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(Circulation. 2001;103:1403.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From the Department of Cardiology, Wilford Hall Medical Center (S.R.S.), Lackland AFB, Tex; and the Department of Cardiology and Joseph J. Jacobs Center for Thrombosis and Vascular Biology (S.G.E., A.M.L., E.J.T.) and the Department of Biostatistics and Epidemiology (K.W.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Steven R. Steinhubl, MD, Wilford Hall Medical Center, Department of Cardiology, 2200 Bergquist Dr, Lackland AFB, TX 78236. E-mail steven.steinhubl{at}59MDW.WHMC.AF.MIL
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Platelet inhibition at the time of a percutaneous coronary intervention has consistently been shown to decrease the risk of thrombotic adverse events but not restenosis. The role of enhanced antiplatelet protection through pretreatment with the platelet ADP-receptor antagonist ticlopidine in preventing both the early and late complications of coronary stenting has not previously been explored.
Methods and Results—In
the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)
trial, 
1600 patients were randomized to stenting with either placebo
or abciximab in addition to aspirin and heparin. All stented patients
also received ticlopidine after the procedure, but 58% of these
patients were given ticlopidine before stenting at the discretion of
the investigating physician. Among patients randomized to placebo,
ticlopidine pretreatment was associated with a significant decrease in
the incidence of the composite end point of death, myocardial
infarction, or target vessel revascularization (TVR) at 1 year
(adjusted hazard ratio, 0.73; 95% CI, 0.54 to 0.98;
P=0.036). Ticlopidine
pretreatment did not significantly influence the risk of death or
myocardial infarction in patients randomized to abciximab. Controlling
for patient characteristics and for the propensity of being on
ticlopidine, Cox proportional hazards regression identified ticlopidine
pretreatment as an independent predictor of the need for TVR at 1 year
(hazard ratio, 0.62; 95% CI, 0.43 to 0.89;
P=0.010) in both
placebo-treated and abciximab-treated
patients.
Conclusions—In the EPISTENT trial, among patients randomized to stenting, starting ticlopidine before the percutaneous coronary intervention was associated with a significant decrease in the incidence of the 12-month composite end point for patients not receiving abciximab and the need for TVR among all patients.
Key Words: stents • restenosis • platelets
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The use of antiplatelet therapy in the form of aspirin during a percutaneous coronary intervention (PCI) was initially empiric.1 Later trials confirmed that the addition of the relatively weak antiplatelet effects of aspirin, with or without dipyridamole, to full anticoagulation with heparin decreased the risk of a periprocedural Q-wave myocardial infarction (MI) by >75%.2 3 Recently, more aggressive antiplatelet therapy with platelet glycoprotein (GP)IIb/IIIa receptor inhibitors has been shown to further reduce thrombotic complications of PCI by up to 50%.4 5 6
The combination of a thienopyridine, ticlopidine, or clopidogrel with aspirin has been shown to synergistically inhibit platelet function and thrombus formation in several animal models and ex vivo human studies.7 8 9 10 Clinically, the benefit of this combination has best been demonstrated by its superior protection against stent thrombosis over that of aspirin with warfarin11 12 13 14 and aspirin alone.12 15
To achieve near-maximal antiplatelet protection at the time
of a PCI from the combination of ticlopidine and aspirin, ticlopidine
must be started at least 3 days before the procedure because of the 4-
to 7-day delay required for it to attain its full antiplatelet
effects.16 In one study of
patients undergoing a PCI, pretreatment with ticlopidine and aspirin
for 
72 hours was associated with a significant decrease in platelet
activation and thrombin generation compared with patients receiving
aspirin 
24 hours or no
pretreatment.17 In another
study, pretreatment with ticlopidine before stenting was found to be
associated with a time-dependent decrease in the incidence of
periprocedural non–Q-wave MI, with maximal benefit requiring 3 days
of
pretreatment.18
In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, a total of 2399 patients were randomly assigned to stent implantation with placebo, stent implantation and abciximab, or balloon angioplasty and abciximab.6 Investigators were encouraged to treat all patients according to their conventional practice before stenting. As a consequence, more than one half of all randomized patients received ticlopidine before their index coronary intervention. To evaluate the potential benefit of ticlopidine pretreatment in stent-treated patients randomized to either abciximab or placebo, we analyzed the clinical outcomes through 1 year of follow-up in these patients, based on their ticlopidine pretreatment status.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Protocol
The details of the EPISTENT trial design have previously been reported.6 In brief, 2399 patients undergoing elective or urgent percutaneous coronary revascularization were enrolled between July 1996 and September 1997 at 63 centers throughout the United States and Canada. Patients were eligible for enrollment if they had at least one target lesion suitable for treatment either by stenting or balloon angioplasty and were not undergoing primary intervention for acute MI.
