From the Department of Medicine II, Johannes Gutenberg University, Mainz,
Germany.
Correspondence to Hans-Jürgen Rupprecht, MD, Department of Medicine II, Johannes Gutenberg-University, Langenbeckstr 1, D-55101 Mainz, Germany.
Methods and Results—Sixty-one patients with successful
implantation of a single Palmaz-Schatz stent in a native
coronary artery were randomly assigned to either group A
(aspirin 300 mg/d+ticlopidine 2x250 mg/d), group B (ticlopidine 2x250
mg/d), or group C (aspirin 300 mg/d). Platelet activation was
evaluated on days 1, 7, and 14 by flow cytometry measurement of
expression of CD62p (p-selectin) and the binding of fibrinogen to the
platelet surface glycoprotein IIb/IIIa receptor.
Platelet aggregation was induced by addition of ADP or collagen.
Differences between treatment groups were compared by ANOVA. Between
days 1 and 14, we observed a significant decrease in collagen-induced
platelet aggregation in group A (62.2±2.5% versus 36.9±3.1%),
whereas an increase was seen in group B (58.3±2.5% versus
67.7±3.2%) and no change was seen in group C
(P<.0001). The ADP-induced aggregation declined
significantly in group A (74.7±1.4% versus 55.3±2.6%), whereas a
delayed reduction was seen in group B (72.0±3.0% versus 52.6±4.2%)
and no change was seen in group C (P=.0017). The CD62p
expression declined significantly in groups A (68.2±2.7% versus
41.3±2.7%) and B (64.8±2.9% versus 39.3±3.5%) but not in group C
(P<.0001). Moreover, the fibrinogen binding decreased
significantly in group A (61.0±4.3% versus 36.3±4.2%) and with
delay in group B (58.3±2.2% versus 39.4±3.0%), whereas no
alterations were seen in group C (P=.012).
Conclusions—Our results demonstrate synergistic and accelerated
platelet inhibitory effects of ticlopidine plus aspirin
in patients after stent implantation compared with a monotherapy with
either ticlopidine or aspirin alone.
Bearing in mind the inherent risks and side effects of ticlopidine and
aspirin, especially the risk of neutropenia for the former and the risk
of gastrointestinal bleeding for the latter, the question as to whether
aspirin or ticlopidine alone or a combination of both might be
sufficient to counteract platelet activation and aggregation after
stenting deserves further investigation. Therefore we randomly assigned
patients after stent implantation to a treatment with aspirin alone,
ticlopidine alone, or a combination of both to compare magnitude and
temporal changes of markers of platelet activation in flow
cytometry and aggregation within the first 2 weeks after stent
implantation.
Patient Selection
Patients with bleeding disorders, contraindications to treatment with
aspirin and/or ticlopidine, abnormal blood cell count, childbearing
potential, acute myocardial infarction, depressed left
ventricular function, renal insufficiency, or an indication
for oral anticoagulation were excluded from the study. Eligible
patients adhering to the prespecified criteria were randomly assigned
to the treatment groups immediately after the intervention and after
written informed consent was obtained. The study was performed
according to the Declaration of Helsinki and the protocol was approved
by the local ethical committee.
Intervention and Adjunctive Concomitant Therapy
Heparin was administered intravenously for 24 hours, when
the pressure bandage was removed to maintain a partial thromboplastin
time of 60 to 90 seconds.
Antiplatelet Therapy
Laboratory Investigations
Blood Sampling
Platelet Aggregation Studies
Flow Cytometric Analysis
For flow cytometric analysis, the platelet gate was
identified by staining control platelets with an CD61 antibody
(clone SZ21, Dianova, dilution 1:100), an epitope constitutively
expressed on the platelet surface. More than 95% of all cells
measured in the delineated window were CD61 positive in all treatment
groups at all time points. As an isotype control, a mouse anti-human
MHC II antibody (OX6) was used.
Platelet Count
Statistics
For the highest concentration of collagen used (33.3 µg/mL), the
inhibitory effects of the platelet
antagonists were surmounted by the collagen concentration
used (Fig 1B
The ED50 for collagen-induced platelet
aggregation increased significantly from 1.7±0.2 to 3.9±0.7 µg/mL
on day 7 and 5.4±0.9 µg/mL on day 14 in group A (P=.0005;
Fig 2
The ADP-induced aggregation was not significantly different on day 1
between the treatment groups (Fig 3A
A significant reduction of platelet aggregation in group A was
measured irrespective of the ADP concentration used (ADP 20, 3.3, or
1.0 µmol/L; Fig 3B
Platelet Adhesion Molecule Expression
Binding of biotin-labeled fibrinogen to the platelet GPIIb/IIIa
receptors was <5% in all samples measured before activation.
