Journal of the American College of Cardiology Vol. 53, No.

16, 2009
© 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2008.12.055

Predictors of Coronary Stent Thrombosis

The Dutch Stent Thrombosis Registry

Jochem W. van Werkum, MD,*† Antonius A. Heestermans, MD,‡ A. Carla Zomer, MD,*
Johannes C. Kelder, MD,* Maarten-Jan Suttorp, MD, PHD,* Benno J. Rensing, MD, PHD,*
Jacques J. Koolen, MD, PHD,§ B. R. Guus Brueren, MD, PHD,§ Jan-Henk E. Dambrink, MD, PHD,‡
Raymond W. Hautvast, MD, PHD,储 Freek W. Verheugt, MD, PHD,† Jurriën M. ten Berg, MD, PHD*
Nieuwegein, Nijmegen, Zwolle, Eindhoven, and Alkmaar, the Netherlands

Objectives This study sought to comprehensively identify predictors of stent thrombosis (ST).

Background Given the devastating consequences of ST, efforts should be directed toward risk stratification to identify pa-
tients at highest risk for ST.

Methods Consecutive patients with angiographic ST were enrolled. Patients who did not suffer from a ST were randomly
selected in a 2:1 ratio and were matched for: 1) percutaneous coronary intervention (PCI) indication; 2) same
date of index PCI; and 3) same interventional center.

Results Of 21,009 patients treated with either a bare-metal or drug-eluting stent, 437 patients (2.1%) presented with a
definite ST. A total of 140 STs were acute, 180 were subacute, 58 were late, and 59 were very late. Undersizing
of the coronary stent, Thrombolysis In Myocardial Infarction flow grade ⬍3, present malignancy, presence of in-
termediate coronary artery disease proximal and distal to the culprit lesion, dissection, lack of aspirin, bifurca-
tion lesions, ejection fraction ⬍30%, and younger age were associated with ST. The lack of clopidogrel therapy
at the time of ST in the first 30 days after the index PCI (hazard ratio [HR]: 36.5, 95% confidence interval [CI]:
8.0 to 167.8), between 30 days and 6 months after the index PCI (HR: 4.6, 95% CI: 1.4 to 15.3), and beyond 6
months (HR: 5.9, 95% CI: 1.7 to 19.8) after the index PCI was strongly associated with ST.

Conclusions Important correlates of ST were identified. Discontinuation of clopidogrel, undersizing of the coronary stent,
present malignancy, and intermediate (ⱖ50% to ⬍70% stenosis) coronary artery disease proximal to the culprit
lesion were the strongest predictors of ST. (J Am Coll Cardiol 2009;53:1399–409) © 2009 by the American
College of Cardiology Foundation

Despite improved stent implantation technologies and more
effective antiplatelet regimens, stent thrombosis (ST) con-
tinues to occur with an estimated incidence varying between
1% and 5% (1– 6). This wide variability in the estimated
From the *Department of Cardiology, St. Antonius Hospital, Nieuwegein, the
Netherlands; †Department of Cardiology, UMC St. Radboud Nijmegen, Nijmegen,
the Netherlands; ‡Department of Cardiology, Isala klinieken, Zwolle, the Nether-
lands; §Department of Cardiology, Catharina ziekenhuis Eindhoven, Eindhoven, the
Netherlands; and the 储Department of Cardiology, Alkmaar Medisch Centrum,
Alkmaar, the Netherlands. The Dutch Stent Thrombosis Registry was supported by
an unrestricted research grant from Sanofi-Aventis and Bristol-Myers Squibb. The
sponsor had no role in the design and conduct of the study in the collection,
management, analysis, and interpretation of the data or in the preparation, review, or
approval of the manuscript. Drs. van Werkum and ten Berg served on scientific
advisory boards for The Medicines Company. Dr. Verheugt received speaker fees
from Sanofi-Aventis and received funding for research from Bayer and Eli Lilly. The
supporting pharmaceutical company Sanofi-Aventis had no role in study design, data
collection, data analysis, data interpretation, or writing of the report. Drs. van
Werkum, Heestermans, and ten Berg had full access to all data and had final
responsibility for the decision to submit for publication.
Manuscript received August 21, 2008; revised manuscript received December 15,
2008, accepted December 18, 2008.
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 hampered, however, by small sample size,
retrospective character of study design, and 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 major-
ity of studies. Furthermore, these studies did not focus on
possible differences in underlying pathophysiological mech-
anisms between: 1) different indications of stent implanta-
tion (stable angina vs. acute coronary syndromes [ACS]);
and 2) early versus late ST.
Because recognition of risk factors attributable to ST
might 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, non–
1400 van Werkum et al. JACC Vol. 53, No. 16, 2009
Predictors of Coronary Stent Thrombosis April 21, 2009:1399–409