All patients were treated with aspirin. Ticlopidine was allowed to be started before the procedure and was to be given in all patients after stent implantation. Patients were classified as having received ticlopidine before the procedure if it had been administered within the 7 days preceding the intervention.
At the time of the procedure, patients were randomized to 1
of 3 treatment groups: (1) abciximab (0.25 mg/kg bolus followed by
0.125 µg · kg-1 ·
min-1, maximum of 10 µg/min, infusion
for 12 hours) and stenting, (2) placebo and stenting, or (3) abciximab
and balloon angioplasty. Patients in the abciximab-treatment groups
received low-dose, weight-adjusted heparin (70 U/kg initial bolus,
target activated clotting time 200 seconds), and patients in the
placebo group received standard-dose, weight-adjusted heparin (100 U/kg
initial bolus, target activated clotting time 300 seconds).
Investigators were blinded to the drug assignment of patients assigned
to stenting.
This study evaluates only those patients randomized to the two stent arms of the EPISTENT trial.
Study End Points
The main end points evaluated in this study were the
composite end point of all-cause mortality, nonfatal MI, or urgent
revascularization at 30 days and the composite end point of all-cause
mortality, MI, and target vessel revascularization (TVR) at 1 year, as
well as its individual components. Follow-up was complete for 99% of
all patients at 1 year.19
End points were determined by a clinical events committee that was
blinded to study group assignment.
Bleeding events were classified as major or minor, according to criteria used by the Thrombolysis in Myocardial Infarction Study Group.20
Statistical Analysis
All patients randomized to the two stent arms of the
EPISTENT trial were included in the analysis. Patients in both the
abciximab and placebo arms were further classified according to whether
or not they received pretreatment with ticlopidine. Baseline
characteristics between ticlopidine pretreatment and no pretreatment
were compared by means of the 
2 test for
proportions. Kaplan-Meier methods were used to calculate the 30-day and
1-year end points, and groups were compared by means of the log-rank
test.
To adjust for the nonrandom pretreatment of patients given ticlopidine, a propensity score was developed to estimate each patient’s probability of receiving ticlopidine pretreatment. This propensity score was based on a logistic regression model that adjusted for all significant demographic and preprocedural covariates available. The country of enrollment (Canada versus the United States) was the most significant predictor of ticlopidine pretreatment. The c statistic for the propensity score model was 0.64. All adjusted hazard ratios reported throughout the text were adjusted for the propensity score.
A multivariable Cox proportional hazard model was used to
examine the impact of ticlopidine treatment on outcome after adjusting
for the use of abciximab and other covariates including propensity
score, age, sex, smoking status, diabetes, hypertension, history of MI,
history of congestive heart failure (CHF), history of peripheral
vascular disease (PVD), prior CABG, and lesion characteristics. An 
value of 0.05 was used for all
analyses.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients and Target Lesion Characteristics
A total of 1603 patients were randomized to stenting with either abciximab or placebo. Nine hundred thirty-two (58%) of these patients were given ticlopidine before the procedure, at the discretion of the investigator. Baseline clinical and lesion characteristics of all ticlopidine-pretreated and nonpretreated patients are shown in Table 1
. Nonpretreated patients were on average
heavier, were more likely to have previously undergone CABG, and more
frequently had had MI within the 7 days preceding the index procedure.
The target lesions of nonpretreated patients also had a higher
proportion of high-risk characteristics. In particular, there were more
type B2 or C lesions, long lesions, and total
occlusions.
|
30-Day Outcomes
The primary end point of the combination of death, MI,
or urgent revascularization occurred by 30 days in 10.8% of all
patients randomized to stent and placebo and in 5.3% of all patients
randomized to stent and abciximab
(P<0.001). Among patients
randomized to placebo who did not receive ticlopidine before the
procedure, their incidence of the combined end point was 13.4%
compared with 8.9% in placebo-treated patients who did receive
pretreatment with ticlopidine
(P=0.033)
(Figure 1). The benefit of pretreatment was primarily due to
a decrease in the occurrence of MI (8.4% versus 12.5%,
P=0.048).
|
Randomization to abciximab in the ticlopidine-pretreated patients was associated with a further, significant decrease in the incidence of the primary end point from 8.9% to 5.2% (P=0.028). The additional antiplatelet protection provided by ticlopidine pretreatment among patients randomized to abciximab had very little influence on the incidence of the combined end point at 30 days (5.2% in pretreated patients versus 5.5% in those not pretreated, P=0.823).
