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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

Steven R. Steinhubl, MD; Stephen G. Ellis, MD; Kathy Wolski, MPH; A. Michael Lincoff, MD; Eric J. Topol, MD; for the EPISTENT Investigators

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

	Abstract

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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

	Introduction

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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 warfarin^{11 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.

	Methods

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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.

	Results

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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.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical and Lesion Characteristics of Patients Receiving Stents Who Were Pretreated and Not Pretreated With Ticlopidine

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).

View larger version (19K): [in this window] [in a new window]   Figure 1. Incidence of 30-day composite end point in patients, based on antiplatelet treatment at start of coronary stent procedure.

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).

View larger version (29K): [in this window] [in a new window]   Figure 2. Incidence of minor (shadowed columns) and major bleeding, based on criteria used by Thrombolysis in Myocardial Infarction Study Group in patients, based on antiplatelet treatment at start of coronary stent procedure.

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%).

View larger version (15K): [in this window] [in a new window]   Figure 3. Incidence of composite end point of death, MI, and TVR over 1 year, based on antiplatelet treatment at start of coronary stent procedure.

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.

View larger version (14K): [in this window] [in a new window]   Figure 4. Incidence of composite end point of death and MI over 1 year, based on antiplatelet treatment at start of coronary stent procedure.

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).

View larger version (27K): [in this window] [in a new window]   Figure 5. TVR rates over 1 year, based on antiplatelet treatment at start of coronary stent procedure (A), and based on ticlopidine pretreatment status only (B).

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.

View this table: [in this window] [in a new window]   Table 2. Cox Proportional Hazards Model for Combined End Point of Death, MI, and TVR at 1 Year

View this table: [in this window] [in a new window]   Table 3. Cox Proportional Hazards Model for Death or MI at 1 Year and TVR at 1 Year

	Discussion

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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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis. N Engl J Med. 1979;301:61–68.[Abstract]
   
2. Schwartz L, Bourassa MG, Lesperance J, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med. 1988;318:1714–1719.[Abstract]
   
3. Barnathan ES, Schwartz JS, Taylor L, et al. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation. 1987;76:125–134.[Abstract/Free Full Text]
   
4. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956–961.[Abstract/Free Full Text]
   
5. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336:1689–1696.[Abstract/Free Full Text]
   
6. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet. 1998;352:87–92.[Medline] [Order article via Infotrieve]
   
7. Cadroy Y, Bossavy J-P, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000;101:2823–2828.[Abstract/Free Full Text]
   
8. Bossavy J-P, Thalamas C, Sagnard L, et al. A double-blind randomised comparison of combined aspirin and ticlopidine versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Blood. 1998;92:1518–1525.[Abstract/Free Full Text]
   
9. Herbert J-M, Dol F, Bernat A, et al. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost. 1998;80:512–518.[Medline] [Order article via Infotrieve]
   
10. Rupprecht H-J, Darius H, Borkowski U, et al. Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation. Circulation. 1998;97:1046–1052.[Abstract/Free Full Text]
    
11. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) Study. Circulation. 1998;98:1597–1603.[Abstract/Free Full Text]
    
12. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three anti-thrombotic regimens following coronary artery stenting. N Engl J Med. 1998;339:1665–1671.[Abstract/Free Full Text]
    
13. Schomig A, Neumann F-J, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334:1084–1089.[Abstract/Free Full Text]
    
14. Urban P, Macaya C, Rupprecht H-J, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS). Circulation. 1998;98:2126–2132.[Abstract/Free Full Text]
    
15. Hall P, Nakamura S, Maiello L, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation. 1996;93:215–222.[Abstract/Free Full Text]
    
16. Di Perri T, Pasini FL, Frigerio C, et al. Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration. Eur J Clin Pharmacol. 1991;41:429–434.[Medline] [Order article via Infotrieve]
    