Abbreviations ST-segment elevated myocar- continued indefinitely. The recommended duration of clo-
and Acronyms dial infarction [NSTEMI] and pidogrel therapy after the index PCI varied from 4 weeks
ST-segment elevated myocar- after BMS implantation during elective angioplasty to 3 to
ACS ⴝ acute coronary
syndrome dial infarction [STEMI]) in a 12 months with DES. For patients presenting with ACS,
BMS ⴝ bare-metal stent(s)
“real world” of mixed bare-metal 12 months clopidogrel therapy was recommended, regard-
stent (BMS) and drug-eluting less of the stent type used. The use of adjunctive devices
CAD ⴝ coronary artery
disease
stent (DES) use. Given the de- (e.g., thrombus aspiration catheter) or glycoprotein IIb/IIIa
CI ⴝ confidence interval
tailed character of our study, we therapy was at the operators’ discretion.
were also able to study the im- Data collection. Detailed data on patient, angiographic,
DES ⴝ drug-eluting stent(s)
pact of the clopidogrel discon- and procedural characteristics for both the cases and control
HR ⴝ hazard ratio
tinuation on the occurrence of subjects were collected. Comprehensive information about
IVUS ⴝ intravascular ST at the different time points
ultrasound
the use of antithrombotic therapy (i.e., aspirin, clopidogrel,
after the index procedure. Coumadin) at the time of the index PCI was also collected.
LVEF ⴝ left ventricular
ejection fraction The duration of clopidogrel use as well as aspirin compli-
Methods ance after patient discharge was assessed with telephonic
NSTEMI ⴝ non–ST-segment
elevated myocardial Study design and population. patient interview as well as data from pharmacy records (the
infarction The Dutch stent thrombosis reg- date of clopidogrel dispensed and the number of days
PCI ⴝ percutaneous istry is a large-scale, multi-centre supplied for each dispense). In case of disagreement, the
coronary intervention
study conducted in 3 high-volume pharmacy data were used for the analysis.
ST ⴝ stent thrombosis centers in the Netherlands (⬎2,500 Angiographic analysis. Angiograms of both the cases and
STEMI ⴝ ST-segment interventions/center/year). All con- the control subjects were reviewed by 2 experienced inter-
elevated myocardial
secutive patients with an angio- ventional cardiologists who were blinded to the objectives of
infarction
graphically confirmed ST pre- this study and outcome data. Calcification was identified as
TIMI ⴝ Thrombolysis In
senting to the participating centers readily apparent radio-opacities within the vascular wall.
Myocardial Infarction
from January 2004 to February Angiographic thrombus was defined as a filling defect seen
2007 were enrolled. Stent throm- in multiple projections surrounded by contrast in the ab-
bosis was defined according to the Academic Research Con- sence of calcification. Angiographically visible, uncovered
sortium criteria for “definite” ST (8). Clinical criteria consisted dissections were graded according to the modified classifi-
of a new episode of chest pain and/or ischemic electrocardio- cation of the Heart, Lung, and Blood Institute (9). Given
graphic changes and/or increase of cardiac biomarkers release. the relatively low incidence of coronary dissections, the
Angiographic criteria consisted of partial or complete occlusion patient population was analyzed on the basis of the presence
within the previously implanted stent with evidence of fresh or absence of any dissection type. The sizing of the
thrombus. On the basis of the elapsed time since stent implanted coronary stent(s) was evaluated by visual esti-
implantation, ST was classified as acute (intraprocedural or mate. It is important to note that the stent deployment was
within 24 h of the procedure), subacute (from 24 h to 30 days), judged on the basis of angiographic appearance and not by
late (⬎30 days to 1 year), or very late (⬎1 year). Acute and quantitative coronary analysis or intravascular ultrasound
subacute ST were also defined as early ST. Likewise, late and (IVUS) analysis. Undersizing of the coronary stent(s) was
very late ST were defined as late ST. considered significant as 1 of the following criteria was met:
MATCHED CONTROL GROUP. Patients who underwent percu- 1) the stent to the reference segment diameter ratio was ⬍1;
taneous coronary intervention (PCI) with stent implanta- 2) inappropriate alignment of the coronary stent with the
tion but with no evidence of ST during follow-up were coronary vessel wall; and 3) mismatch in post-deployment
recruited and served as control subjects in a 2:1 ratio. stent dimensions in relation to the proximal and distal
Control subjects were individually matched to case subjects segments of the target vessel.
by the following criteria: 1) similar indication (either stable The presence of intermediate coronary artery disease
angina or ACS [NSTEMI, STEMI]) for the index-PCI (CAD), defined as a visually estimated percentage of coro-
procedure; 2) same date of the index PCI procedure (⫾1 day nary stenosis of ⱖ50% but ⱕ70%, proximal and distal to the
in a minority of STEMI patients); and 3) same performing stented segment(s) of the target vessel were also scored.
institution. Statistical analysis. Continuous variables were presented
Procedural details and adjunctive medical therapy. The as mean ⫾ SD and were compared with the Student t test
PCI was performed by standard techniques via the femoral or Mann-Whitney U test. The chi-square or Fisher exact
approach in most cases. During PCI, patients were antico- test was used to analyze differences in categorical variables.
