University of Groningen Antiplatelet therapy in myocardial ... · Predictors of coronary stent...
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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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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
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
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R19
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Coronary stent thrombosis
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
50% proximal of culprit≥CAD
Dissection
TIMI flow post-PCI <3
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
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
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R26
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Chapter 9
144
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%
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
50% proximal of culprit≥CAD
Dissection
TIMI flow post-PCI <3
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
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
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Coronary stent thrombosis
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
50% distal of culprit≥CAD
Bifurcation
LVEF <30%
no ASA
Malignancy
50% proximal of culprit≥CAD
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
50% proximal of culprit≥CAD
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
Total No of stents (per stent)
Any DES
50% distal of culprit≥CAD
Bifurcation
LVEF <30%
no ASA
Malignancy
50% proximal of culprit≥CAD
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
50% proximal of culprit≥CAD
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
Total No of stents (per stent)
Any DES
50% distal of culprit≥CAD
Bifurcation
LVEF <30%
no ASA
Malignancy
50% proximal of culprit≥CAD
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
50% proximal of culprit≥CAD
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
Total No of stents (per stent)
Any DES
50% distal of culprit≥CAD
Bifurcation
LVEF <30%
no ASA
Malignancy
50% proximal of culprit≥CAD
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
50% proximal of culprit≥CAD
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
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
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Chapter 9
146
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).
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
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Coronary stent thrombosis
147
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).
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
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Chapter 9
148
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
R1
R2
R3
R4
R5
R6
R7
R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
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R24
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Coronary stent thrombosis
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.
R1
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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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