Ticlopidine pretreatment, irrespective of treatment group,
was not associated with an increased incidence of major or minor
bleeding
(Figure 2).
|
1-Year Outcomes
At 1 year, the group of patients with the least
antiplatelet protection at the time of the stent procedure—those in
the placebo group without ticlopidine pretreatment—had the highest
incidence of the composite end point of death, MI, or TVR (28.5%)
(Figure 3). Among patients randomized to placebo,
pretreatment with ticlopidine was associated with a 27% relative
decrease and a 7.8% absolute decrease in the occurrence of the
composite end point at 1 year
(P=0.008). Although patients
with the greatest antiplatelet protection at the time of their
procedure—those randomized to abciximab who also received ticlopidine
pretreatment—had the lowest composite event rate at 1 year (19.5%),
it did not differ significantly from the event rate in the abciximab+no
pretreatment cohort (20.9%) or the placebo+ticlopidine pretreatment
group (20.7%).
|
The benefit of antiplatelet therapy in reducing death and MI
occurred early and was maintained throughout the period of 1-year
follow-up
(Figure 4). Among patients randomized to placebo, ticlopidine
pretreatment compared with no pretreatment was associated with an
4% absolute reduction in death and MI at 30 days, which remained
essentially constant out to 1 year (11.2% versus 15.8%,
P=0.048). Patients randomized
to abciximab compared with patients randomized to placebo with no
ticlopidine pretreatment had an 8% absolute reduction in the
incidence of death and MI at 30 days that also remained relatively
constant throughout 1 year of follow-up (6.8% versus 15.8%,
P<0.001) and was not
influenced by ticlopidine pretreatment.
|
Ticlopidine pretreatment had its greatest influence on the
incidence of TVR. The highest rate of TVR at 1 year was among patients
randomized to placebo without ticlopidine pretreatment, whereas the
lowest incidence was found in ticlopidine-pretreated patients in the
placebo cohort (12.2% versus 20.2%,
P=0.002)
(Figure 5A). Among all patients, irrespective of
randomization to abciximab or placebo, ticlopidine pretreatment was
associated with an 25% relative decrease in the need for TVR (13.3
versus 17.9, P=0.014)
(Figure 5B).
|
Multivariable Model
To clarify the role of ticlopidine pretreatment in the
prevention of adverse events in this population, multivariate modeling
was performed. The propensity score was included in each model. For
patients randomized to placebo, ticlopidine pretreatment remained a
significant predictor of the 1-year combined end point (adjusted hazard
ratio [HR], 0.731; 95% CI, 0.545 to 0.980;
P=0.036) and the individual end
point of TVR (adjusted HR, 0.611; 95% CI, 0.423 to 0.884;
P=0.008). After adjusting for
covariates, ticlopidine pretreatment compared with no pretreatment was
associated with a nonsignificant trend toward a decrease in the risk of
death or MI (adjusted HR, 0.780; 95% CI, 0.525 to 1.159;
P=0.2190).
When the overall population was analyzed, neither
ticlopidine pretreatment nor randomization to abciximab was found to be
a significant predictor of improved outcomes in terms of the combined
end point
(Table 2). However, when the effect of antiplatelet therapy
on the components of the combined end point was analyzed, the risk of
death or MI was significantly diminished with abciximab treatment,
whereas the risk of TVR was significantly reduced in
ticlopidine-pretreated patients
(Table 3). Interestingly, the interaction term for
ticlopidine and abciximab was found to be significant for the outcome
of TVR. That is, even though ticlopidine pretreatment was associated
with a lower incidence of TVR among all patients, by multivariable
modeling, treatment with abciximab in ticlopidine-pretreated patients
diminished this benefit.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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These findings from the subset of stented patients in the EPISTENT trial suggest that the additional antiplatelet protection provided by the combination of ticlopidine and aspirin compared with aspirin alone before the start of a coronary intervention provides a sustained benefit in the reduction of adverse events for patients not receiving abciximab. The most marked effect of ticlopidine pretreatment was its association with a significant decrease in the need for TVR among all patients.