17. Gregorini L, Marco J, Fajadet J, et al. Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilatation procedures. J Am Coll Cardiol. 1997;29:13–20.[Abstract]
    
18. Steinhubl SR, Lauer MS, Mukherjee DP, et al. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions. J Am Coll Cardiol. 1998;32:1366–1370.[Abstract/Free Full Text]
    
19. Topol EJ, Mark DB, Lincoff AM, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Lancet. 1999;354:2019–2024.[Medline] [Order article via Infotrieve]
    
20. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial phase 1: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1–11.[Abstract]
    
21. Willerson JT, Yao SK, McNatt J, et al. Frequency and severity of cyclic flow alterations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury. Proc Natl Acad Sci U S A. 1991;88:10624–10628.[Abstract/Free Full Text]
    
22. Friedman RF, Stemerman MB, Wenz B, et al. The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. J Clin Invest. 1977;60:1191–1201.
    
23. EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet. 1994;343:881–886.[Medline] [Order article via Infotrieve]
    
24. Byrne A, Moran N, Maher M, et al. Continued thromboxane A2 formation despite administration of a platelet glycoprotein IIb/IIIa antagonist in patients undergoing coronary angioplasty. Arterioscler Thromb Vasc Biol. 1997;17:3224–3229.[Abstract/Free Full Text]
    
25. Chandrasekar B, Tanguay J-F. Platelet and restenosis. J Am Coll Cardiol. 2000;35:555–562.[Abstract/Free Full Text]
    
26. LeBreton H, Plow EF, Topol EJ. Role of platelets in restenosis after percutaneous coronary revascularization. J Am Coll Cardiol. 1996;28:1643–1651.[Abstract]
    
27. Gawaz M, Ruf A, Neumann F-J, et al. Effect of glycoprotein IIb/IIa receptor antagonism on platelet membrane glycoproteins after coronary stent placement. Thromb Haemost. 1998;80:994–1001.[Medline] [Order article via Infotrieve]
    
28. Neumann F-J, Gawaz M, Dickfield T, et al. Antiplatelet effect of ticlopidine after coronary stenting. J Am Coll Cardiol. 1997;29:1515–1519.[Abstract]
    
29. Fredrickson BJ, Turner NA, Kleiman NS, et al. Effects of abciximab, ticlopidine, and combined abciximab/ticlopidine therapy on platelet and leukocyte function in patients undergoing coronary angioplasty. Circulation. 2000;101:1122–1129.[Abstract/Free Full Text]
    
30. Golino P, Ambrosio G, Ragni M, et al. Inhibition of leukocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury. Thromb Haemost. 1997;77:783–788.[Medline] [Order article via Infotrieve]
    
31. Kumar A, Hoover JL, Simmons CA, et al. Remodeling and neointimal formation in the carotid artery of normal and P-selectin-deficient mice. Circulation. 1997;96:4333–4342. [Abstract/Free Full Text]
    

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				G Montalescot, H R Andersen, D Antoniucci, A Betriu, M J de Boer, L Grip, F J Neumann, and M T Rothman Recommendations on percutaneous coronary intervention for the reperfusion of acute ST elevation myocardial infarction Heart, June 1, 2004; 90(6): e37 - e37. [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]

				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]

				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]

				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]

				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]

				G. N. Levine, M. J. Kern, P. B. Berger, D. L. Brown, L. W. Klein, D. J. Kereiakes, T. A. Sanborn, A. K. Jacobs, and for the American Heart Association Diagnostic and Management of Patients Undergoing Percutaneous Coronary Revascularization Ann Intern Med, July 15, 2003; 139(2): 123 - 136. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				D.J. Moliterno and E.J. Topol The TARGET trial: hit or miss? Eur. Heart J., June 1, 2002; 23(11): 835 - 837. [Full Text] [PDF]

				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]

				Ticlopidine Before Stenting Reduces Adverse Events Journal Watch Cardiology, May 4, 2001; 2001(504): 3 - 3. [Full Text]

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