agulated with 70 IU/kg of unfractionated heparin. All Conditional logistic regression analysis was performed to
patients were treated with aspirin (80 to 100 mg) before determine independent predictors of ST. Selected variables
PCI and were loaded with clopidogrel (300 to 600 mg) if were first entered into the univariate analysis. Variables with
they were not taking maintenance therapy. Aspirin was p ⬍ 0.05 by univariate analysis were then entered in the
JACC Vol. 53, No. 16, 2009
April 21, 2009:1399–409
conditional logistic regression analysis for identification of
predictors of ST.
To study the impact of the determinant “lack of clopi-
dogrel therapy at different time points after the index PCI
(⬍24 h, 1 to ⱕ30 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 control subjects were also further subdivided into 3
groups: 1) those who were taking clopidogrel at the (“vir-
tual”) time of ST; 2) those who had discontinued the
clopidogrel within 14 days before the ST; and 3) those who
had discontinued the clopidogrel longer than 14 days before
the ST (it is important to note that we also made an attempt
to perform a sensitivity analysis with varying time-intervals
for the time between clopidogrel cessation and the ST;
however, due to the relatively small patient groups with late
and very late ST who discontinued the clopidogrel treat-
ment, no reliable estimates could be provided when the time
interval between clopidogrel cessation and the occurrence of
ST exceeded 14 days; for the first 14 days, the hazard ratio
[HR] remained relatively constant [data not shown]).
The independent “baseline” predictors of ST from con-
ditional 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.
Results
During the study period, a total of 21,009 patients under-
went stent implantation in the participating hospitals. A
total of 31,065 stents were implanted (19,840 BMS and
11,225 DES). As expected, there were significant differ-
ences in age, prevalence of cardiovascular risk factors, lesion
characteristics, and the prevalence of other clinical comor-
bidities between patients who received a BMS and patients
who received a DES (Table 1). During a median follow-up
of 30.9 months (25th to 75th percentiles: 23.6 to 41.9
months), 437 patients (2.1%) presented with an angio-
graphic 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 STs
were related to a BMS (cumulative incidence: 2.2%), 152
stent thromboses were related to a DES (cumulative inci-
dence: 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 2 different types of coronary stents: p ⫽ 0.38).
We were able to match 866 control subjects to the case
subjects (99.0%). Detailed clinical, procedural, and angio-
graphic features of the patients with ST and the matched
control subjects are described in Table 2.
van Werkum et al. 1401
Predictors of Coronary Stent Thrombosis
Comprehensive risk-factor identification: all cases versus
all matched control subjects. Independent clinical, proce-
dural, and angiographic predictors of ST when comparing
all cases with all matched control subjects in multivariate
analysis are depicted in Figure 1. Cessation of clopidogrel at
various time points, undersizing, present malignant disease,
the presence of intermediate CAD proximal to the culprit
lesion, suboptimal procedural result (Thrombolysis In Myo-
cardial Infarction [TIMI] flow grade ⬍3 after PCI), uncov-
ered dissection, bifurcation stenting, left ventricular ejection
fraction (LVEF) ⬍30%, peripheral artery disease, the pres-
ence of intermediate CAD distal to the culprit lesion, no
aspirin therapy, diabetes mellitus, use of any DES, and
younger age were associated with the occurrence of ST.
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 of 11.207
patients, cumulative incidence: 1.00%). However, the cu-
mulative incidence of ST was higher when the indication for
index stent implantation was unstable angina/NSTEMI (72
of 3,960 patients, cumulative incidence: 1.8%) and STEMI
(252 of 5,842, cumulative incidence: 4.3%). The timing of
ST was also significantly different throughout the different
indications for stent implantation (p ⫽ 0.0003). The
STEMI patients experienced an early ST significantly more
often (79% of all STs in STEMI patients were early vs. 65%
of all STs in stable angina and NSTEMI patients), whereas
the proportion of late and very late ST was higher in the
stable angina and NSTEMI group.
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 CAD proximal to the culprit lesion, malignant
disease, suboptimal procedural result (TIMI flow grade ⬍3
after PCI), LVEF ⬍30%, uncovered dissection, multivessel
disease, left descending coronary artery 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 grade
⬍3 after PCI), uncovered dissection, the presence of inter-
mediate CAD proximal to the culprit lesion, bifurcation
lesion, any DES, no aspirin therapy, LVEF ⬍30%, the
presence of intermediate CAD distal to the culprit lesion,
and multivessel disease. Of note, periprocedural use of
glycoprotein IIb/IIIa therapy for the indication ACS (in-
cluding STEMI) was associated with a reduction of ST. It is
important to note that the time-varying covariable “cessa-
tion of clopidogrel” was not included in these multivariate
models.
Risk factors for early ST and late ST. Almost 75% of the
STs occurred within 30 days after stent implantation. Figure 3
displays the independent predictors of early ST (ⱕ30 days
1402 van Werkum et al. JACC Vol. 53, No. 16, 2009
Predictors of Coronary Stent Thrombosis April 21, 2009:1399–409