Stimulation of fibrinogen binding by ADP (100 µmol/L) resulted
in a comparable increase in all three groups on day 1 (Fig 5A
Clinical Results
It is the merit of a group of French
investigators2 5 who first demonstrated that a
combination of aspirin and ticlopidine, another antiplatelet drug
that acts by the inhibition of the ADP-induced platelet activation,
was clearly superior to the conventional oral anticoagulation regimen
with regard to a reduction of subacute stent thrombosis. A
randomized single-center trial thereafter reported a reduction of major
adverse cardiac events from 6.2% with oral anticoagulation to 1.5%
with a combined antiplatelet treatment involving ticlopidine and
aspirin.1 This correlated with a reduced stent
occlusion rate of 0.8% compared with 5.4% with anticoagulation. In
addition, the rate of noncardiac events, comprising mainly hemorrhagic
complications, was reduced from 12.3% to 1.2%.1
Major multicenter trials (STARS, FANTASTIC) have confirmed these
results.23 24
Gawaz et al25 recently demonstrated that
platelet activation after coronary stent implantation can
be modified by selection of antithrombotic strategies. He found an
increase in fibrinogen receptor activity in patients receiving oral
anticoagulation compared with a decrease in patients receiving
ticlopidine. Platelet surface expression of CD62p was enhanced in
patients under oral anticoagulation but not in patients treated with
ticlopidine. In another study, Neumann et al26
were able to demonstrate that platelet fibrinogen receptor
expression was an independent predictor of subacute stent
occlusion, whereas prothrombin fragment F1 and F2, sensitive markers of
thrombin generation, and fibrinogen, the final substrate of the
coagulation cascade, did not show a strong correlation to the risk of
stent occlusion.
With regard to potential side effects of either aspirin or ticlopidine,
which is known to cause leukopenia in
To determine whether monotherapy with ticlopidine, aspirin, or a
combination of both agents are equivalent or whether there might be a
meaningful difference, we compared these three treatment strategies in
61 randomly assigned patients and determined the collagen-induced as
well as ADP-induced platelet aggregation immediately after stent
implantation and 1 week and 2 weeks after stent implantation. In
addition, platelet activation was determined by means of the
ADP-induced CD62p expression and the ADP-induced fibrinogen binding to
platelets.
In patients with aspirin monotherapy no change in collagen-induced
platelet activation occurred during the observation period because
all patients were already pretreated with aspirin before stent
implantation. Although the results in the ticlopidine group on day 7
might still be contaminated by the long-lasting effects of aspirin
pretreatment (Fig 1A
Monotherapy with aspirin alone did not alter the ADP-induced
platelet aggregation, whereas monotherapy with ticlopidine led to a
marked decrease in platelet aggregation, pointing out that
ticlopidine in contrast to aspirin acts by inhibition of the
ADP-induced platelet activation. This effect increased over time
during the observation period in the ticlopidine group. The combined
treatment with aspirin and ticlopidine led to a highly significant
suppression of ADP-induced platelet aggregation, which was already
completely present 1 week after randomization. Thus the combination
of both antiplatelet agents obviously caused a faster inhibition of
the ADP-induced platelet aggregation compared with a monotherapy
with ticlopidine, suggesting a possible role for
thromboxane A2 for the augmentation
of the stimulatory effect of ADP.
The ADP-induced expression of CD62p was not altered during follow-up in
the aspirin group, but a significant reduction of the percentage of
CD62p-positive cells was measured in both the ticlopidine as well as
the aspirin+ticlopidine group, with a trend toward a faster effect in
the latter.
The ADP-induced binding of fibrinogen to the GPIIb/IIIa receptors did
not change in the aspirin group but was markedly reduced in the two
ticlopidine groups. Again, the combined treatment revealed a relevant
decrease of the ADP-induced fibrinogen binding already on day 7,
whereas a comparable effect was seen in the ticlopidine group on day
14.
