temporal relationship between

the discontinuation of clopidogrel and ST. After introducing this time-varying co-variate

in the multivariate Cox proportional hazard model, “cessation of clopidogrel within 14

days prior to ST” in the first 30 days after the index PCI emerged as a highly significant

predictor of ST (HR 36.9, 95% CI: 7.9-173.3). Similarly, “cessation of clopidogrel within

14 days prior to ST” between 30 days and 6 months after the index PCI was also

independently associated with the occurrence of ST (HR 21, 95% CI: 2.2-198.3). The

number of events beyond the 6 months time-frame after stent implantation was too

small to reliably estimate the impact of “cessation of clopidogrel and the subsequent

occurrence of ST within 14 days” on the occurrence of ST in this subcategory of

patients.Another important finding relates to the magnitude of impact of “cessation

of clopidogrel and the subsequent occurrence of ST within 14 days” between DES and

BMS. The risk for stent thrombosis associated with “Cessation of clopidogrel and the

subsequent occurrence of ST within 14 days” was significantly higher in patients who

had received a DES as compared to those who had received a BMS (OR for DES: 1.88,

95%CI: 1.21-2.94, p=0.0052).

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Figure 4: Proportion of cases and their matched controls taking clopidogrel therapy according

to the elapsed time between stent implantation and the occurrence of ST.

A significant higher percentage of the patients with ST did not use aspirin therapy at the

time of the index as compared to their matched control (13.1% versus 4.5%, p<0.0001).

The predominant reasons for no aspirin treatment were coumadin use in 85/96 (84.4%)

patients and allergy to aspirin in 7/96 (7.3%) patients. Multivariate logistic regression

analysis identified that the absence of aspirin therapy was also strong independent

predictor of ST (HR 1.91 95% CI: 1.01-3.88, p=0.0487).

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DISCUSSION

Given the devastating consequences of ST, great efforts should be directed to identify

those patients at highest risk, who would probably benefit most from an alternative

strategy. The findings of the present study add considerably to the understanding of the

profiles of patients at high risk for ST.

Although previous studies have already recognized multiple risk-factors that confer a

significant risk of ST [1-3, 5, 7, 10], many of these studies have limitations, mostly related

to an overall small sample size with a limited number of cases. Also, the identified

determinants of ST represent those that have been looked for and many theoretical

likely factors (such as present malignancy, severity of atherosclerotic disease, aspirin

use) are not investigated in most published studies.

The case-control design of our study as well as the acquisition of very detailed data

on medical history, medication use and angiographic characteristics enabled us to

comprehensively examine the most important risk-factors that are associated with

ST. Moreover, the large sample size allowed identification of relatively infrequent

determinants.

The highly variable duration of clopidogrel use throughout the years of patient

recruitment (2004-2007) allowed us to comprehensive study the impact of early

clopidogrel cessation after stent implantation. As expected, lack of clopidogrel therapy

at the time of the ST in the first 6 months after the index PCI was identified as the

strongest independent predictor of ST and this observation is in line with some [1, 2, 11)

but not all [3, 7] previous reports. Also, we predefined a likely “vulnerable time-frame”

between cessation of clopidogrel and the occurrence of ST (<14 days) and demonstrated

that this is the period that patients are at the highest risk for ST, especially when the

discontinuation of clopidogrel was within the first 6 months after stent implantation.

A novel and very important finding of the present study, contrary to a recently published

study [7], is the fact that the lack of clopidogrel therapy (but not necessarily cessation of

clopidogrel within the 14 days preceding the ST) beyond 6 months after index PCI was

a predictor of ST. A likely explanation for this difference may be the fact that previous

studies were hampered by a very low number of events (16 patients of whom 7 did

not use clopidogrel at time of ST) >6 months after coronary stent implantation [7].

Nonetheless, our results should also be interpreted with caution because only a small

portion of patients with ST beyond 6 months had discontinued the clopidogrel in the 14

days preceding the ST.

It remains pure speculative why “lack of clopidogrel therapy after 6 months from the

index stent implantation” but not “cessation of clopidogrel and the occurrence of ST

(<14 days)” beyond 6 months was a predictor of late and very late ST. Perhaps that the

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149

loss of protection by clopidogrel therapy rather than a “rebound in platelet reactivity”

may explain these findings.