BMS Versus DES

Table 1 BMS Versus DES

Characteristics DES and Mixed Stents (n ⴝ 418) BMS (n ⴝ 885) p Value

Clinical factors
Female/total (%) 123/416 (29.6) 220/883 (24.9) 0.0797
Age, yrs 60.2 ⫾ 12.0 62.7 ⫾ 11.7 0.0004
Body mass Index, kg/m2 27.0 ⫾ 4.1 27.2 ⫾ 3.9 0.5379
Current smoking/total (%) 259/418 (62.0) 546/885 (61.7) 0.9513
History/total (%)
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
PAD 30/418 (7.2) 74/885 (8.4) 0.5119
MDRD eGFR ⬍60 ml/min/1.73 m2 68/368 (18.5) 143/754 (19.0) 0.8710
LVEF/total (%)
⬎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/total (%)
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/total (%)
ACC/AHA B2 or C 281/418 (67.2) 569/885 (64.3) 0.3189
Severe calcification 55/418 (13.2) 94/885 (10.6) 0.1919
Bifurcation lesion 171/418 (40.9) 265/885 (29.9) 0.0001
Lesion in coronary ostium 10/410 (2.4) 25/871 (2.9) 0.7174
Excentric lesion 46/410 (11.2) 102/869 (11.7) 0.8516
Chronic total occlusion 17/407 (4.2) 10/861 (1.2) 0.0012
Visible thrombus 179/411 (43.6) 576/868 (66.4) ⬍0.0001
Tortuosity 9/418 (2.2) 24/885 (2.7) 0.7060
Multivessel disease 122/418 (29.2) 261/885 (29.5) 0.9481
Coronary 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
Vein graft 8/418 (1.9) 18/885 (2.0) 1.0000