It is remarkable that the expression of the adhesion molecule CD62p
being necessary for platelet adhesion is reduced to a comparable
magnitude as the aggregation response. This might indicate a possible
role for ticlopidine and aspirin in inhibition of platelet adhesion
processes in vivo. There is recent evidence in the literature that
aspirin might produce an artifact during aggregation in
platelet-rich plasma that is not present if aggregation is
performed in whole blood.28 However, because
platelet aggregation in platelet-rich plasma is a widely
performed and acknowledged test for the evaluation of platelet
activity ex vivo, we used this method, for which many other clinical
studies exist. This is in contrast to whole blood aggregation, which is
rarely used in clinical studies. In addition, we performed flow
cytometric analysis to circumvent the problems with
platelet aggregation in platelet-rich plasma and to involve a
second, independent method for the evaluation of platelet activity
and the inhibitory effects of platelet-active
drugs.
Our results demonstrate a synergistic
platelet-inhibitory effect of ticlopidine plus aspirin
in patients after stent implantation that might be responsible for the
beneficial effects of this drug combination in patients after stent
implantation. The combined inhibition of ADP and
arachidonic acid pathway–dependent platelet
activation antagonized the two most important avenues of platelet
stimulation within the coronary circulation. Whether
clopidrogrel, the likely successor of ticlopidine, yields equivalent
platelet inhibitory effects needs to be shown in future
trials.29 From the above data it can be concluded
that the combination of aspirin and ticlopidine is clearly superior in
terms of platelet aggregation parameters and
platelet activation markers compared with a monotherapy with
ticlopidine or aspirin and thus should be the preferred treatment
strategy after stent implantation.
Received October 31, 1997;
accepted November 25, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation
Abstract
Top
Abstract
Introduction
Results
Discussion
References
Background—This study was performed
to analyze the influence of either aspirin, ticlopidine, or
their combination on platelet activation and aggregation
parameters after stent implantation.
Key Words: stents • platelet aggregation inhibitors • aspirin
Introduction
Top
Abstract
Introduction
Results
Discussion
References
Combined
antiplatelet therapy with ticlopidine and aspirin has been shown to
lower the risk of subacute stent thrombosis compared with
conventional anticoagulant therapy.1 2 3 4 5 This has
enabled stenting to become a breakthrough technology in interventional
cardiology, and the rate of stent implantation now
amounts to 30% to 50% of all procedures in most
centers.6 7
Patients with successful implantation of a single Palmaz-Schatz
stent in a native coronary artery were selected for the study
if there was a low risk for subacute stent thrombosis. This
included a vessel diameter of the stented segment of 
3.0 mm,
absence of thrombus formation before and after stent placement, a TIMI
grade 3 blood flow, absence of a residual dissection, and absence of a
residual lesion >20% within or adjacent to the stent.
All patients received 10 000 IU of heparin. The first 5000 U was
given after arterial puncture and another 5000 U
immediately before guidewire insertion. Palmaz-Schatz stents were
folded by hand on the angioplasty balloon (Europass, Cordis), and
implantation was performed with a pressure of 10 to 16 atm. The
arterial sheath was left in the groin for 12 to 24 hours.
After sheath removal, manual compression of the groin was carried out
until hemostasis occurred. Thereafter, a pressure bandage was applied
for at least 12 hours.
All patients were pretreated with 100 mg aspirin/d for at least 1
week before randomization, with the last drug intake at the day of
percutaneous transluminal coronary angioplasty.
According to the randomization schedule, the patients were attributed
to one of three antiplatelet regimens, starting immediately after
the procedure for a duration of four weeks: group A: aspirin 300
mg/d+ticlopidine 2x250 mg/d, group B: ticlopidine 2x250 mg/d, and
group C: aspirin 300 mg/d. After the initial 4-week treatment period,
antiplatelet therapy was continued with aspirin 100 mg/d.
The following laboratory tests were performed on day 1, day 7, and
day 14 after stent implantation.
Venous blood was withdrawn immediately after patient randomization
before intake of the first dose of study medication, on day 7 and on
day 14 of treatment. Twenty milliliters of blood was drawn by
venipuncture and anticoagulated in acid citrate dextrose
(15% vol/vol; Biostabil, Biotest). Blood was centrifuged for
12 minutes at 180g at room temperature to obtain
platelet-rich plasma. Aliquots of the platelet-rich plasma were
used for platelet aggregation studies, for the preparation of
platelet-poor plasma (centrifugation
1500g, 10 minutes) to calibrate the platelet
aggregometer, and another aliquot for flow cytometric
analysis.