Antiplatelet protection at the time of a PCI has
consistently been shown to reduce the risk of early major adverse
cardiac events. Aspirin alone added to heparin decreased the risk of MI
by 75%, and in this study, the addition of abciximab to aspirin
compared with aspirin alone with no ticlopidine pretreatment led to a
further decrease in major adverse events by 60%. Although this
study showed a 33% decrease in the incidence of death, MI, or urgent
revascularization at 30 days when ticlopidine was added to aspirin, it
is important to emphasize that these results may underestimate the
actual benefit achievable when full antiplatelet protection with a
thienopyridine and aspirin is obtained before coronary stenting. The
actual duration of treatment with ticlopidine before PCI is unknown in
the EPISTENT patient population. It seems unlikely that more than a
small percentage of patients were pretreated for the 3 days previously
shown to be associated with a maximal decrease in periprocedural
non–Q-wave MIs18 and even
fewer for the 7 days necessary to achieve the full antiplatelet effects
of ticlopidine.16 Because
the level of platelet inhibition achieved with GPIIb/IIIa inhibitors,
as measured by turbidimetric aggregometry, is significantly greater
than that achievable with a thienopyridine and aspirin, it might be
speculated that this combination would not be able to provide
equivalent protection from thrombotic complications. However, as
exemplified by aspirin, which has no measurable effect on turbidimetric
aggregometry with 20 µmol/L ADP, protection from thrombotic adverse
events and in vitro inhibition of platelet aggregation may not
correlate with each other.
Although the results of early studies in various animal
models supported the hypothesis that the prevention of thrombus
formation at the site of intra-arterial injury could prevent neointimal
hyperplasia,21 22
studies of the long-term benefit of aggressive antiplatelet protection
with GPIIb/IIIa inhibitors on clinical restenosis have yielded mixed
results.5 23 The
results of this study suggest that pretreatment with ticlopidine was
independently associated with a 25% decrease in the risk of TVR at 1
year. One possible explanation for the greater benefit of ticlopidine
pretreatment compared with abciximab for preventing restenosis despite
being a weaker inhibitor of platelet aggregation might be related to
the mechanism of its antiplatelet effects. Whereas the GPIIb/IIIa
inhibitors potently prevent the binding of platelets to each other,
they do not prevent the activation of
platelets.24 Therefore, they
still allow for the local release of the contents of intracellular
platelet granules such as platelet-derived growth factor (PDGF),
transforming growth factor-ß, and other growth and mitogenic factors
that have been postulated to play a central role in
restenosis.25 26
On the other hand, ticlopidine prevents ADP-related recruitment and
activation of platelets. This difference in mechanism probably explains
the increase in expression of P-selectin, located in the platelet
-granule, which has been reported with abciximab treatment during
stenting compared with
control.27 Conversely,
treatment with ticlopidine and aspirin compared with aspirin alone
after stenting has been found to decrease the expression of
P-selectin,10 28
with pretreatment having an even greater
effect.17 P-selectin
mediates interactions between platelets and leukocytes, and a recent
study found that treatment with abciximab, with or without ticlopidine
pretreatment, significantly enhanced P-selectin–mediated leukocyte
adhesion on a platelet surface, whereas when ticlopidine was
administered alone, virtually no leukocyte adhesion was
seen.29 This in vitro
finding is consistent with the findings in this study of a significant
unfavorable interaction between abciximab and ticlopidine pretreatment
on the risk of TVR. The results of several animal models of restenosis
suggest that this ability of ticlopidine to prevent
P-selectin–mediated leukocyte adhesion might be important in
decreasing neointimal
formation.30 31
As noted earlier, because it is likely that ticlopidine pretreatment in
this study was not given for 72 hours in the majority of patients, it
is possible that the results of this study underestimate the true
potential benefit of longer pretreatment on the incidence of
restenosis.
Study Limitations
The primary limitation to this study is that
ticlopidine pretreatment was not controlled or randomized. Therefore,
the actual duration of pretreatment was unknown. Also, because
pretreatment was at the discretion of the investigator, it is likely
that a more stable patient population received ticlopidine
pretreatment. Although propensity score methods were used and a
multivariate analysis found that ticlopidine pretreatment in patients
not receiving abciximab was an independent predictor of a decreased
incidence of the composite end point, and in particular TVR at 1 year,
it is possible that these results may still be influenced by an
accumulation of multiple small benefits of the patient population’s
characteristics or other unmeasured confounders (eg, medical centers or
physicians who pretreated with ticlopidine may provide better overall
care) that were not adequately balanced because of a lack of
randomization.
Conclusions
The results of this study suggest that starting
treatment with the ADP-receptor antagonist ticlopidine in patients
before coronary stenting can decrease the risk of death and MI in
patients not receiving abciximab and decrease the need for TVR in all
patients irrespective of abciximab treatment. Determination of the
actual benefit and safety of a strategy of full platelet inhibition
with an ADP-receptor antagonist and aspirin before a PCI will require a
large-scale, randomized clinical trial. The currently ongoing CREDO
(Clopidogrel for the Reduction of Events During Observation) trial will
evaluate the safety and efficacy of pretreatment versus no pretreatment
with clopidogrel before coronary
stenting.