Continued on next page

after the index PCI) with associated odds ratios and 95%
confidence interval (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 grade ⬍3 after PCI), the
presence of intermediate CAD proximal to the culprit
lesion, present malignant disease, no aspirin, LVEF ⬍30%,
bifurcation lesion, the presence of intermediate CAD distal
to the culprit lesion, any DES, and total number of stents.
Glycoprotein IIb/IIIa was protective for the occurrence of
early ST.
The following determinants were independently associ-
ated with the occurrence of late ST: undersizing, present
malignant disease, the presence of intermediate CAD prox-
imal 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.
The influence of antiplatelet therapy on the occurrence
of ST. The proportion of cases and matched control
subjects that were receiving clopidogrel therapy for the
time-frames of the different categories of ST is presented in
Figure 4. In detail, a total of 134 (30.7%) cases were not
taking clopidogrel therapy at the time of the ST. Of these,
in 9 of 140 (6.4%) patients presenting with an acute ST, the
clopidogrel was erroneously not initiated; 30 of 179 (16.7%)
JACC Vol. 53, No. 16, 2009 van Werkum et al. 1403
April 21, 2009:1399–409 Predictors of Coronary Stent Thrombosis

Continued
Table 1 Continued

Characteristics DES and Mixed Stents (n ⴝ 418) BMS (n ⴝ 885) p Value

Procedural characteristics/total (%)
TIMI flow grade 3 before PCI 219/418 (52.4) 376/885 (42.5) 0.0009
TIMI flow grade 3 after PCI 377/418 (90.2) 788/885 (89.0) 0.5638
Rescue PCI 15/417 (3.6) 80/885 (9.0) 0.0003
Thrombosuction/aspiration 8/406 (2.0) 31/849 (3.7) 0.1198
PCI for restenosis 33/418 (7.9) 13/885 (1.5) ⬍0.0001
GP IIb/IIIa therapy 107/405 (26.4) 319/850 (37.5) 0.0001
Clopidogrel 416/418 (99.5) 883/884 (99.9) 0.2428
Aspirin 384/418 (91.9) 822/884 (93.0) 0.4960
Coumadin 35/417 (8.4) 62/883 (7.0) 0.4286
No-reflow 9/418 (2.2) 28/885 (3.2) 0.3733
Dissection 40/418 (9.6) 87/885 (9.8) 0.9206
Undersizing 44/418 (10.5) 55/885 (6.2) 0.0072
Nonculprit stenosis distal of the stented segment that is left untreated (⬎50%) 30/418 (7.2) 78/885 (8.8) 0.335
Nonculprit stenosis proximal of the stented segment that 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 ⬍0.0001
Minimal stent diameter*, mm 2.93 ⫾ 0.4 3.16 ⫾ 0.4 ⬍0.0001
Maximal balloon pressure, atm 14.2 ⫾ 2.5 13.7 ⫾ 2.5 0.0005

*The “predicted” stent diameter of the smallest implanted coronary stent after final maximal deployment pressure.
ACC/AHA ⫽ American College of Cardiology/American Heart Association; BMS ⫽ bare-metal stent(s); CABG ⫽ coronary artery bypass grafting; CAD ⫽ coronary artery disease; DES ⫽ drug-eluting stent(s);
DM ⫽ diabetes mellitus; GP ⫽ glycoprotein; LAD ⫽ left anterior descending artery; LVEF ⫽ left ventricular ejection fraction; MDRD eGFR ⫽ Modification of Diet in Renal Disease Study Equation for Estimating
Glomerular Filtration Rate; MI ⫽ myocardial infarction; NSTEMI ⫽ non–ST-segment elevated myocardial infarction; PAD ⫽ peripheral artery disease; PCI ⫽ percutaneous coronary intervention; RCA ⫽ right
coronary artery; RCX ⫽ right circumflex artery; STEMI ⫽ ST-segment elevated myocardial infarction; TIMI ⫽ Thrombolysis In Myocardial Infarction; UAP ⫽ unstable angina pectoris.