Platelet aggregation was performed in platelet-rich plasma
by addition of ADP or collagen and the alterations in light
transmission were measured photometrically (APACT Aggregometer) and
analyzed automatically. The aggregometer was calibrated for the
difference in light transmission between platelet-poor and
platelet-rich plasma, which was set as 100% by definition.
Alterations in light transmission in response to the respective
aggregating agent were expressed as percentage of light transmission.
ADP (Boehringer Mannheim) was added in concentrations between 1
to 20 µmol/L to facilitate construction of a dose-response curve
and calculation of ED50 values, with 1.0, 3.3,
and 20.0 µmol/L used for each time point. Collagen was used as
the aggregating agent in at least three concentrations of 1.0, 3.3, and
33.3 µg/mL plus additional concentrations if necessary for the
evaluation of a dose-response relation.
Platelet activation was evaluated by flow cytometry
measurement of the surface membrane expression of CD62p (p-selectin,
GMP140) by use of a monoclonal antibody (clone CLBI Cell Systems,
dilution 1: 300) and the binding of fibrinogen to the platelet
glycoprotein (GP)IIb/IIIa receptor.8
Aliquots of platelet-rich plasma were activated by addition
of ADP (1.0, 10, 100 µmol/L), and reaction was terminated after
5 minutes by fixation of the cells with
paraformaldehyde (1%) for 30 minutes.
Platelets were counted in venous blood samples taken in EDTA
by an automatic cell counter (Coulter Instruments).
Continuous data are expressed as mean±SEM. ANOVA for repeated
measures was used for comparisons between different time points and
between treatment groups as well. A value of P<.05 was
considered to indicate a statistically significant difference.
Results
Top
Abstract
Introduction
Results
Discussion
References
Platelet Aggregation Studies
Platelet aggregation ex vivo was induced by addition of
collagen 1.0, 3.3, and 33.3 µg/mL. In Fig 1A
, the results of collagen 3.3 µg/mL
are depicted. The initial values in groups A, B, and C were not
significantly different before initiation of therapy. After 7 days of
therapy, a significant decrease in group A from 62.2±2.5% to
46.2±3.9% was observed. A further decline in platelet aggregation
response to 36.9±3.1% occurred until the end of the observation
period on day 14 (P=.0001). In contrast, in group B a
significant increase in collagen-induced platelet aggregation from
58.3±2.5% to 70.9±3.5% was seen on day 7 when compared with day 1.
During the second week of the observation period, the collagen-induced
platelet aggregation amounted to 67.7±3.2% (P=.005).
In group C there was no significant alteration in collagen-induced
platelet aggregation detectable (P<.0001 for comparison
of treatment groups by ANOVA (Fig 1A). The influence of different
collagen concentrations on platelet aggregation in group A is shown
in Fig 1B.
View larger version (45K):
[in a new window]
Figure 1. A, Time-dependent alterations in collagen-induced
platelet aggregation (collagen 3.3 µg/mL) measured as percentage
of light transmittance in groups A (ticlopidine+aspirin), group B
(ticlopidine), and group C (aspirin). Numbers within bars
represent mean±1 SEM. Probability values relate to differences
between different time points in each treatment group. Comparison of
treatment groups by ANOVA revealed a value of P<.0001.
B, Dose-dependent platelet stimulatory effects of collagen (33.3,
3.3, or 1.0 µg/mL) in patients of group A receiving ticlopidine and
aspirin. Numbers within bars represent mean±1 SEM. Probability
values relate to differences between different time points in each
treatment group. 
). In the lower concentrations (1.0 and 3.3 µg/mL), a
significant decrease in platelet aggregation response was seen
during the observation period. ). In group B a slight decrease of
the ED50 was seen after withdrawal of the routine
aspirin medication. In contrast, the ED50 was
unaltered in patients receiving aspirin only (P<.0001 for
comparison of treatment groups by ANOVA).