Received September 25, 2000; revision received November 14, 2000; accepted November 18, 2000.
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W.-H. Chen, P.-Y. Lee, W. Ng, H.-F. Tse, and C.-P. Lau Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1122 - 1126. [Abstract] [Full Text] [PDF]
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 A. J. Chaves, A. G.M.R. Sousa, L. A. Mattos, A. Abizaid, R. Staico, F. Feres, M. Centemero, L. F. Tanajura, A. Abizaid, I. Pinto, et al. Volumetric Analysis of In-Stent Intimal Hyperplasia in Diabetic Patients Treated With or Without Abciximab: Results of the Diabetes Abciximab steNT Evaluation (DANTE) Randomized Trial Circulation, February 24, 2004; 109(7): 861 - 866. [Abstract] [Full Text] [PDF]
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M. Dalby, G. Montalescot, C. B. d. Sollier, E. Vicaut, T. Soulat, J.-P. Collet, R. Choussat, V. Gallois, G. Drobinski, L. Drouet, et al. Eptifibatide provides additional platelet inhibition in Non-ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel: Results of the platelet activity extinction in Non-Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study J. Am. Coll. Cardiol., January 21, 2004; 43(2): 162 - 168. [Abstract] [Full Text] [PDF]
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A. W. Chan, D. J. Moliterno, P. B. Berger, G. W. Stone, P. M. DiBattiste, S. L. Yakubov, S. K. Sapp, K. Wolski, D. L. Bhatt, E. J. Topol, et al. Triple antiplatelet therapy during percutaneous coronary intervention is associated withimproved outcomes including one-year survival: Results from the do tirofiban and reoprogive similar efficacy outcome trial (TARGET) J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1188 - 1195. [Abstract] [Full Text] [PDF]
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J. E. Tcheng and M. E. Campbell Platelet inhibition strategies in percutaneous coronary intervention: Competition or coopetition? J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1196 - 1198. [Full Text] [PDF]
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M. J. Ross, H. C. Herrmann, D. J. Moliterno, J. C. Blankenship, L. Demopoulos, P. M. DiBattiste, S. G. Ellis, Z. Ghazzal, J. L. Martin, J. White, et al. Angiographic variables predict increased riskfor adverse ischemic events after coronarystenting with glycoprotein IIb/IIIa inhibition: Results from the TARGET trial J. Am. Coll. Cardiol., September 17, 2003; 42(6): 981 - 988. [Abstract] [Full Text] [PDF]
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S. R. Steinhubl, P. B. Berger, J. T. Mann III, E. T. A. Fry, A. DeLago, C. Wilmer, and E. J. Topol Clopidogrel and Percutaneous Coronary Interventions--Reply JAMA, April 16, 2003; 289(15): 1926 - 1927. [Full Text] [PDF]
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D. J. Moliterno and A. W. Chan Glycoprotein IIb/IIIa inhibition in early intent-to-stent treatment of acute coronary syndromes: EPISTENT, ADMIRAL, CADILLAC, and TARGET J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 49S - 54S. [Abstract] [Full Text] [PDF]
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S. R. Steinhubl, P. B. Berger, J. T. Mann III, E. T. A. Fry, A. DeLago, C. Wilmer, E. J. Topol, and for the CREDO Investigators Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Randomized Controlled Trial JAMA, November 20, 2002; 288(19): 2411 - 2420. [Abstract] [Full Text] [PDF]
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F.-J. Neumann and N. Jander How to best counteract the enemies? By ensuring adequate oxygen delivery Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G35 - G42. [Abstract] [PDF]
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P. B. Berger and S. Steinhubl Clinical Implications of Percutaneous Coronary Intervention-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) Study: A US Perspective Circulation, October 22, 2002; 106(17): 2284 - 2287. [Full Text] [PDF]
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G. W. Stone, D. J. Moliterno, M. Bertrand, F.-J. Neumann, H. C. Herrmann, E. R. Powers, C. L. Grines, J. W. Moses, D. J. Cohen, E. A. Cohen, et al. Impact of Clinical Syndrome Acuity on the Differential Response to 2 Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Coronary Stenting: The TARGET Trial* Circulation, May 21, 2002; 105(20): 2347 - 2354. [Abstract] [Full Text] [PDF]
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