patients with a subacute ST had discontinued the clopi-
dogrel for a median of 5 days (interquartile range: 3 to 7
days); 39 of 58 (67.2%) patients with a late ST had
discontinued the clopidogrel for a median of 13 days
(interquartile range: 7 to 61 days); and 56 of 59 (94.9%)
patients with a very late ST had discontinued the clopi-
dogrel for a median of 200 days (interquartile range: 23 to
981 days).
After applying the exact elapsed time-frame between the
index PCI and ST for every case to their matched control
subjects, we show that a significant higher proportion of
control subjects were taking clopidogrel therapy at the
“virtual time” of occurrence of ST (Fig. 4). 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 to 167.8). Likewise, the lack of clopi-
dogrel therapy at the time of ST between 30 days and 6
months after the index PCI was also linked to the occur-
rence of ST (HR: 4.6, 95% CI: 1.4 to 15.3). Multivariate
Cox proportional hazard analysis also found that discontin-
uation of clopidogrel therapy after 6 months from the index
stent implantation was a predictor of ST (HR: 5.9, 95% CI:
1.7 to 19.8).
Alternatively, given the fact that clopidogrel irrevers-
ibly inhibits the human platelet throughout its entire
lifespan (10 to 12 days), we hypothesized that cessation
of clopidogrel ⬍14 days before the ST would reveal the
temporal relationship between the discontinuation of
clopidogrel and ST. After introducing this time-varying
covariate in the multivariate Cox proportional hazard
model, “cessation of clopidogrel within 14 days before
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
to 173.3). Similarly, “cessation of clopidogrel within 14
days before 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 to 198.3). The
number of events beyond the 6-month 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 ST 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 with those who had received
a BMS (odds ratio for DES: 1.88, 95% CI: 1.21 to 2.94,
p ⫽ 0.0052).
A significantly higher percentage of the patients with ST
did not use aspirin therapy at the time of the index as
compared with their matched control (13.1% vs. 4.5%, p ⬍
0.0001). The predominant reasons for no aspirin treatment
were Coumadin use in 85 of 96 (84.4%) patients and allergy
to aspirin in 7 of 96 (7.3%) patients. Multivariate logistic
regression analysis identified that the absence of aspirin
therapy was also a strong independent predictor of ST (HR:
1.91 95% CI: 1.01 to 3.88, p ⫽ 0.0487).
1404 van Werkum et al. JACC Vol. 53, No. 16, 2009
Predictors of Coronary Stent Thrombosis April 21, 2009:1399–409

Baseline Clinical, Lesion, and Procedural Characteristics

Table 2 Baseline Clinical, Lesion, and Procedural Characteristics

Cases (n ⴝ 437) Matched Control Subjects (n ⴝ 866) p Value

Clinical characteristics/total (%)
Female/total (%) 108/437 (24.7) 235/862 (27.3) 0.3512
Age, yrs 61.0 ⫾ 11.8 62.3 ⫾ 11.7 0.0616
Body mass index, kg/m2 27.2 ⫾ 4.1 27.0 ⫾ 3.8 0.5541
Current smoking/total (%) 285/437 (65.2) 520/866 (60.1) 0.0705
History/total (%)
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
PAD 48/437 (11.0) 56/866 (6.5) 0.0065
MDRD eGFR ⬍60 ml/min/1.73 m2 73/407 (17.9) 138/715 (19.3) 0.6336
LVEF/total (%)
⬎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) ⬍0.0001
Indication/total (%)
Stable angina 113/437 (25.9) 242/866 (27.9) Matched item
UAP/NSTEMI 72/437 (16.5) 124/866 (14.3) Matched item
STEMI 252/437 (57.7) 500/866 (57.7) Matched item
Lesion characteristics/total (%)
ACC/AHA B2 or C 334/437 (76.4) 516/866 (59.6) ⬍0.0001
Severe calcification 85/437 (19.5) 64/866 (7.4) ⬍0.0001
Bifurcation lesion 228/437 (51.7) 210/866 (24.3) ⬍0.0001
Lesion in coronary ostium 10/420 (2.4) 25/861 (2.9) 0.7159
Excentric lesion 56/419 (13.4) 92/860 (10.7) 0.1636
Chronic total occlusion 11/417 (2.6) 16/851 (1.9) 0.4098
Visible thrombus 260/418 (62.2) 495/861 (57.5) 0.1152
Tortuosity 11/437 (2.5) 22/866 (2.5) 1.0000
Multivessel disease 181/437 (41.4) 202/866 (23.3) ⬍0.0001
Coronary 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
Vein graft 5/437 (1.1) 21/866 (2.4) 0.1435