View larger version (15K):
[in a new window]
Figure 2. Time-dependent alterations in the ED50
for collagen-induced platelet aggregation in patients of group A
(ticlopidine+aspirin, dashed line), group B (ticlopidine, black line),
and group C (aspirin, gray line). Data represent mean±1 SEM.
Probability values relate to differences between different time points
in each treatment group. Comparison of treatment groups by ANOVA
revealed a value of P<.0001. ).
Aggregation declined in group A from 74.7±1.4% on day 1 to
57.0±2.6% on day 7 and to 55.3±2.6% on day 14 (P=.0001).
In group B only a moderate reduction of the ADP-induced platelet
aggregation from 72.0±3.0% on day 1 to 61.6±3.0% on day 7 and a
further reduction to 52.6±4.2% on day 14 was measured
(P=.0002). In group C no significant changes compared with
the baseline value were noted (P=.0017 for comparison of
treatment groups by ANOVA).
View larger version (48K):
[in a new window]
Figure 3. A, Time-dependent alterations in ADP-induced
platelet aggregation (ADP 20 µmol/L) measured as percentage
of light transmittance in group A (ticlopidine+aspirin), group B
(ticlopidine), and group C (aspirin). Numbers within bars
represent mean±1 SEM. Probability values relate to differences
between different time points in each treatment group. Comparison of
treatment groups by ANOVA revealed a value of P<.0017.
B, Dose-dependent platelet stimulatory effects of ADP (20.0, 3.3,
or 1.0 µmol/L) in patients of group A receiving ticlopidine and
aspirin. Numbers within bars represent mean±1 SEM. Probability
values relate to differences between different time points in each
treatment group. ).
As a marker of platelet adhesion molecule expression, the
ADP-induced expression of CD62p was measured. Basal CD62p expression in
the absence of stimulating agents was <5% of positive cells in all
groups. Activation of platelets with ADP (100 µmol/L)
resulted in an increase in CD62p-positive cells, which was not
different for the three treatment groups (Fig 4A). In group A, CD62p expression
declined from 68.2±2.7% to 43.7±3.1% on day 7 and to 41.3±2.7% on
day 14 (P=.0001). In group B the percentage of positive
cells decreased from 64.8±2.9% to 46.7±3.8% on day 7 and to
39.3±3.5% on day 14 (P=.0001). In contrast, no significant
changes were noted in group C during the 2-week observation period
(P<.0001 for comparison of treatment groups by ANOVA). The
number of CD62p-positive cells in group A decreased significantly,
independent of the ADP concentrations used (Fig 4B).
View larger version (43K):
[in a new window]
Figure 4. A, CD62p (p-selectin)-positive platelets after
stimulation with ADP (100 µmol/L) for patients in group A
(ticlopidine+aspirin), group B (ticlopidine), and group C (aspirin).
Numbers within bars represent mean±1 SEM. Probability values
relate to differences between different time points in each treatment
group. Comparison of treatment groups by ANOVA revealed a value of
P<.0001. B, CD62p (p-selectin)-positive platelets
after stimulation with ADP (100, 10, or 1 µmol/L) for patients
in group A (ticlopidine+aspirin). Numbers within bars represent
mean±1 SEM. Probability values relate to differences between different
time points in each treatment group. ). In group A fibrinogen binding
decreased significantly from 61.0±4.3% on day 1 to 40.8±3.8% on day
7 and to 36.3±4.2% on day 14 (P=.0001). In group B, a
moderate reduction of positive cells from 58.3±2.2% on day 1 to
52.5±4.2% on day 7 was observed, with a further decrease on day 14 to
39.4±3.0% (P=.0001). In contrast, in group C there were no
significant time-dependent alterations in fibrinogen binding
(P=.012 for comparison of treatment groups by ANOVA). The
fibrinogen binding decreased significantly in group A only when an ADP
concentration of 100 µmol/L was used (Fig 5B).
View larger version (41K):
[in a new window]
Figure 5. A, Fibrinogen receptor (glycoprotein
IIb/IIIa) occupation measured as binding of biotin-labeled fibrinogen
and its time-dependent alterations after stimulation with ADP (100
µmol/L) for patients in group A (ticlopidine+aspirin), group B
(ticlopidine), and group C (aspirin). Numbers within the bars
represent mean±1 SEM. Probability values relate to differences
between different time points in each treatment group. Comparison of
treatment groups by ANOVA revealed a value of P=.012. B,
Platelet fibrinogen receptor (glycoprotein IIb/IIIa)
occupation after stimulation with ADP (100, 10, or 1 µmol/L) for
patients in group A (ticlopidine+aspirin). Numbers within bars
represent mean±1 SEM. Probability values relate to differences
between different time points in each treatment group.