Undersizing of the coronary stent was the second strongest predictor of ST in our

study. Indeed, previous studies have elucidated the importance of correct sizing

of coronary stents, in particular in patients with a high thrombotic burden with

subsequent vasoconstriction or severe and diffuse target vessel disease [12-16]. Despite

improvements in techniques and materials in the last decade, previous reports have

suggested that the incidence of incomplete stent deployment and undersizing ranges

from 20% to 30% and this percentage is even higher when assessed by intravascular

ultrasound [15, 17]. Notwithstanding the results of previous studies suggesting that the

judgment of the correct sizing and/or deployment of coronary stents is superior with the

use of IVUS [18], we demonstrated that the identification of undersizing of a coronary

stent by the simple means of eyeballing is a strong predictor of ST. In most of the cases,

undersizing was probably due to severe calcification or related to a high thrombotic

burden with subsequent vasoconstriction. However, also incorrect judgment of the true

coronary vessel size by the performing operator is a likely explanation for undersizing

in a considerable number of cases.

The long-term safety of DES has been a main topic of debate at recent international

cardiology meetings. In our study, patients who received a DES had higher baseline

risk-profiles and more complex lesion characteristics. Nonetheless, the use of a DES

was not independently associated with late or very late ST. In contrast, any DES use was

independently associated with ST in both the all cases versus all controls analysis as

well as in the sub analysis on risk-factors for early ST

Several previous studies have elucidated the importance of mechanical (both

angiographic and procedural factors) aetiologies underlying early ST [12, 15, 17].

Given the more complex lesion characteristics (an off-label DES indication) and limited

flexibility of the first generation of DES, uncovered endothelial damage during DES

implantation might explain this association between early ST and DES use.

Study limitations

Several limitations of the present study need to be acknowledged. First, notwithstanding

that a case-control design enables the evaluation of rare events such as ST, a case-

control design is at the same time vulnerable to several sorts of bias. Indeed, three

control patients were excluded from analysis because they were admitted for ST in

another non-participating hospital during follow-up. However, given the size of the

control group (2:1 ratio), the random selection of controls and the extent of differences in

clinical procedural and angiographic findings between cases and controls, it is unlikely

that the results would have changed considerably by increasing the number of controls.

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Chapter 9

150

Second, only angiographically documented cases with ST (“definite”) were reported.

This might have led to an underestimation of the actual incidence of ST because patients

who had suffered from a sudden cardiac death or from a silent stent occlusion were not

included in our analysis. Third, one may question our evaluation of the sizing of coronary

stents by simple means of eyeballing instead of using sophisticated techniques such as

IVUS or QCA. Nonetheless, visual estimation was able to detect undersizing in 18.1% of

the cases and in only 2.3% of the controls, which makes it a valuable tool.

Conclusion

We identified several important predictors of ST in the contemporary era of mixed

DES and BMS use. Discontinuation of clopidogrel, undersizing of the coronary stent,

presence of intermediate (>30%) coronary artery disease proximal to the culprit lesion

and concomitant malignant disease were the strongest predictors of ST. Risk-factors for

ST also vary throughout the different indications for PCI (stable angina versus ACS) and

differ for the different categories of ST (early vs late ST).

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REFERENCE LIST

1. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.

2. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113:1108-13.

3. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667-78.

4. Smit JJ, van ‘t Hof AW, de Boer MJ, et al. Incidence and predictors of subacute thrombosis in patients undergoing primary angioplasty for an acute myocardial infarction. Thromb Haemost 2006;96:190-5.

5. Rinaldi MJ, Kirtane AJ, Piana RN, et al. Clinical, procedural, and pharmacologic correlates of acute and subacute stent thrombosis: results of a multicenter case-control study with 145 thrombosis events. Am Heart J 2008;155:654-60.

6. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584-91.

7. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745-54.

8. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.

9. Huber MS, Mooney JF, Madison J, Mooney MR. Use of a morphologic classification to predict clinical outcome after dissection from coronary angioplasty. Am J Cardiol 1991;68:467-71.

10. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006;98:352-6.

11. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967-71.

12. Moussa I, Di MC, Reimers B, Akiyama T, Tobis J, Colombo A. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: frequency, predictors and clinical outcome. J Am Coll Cardiol 1997;29:6-12.

13. Takano Y, Yeatman LA, Higgins JR, et al. Optimizing stent expansion with new stent delivery systems. J Am Coll Cardiol 2001;38:1622-7.

14. Brodie BR, Cooper C, Jones M, Fitzgerald P, Cummins F. Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial. Catheter Cardiovasc Interv 2003;59:184-92.

15. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study. Circulation 2003;108:43-7.

16. Cheneau E, Satler LF, Escolar E, et al. Underexpansion of sirolimus-eluting stents: incidence and relationship to delivery pressure. Catheter Cardiovasc Interv 2005;65:222-6.

17. Uren NG, Schwarzacher SP, Metz JA, et al. Predictors and outcomes of stent thrombosis: an intravascular ultrasound registry. Eur Heart J 2002;23:124-32.

18. Briguori C, Tobis J, Nishida T, et al. Discrepancy between angiography and intravascular ultrasound when analysing small coronary arteries. Eur Heart J 2002;23:247-54.

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Chapter 9

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