Continued on next page

Discussion factors (such as present malignancy, severity of atheroscle-

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
rotic 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 through-
out the years of patient recruitment (2004 to 2007) allowed
us to comprehensively study the impact of early clopidogrel
cessation after stent implantation. As expected, lack of
JACC Vol. 53, No. 16, 2009 van Werkum et al. 1405
April 21, 2009:1399–409 Predictors of Coronary Stent Thrombosis

Continued
Table 2 Continued

Cases (n ⴝ 437) Matched Control Subjects (n ⴝ 866) p Value

Procedural characteristics/total (%)
BMS 270 (61.8%) 614 (70.9%) 0.0015
DES 152 (34.8%) 238 (27.5%)
Mixed stent(s) 15 (34.3%) 14 (1.6%)
TIMI flow grade 3 before PCI 178/437 (40.7) 417/866 (48.2) 0.0114
TIMI flow grade 3 after PCI 346/437 (79.2) 819/866 (94.6) ⬍0.0001
Rescue PCI 35/436 (8.0) 60/866 (6.9) 0.4986
Thrombosuction/aspiration 14/417 (3.4) 25/836 (3.0) 0.7315
PCI for restenosis 20/437 (4.6) 26/866 (3.0) 0.1543
No-reflow 17/437 (3.9) 20/866 (2.3) 0.1135
Dissection 75/437 (17.2) 52/866 (6.0) ⬍0.0001
Undersizing 79/437 (18.1) 20/866 (2.3) ⬍0.0001
Nonculprit stenosis distal of the stented segment that is left untreated (⬎50%) 62/437 (14.2) 46/866 (5.3) ⬍0.0001
Nonculprit stenosis proximal of the stented segment that 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 ⬍0.0001
Total number of stents 1.54 ⫾ 0.82 1.34 ⫾ 0.67 ⬍0.0001
Minimal stent diameter*, mm 3.0 ⫾ 0.4 3.13 ⫾ 0.4 ⬍0.0001
Maximal balloon pressure, atm 13.7 ⫾ 2.5 13.9 ⫾ 2.5 0.1823
Antithrombotic medication at the time of the index PCI
GP IIb/IIIa therapy 136/429 (31.7) 290/826 (35.1) 0.2331
Clopidogrel 428/437 (97.9) 861/866 (99.4) 0.97
Aspirin 379/436 (86.9) 827/866 (95.5) ⬍0.0001
Coumadin 48/435 (11.0) 49/865 (5.7) 0.0007

*The “predicted” stent diameter of the smallest implanted coronary stent after final maximal deployment pressure.
Abbreviations as in Table 1.

Figure 1 Independent Risk Factors for ST

A comparison of the total group of patients with stent thrombosis (ST) with all matched-control subjects. Represented by hazard ratio (HR) and 95% confidence interval
(CI). ASA ⫽ acetyl salicylic acid; CAD ⫽ coronary artery disease; DES ⫽ drug-eluting stent(s); DM ⫽ diabetes mellitus; LVEF ⫽ left ventricular ejection fraction; PAD ⫽
peripheral artery disease; PCI ⫽ percutaneous coronary intervention; TIMI ⫽ Thrombolysis In Myocardial Infarction.
1406 van Werkum et al. JACC Vol. 53, No. 16, 2009
Predictors of Coronary Stent Thrombosis April 21, 2009:1399–409

Figure 2 Independent Risk Factors for ST for the Different Indications of Index Stent Implantation

(A) Cases and matched controls with stable angina as indications for index PCI. (B) Cases and matched controls with acute coronary syndrome
as indication for index PCI. Represented by odds ratio (OR) and 95% CI. GP ⫽ glycoprotein; LAD ⫽ left anterior descending; other abbreviations as in Figure 1.