With regard to clinical or lesion characteristics, there were no
significant differences between the three groups of patients (Table).
The patients randomized for this study did not experience any angina
attacks, infarctions, subacute stent thromboses, or any other
adverse cardiovascular events. One major bleeding event
with a drop in hemoglobin concentration by 4 mg/dL occurred at the
groin puncture site of one patient in group C; however, a transfusion
of red blood cells was not required. There was no necessity for repeat
interventions during the follow-up period of 2 weeks or until the
medication was altered to aspirin 100 mg/d 4 weeks after stenting. As a
safety measure with regard to the ticlopidine administration, white
blood cell counts of all patients involved in this study were taken 2,
4, and 6 weeks after intervention. No clinically relevant alterations
in white blood cell counts were detected.
View this table:
[in a new window]
Table 1. Patient and Lesion Characteristics
Discussion
Top
Abstract
Introduction
Results
Discussion
References
Since its introduction by Sigwart et al,9
coronary stent implantation has been hampered for many years by
the occurrence of subacute stent thromboses and bleeding
complications.6 7 10 11 Certain investigators
demonstrated a reduction of the aforementioned complications by means
of improved stent deployment techniques and more adequate
postprocedural management.3 8 12 13 14 15 16 17 18 19 20 21 22 
1% of all patients and skin
rash and diarrhea in a sizeable number of patients, the question arose
as to whether a combined treatment with aspirin and ticlopidine would
be necessary or whether a monotherapy would be sufficient to counteract
the problem of stent thrombosis. Especially in the light of improved
implantation techniques with high-pressure balloon inflation and
intravascular ultrasound guidance, it was suggested that the
antithrombotic strategy might not be of major concern after optimal
stent deployment.18 An observational trial with
ticlopidine alone for 3 to 6 months and subcutaneous heparin for 1 week
revealed a subacute stent thrombosis rate of 4.2%, a myocardial
infarction rate of 1.2%, and a death rate of
2%.15 A randomized trial comparing a monotherapy
of aspirin with a combination of ticlopidine and aspirin was
prematurely terminated because 3 of 103 patients in the aspirin group
died compared with none of 123 patients in the ticlopidine+aspirin
group.27 Although the total event rate (3.9%
versus 0.8%) did not reveal a statistically significant difference,
the authors believed that it was not justified to withhold ticlopidine
from their patients any longer. Preliminary data from the much larger
STARS trial suggest a relevant reduction of clinical events through the
use of a combination of ticlopidine and aspirin compared with a
monotherapy with aspirin.23 ), collagen-induced aggregation on day 14 is still
higher if compared with day 1. Thus the increased aggregation response
on day 7 represents an aspirin withdrawal phenomenon. There is
no clear evidence for an aspirin rebound phenomenon because aggregation
responses on days 7 and 14 are not strikingly different from each
other. Surprisingly, the combination of aspirin and ticlopidine
resulted in a significant reduction of collagen-induced platelet
aggregation, suggesting a synergistic platelet
inhibitory effect of both agents. Accordingly, we found no
change of the ED50 for collagen-induced
platelet aggregation in the aspirin group, a slight decrease in the
ticlopidine group, but a significant increase in the
aspirin+ticlopidine group.
Footnotes
The authors contributed equally to the paper.
References
Top
Abstract
Introduction
Results
Discussion
References
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S. R. Steinhubl, S. G. Ellis, K. Wolski, A. M. Lincoff, and E. J. Topol Ticlopidine Pretreatment Before Coronary Stenting Is Associated With Sustained Decrease in Adverse Cardiac Events : Data From the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial Circulation, March 13, 2001; 103(10): 1403 - 1409. [Abstract] [Full Text] [PDF]
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D. L. Bhatt, D. P. Chew, A. T. Hirsch, P. A. Ringleb, W. Hacke, and E. J. Topol Superiority of Clopidogrel Versus Aspirin in Patients With Prior Cardiac Surgery Circulation, January 23, 2001; 103(3): 363 - 368. [Abstract] [Full Text] [PDF]
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