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 discon-
tinuation 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 that the lack of
clopidogrel therapy (but not necessarily cessation of clopi-
dogrel within the 14 days preceding the ST) beyond 6 months
after index PCI was a predictor of ST. A likely explanation for
this difference might be that previous studies were hampered
JACC Vol. 53, No. 16, 2009
April 21, 2009:1399–409
Figure 3 Independent Risk Factors for Early (<30 Days) and Late (>30 Days) ST
(A) Predicators of early (ⱕ30 days) stent thrombosis. (B) Predicators of late (⬎30 days)
stent thrombosis. Represented by OR and 95% CI. Abbreviations as in Figures 1 and 2.
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 as to why “lack of clopidogrel
therapy after 6 months from the index stent implantation”
van Werkum et al. 1407
Predictors of Coronary Stent Thrombosis
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 the loss of protection by clopidogrel
therapy rather than a “rebound in platelet reactivity” might
explain these findings.
Undersizing of the coronary stent was the second stron-
gest predictor of ST in our study. Indeed, previous studies
have elucidated the importance of correct sizing of coronary
1408 van Werkum et al.
Predictors of Coronary Stent Thrombosis
Figure 4 Adherence to Clopidogrel Therapy
Proportion of cases and their matched control subjects taking clopidogrel therapy
according to the elapsed time between stent implantation and the occurrence of stent thrombosis (ST).
stents, in particular in patients with a high thrombotic
burden with subsequent vasoconstriction or severe and
diffuse target vessel disease (12–16). Previous reports have
suggested that, despite improvements in techniques and
materials in the last decade, the incidence of incomplete
stent deployment and undersizing ranges from 20% to 30%,
and this percentage is even higher when assessed by IVUS
(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 under-
sizing 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. How-
ever, incorrect judgment of the true coronary vessel size by the
performing operator is also 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. None-
theless, the use of a DES was not independently associated
JACC Vol. 53, No. 16, 2009
April 21, 2009:1399–409
with late or very late ST. In contrast, any DES use was
independently associated with ST in both the all-cases
versus all-control subjects 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)
etiologies 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, 3 control patients
were excluded from analysis because they were admitted for
ST in another nonparticipating hospital during follow-up.
However, given the size of the control group (2:1 ratio), the
random selection of control subjects and the extent of differ-
ences in clinical procedural and angiographic findings between
cases and control subjects, it is unlikely that the results would
have changed considerably by increasing the number of control
JACC Vol. 53, No. 16, 2009
April 21, 2009:1399–409
subjects. 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
might question our evaluation of the sizing of coronary stents
by simple means of eyeballing instead of using sophisticated
techniques such as IVUS or quantitative coronary analysis.
Nonetheless, visual estimation was able to detect undersizing in
18.1% of the cases and in only 2.3% of the control subjects,
which makes it a valuable tool.
Conclusions
We identified several important predictors of ST in the
contemporary era of mixed DES and BMS use. Discon-
tinuation of clopidogrel, undersizing of the coronary stent,
presence of intermediate CAD proximal to the culprit lesion,
and concomitant malignant disease were the strongest predic-
tors of ST. Risk factors for ST also vary throughout the
different indications for PCI (stable angina vs. ACS) and differ
for the different categories of ST (early vs. late ST).
Reprint requests and correspondence: Dr. Jurriën M. ten Berg,
Department of Cardiology, St. Antonius Hospital, P.O. Box 2500,
3435 CM Nieuwegein, the Netherlands. E-mail: berg03@
antonius.net.
REFERENCES
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
van Werkum et al. 1409
Predictors of Coronary Stent Thrombosis
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 morpho-
logic 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, pre-
dictors and clinical outcome. J Am Coll Cardiol 1997;29:6 –12.
13. Takano Y, Yeatman LA, Higgins JR, et al. Optimizing stent expan-
sion 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 deploy-
ment? 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 angiogra-
phy and intravascular ultrasound when analysing small coronary
arteries. Eur Heart J 2002;23:247–54.
Key Words: bare-metal stent y clopidogrel y drug-eluting stent y
predictors y stent thrombosis.