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Original Contribution |

Platelet Glycoprotein IIb/IIIa Integrin Blockade With Eptifibatide in Coronary Stent Intervention:  The ESPRIT Trial: A Randomized Controlled Trial FREE

J. Conor O'Shea, MD; Gail E. Hafley, MS; Sally Greenberg, PhD; Vic Hasselblad, PhD; Todd J. Lorenz, MD; Michael M. Kitt, MD; John Strony, MD; James E. Tcheng, MD; for the ESPRIT Investigators
[+] Author Affiliations

Author Affiliations: Duke Clinical Research Institute, Durham, NC (Drs O'Shea, Hasselblad, and Tcheng and Ms Hafley); COR Therapeutics Inc, South San Francisco, Calif (Drs Greenberg, Lorenz, and Kitt); and Schering-Plough Research Institute, Kenilworth, NJ (Dr Strony).


JAMA. 2001;285(19):2468-2473. doi:10.1001/jama.285.19.2468.
Text Size: A A A
Published online

Context The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial showed the efficacy of adjunctive, double-bolus eptifibatide therapy in reducing ischemic complications of nonurgent coronary stent implantation at 48 hours and at 30 days.

Objective To determine whether the beneficial effects of eptifibatide persist at 6 months after treatment.

Design Follow-up study of a randomized, double-blind, placebo-controlled, crossover-permitted trial conducted from June 1999 through February 2000.

Setting Ninety-two tertiary care centers in the United States and Canada.

Participants A total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation.

Intervention Patients were randomly assigned to receive placebo or eptifibatide (two 180-µg/kg boluses 10 minutes apart and continuous infusion of 2.0 µg/kg per minute), started immediately before stent implantation and continued for 18 to 24 hours. Complete follow-up data were available for 988 (95.0%) of 1040 patients given eptifibatide and 977 (95.4%) of 1024 patients given placebo.

Main Outcome Measures Composite rates of death or myocardial infarction (MI); death, MI, or target vessel revascularization; and their individual components 6 months after enrollment, compared between the 2 groups.

Results By 6 months, the composite end point of death or MI had occurred in 7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P = .002). The composite of death, MI, or target vessel revascularization was 14.2% in eptifibatide-treated patients vs 18.3% in placebo-treated patients (HR, 0.75; 95% CI, 0.60-0.93; P = .008). Most of this benefit accrued early (<48 hours after initiation of therapy) and was maintained through 6 months. Six-month mortality in the eptifibatide group was 0.8% vs 1.4% in the placebo group (HR, 0.56; 95% CI, 0.24-1.34; P = .19) and target vessel revascularization occurred in 8.6% of the eptifibatide group vs 9.4% of the placebo group (HR, 0.91; 95% CI, 0.68-1.22; P = .51).

Conclusion Adjunctive eptifibatide therapy during coronary stent implantation provides benefit through 6-month follow-up.

Figures in this Article

Coronary thrombosis is central to the pathogenesis of atherosclerosis, acute myocardial infarction (AMI), acute coronary syndromes, and ischemic complications of percutaneous coronary intervention (PCI).1 Aside from the obvious and dramatic effects of abrupt thrombosis of an epicardial vessel, the effects of thrombosis on microcirculation (such as microembolization and vasospasm) also portend poor outcomes in coronary artery disease.2 Several large, randomized clinical trials have shown that inhibition of platelet aggregation with platelet glycoprotein (Gp) IIb/IIIa receptor antagonists improves outcomes in patients presenting with acute coronary syndromes and after PCI.3,4 These agents mitigate the thrombotic cascade both by blocking Gp IIb/IIIa, the primary surface-membrane receptor responsible for platelet aggregation, and by indirectly inhibiting the generation of thrombin.511

Eptifibatide is an intravenous, rapidly reversible, competitive inhibitor of Gp IIb/IIIa. Therapy with eptifibatide has been shown to reduce short-term adverse cardiac events in several coronary indications, including PCI,12 AMI with13 or without14 ST-segment elevation, and unstable angina.14 In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, high-dose, double-bolus eptifibatide was evaluated in nonurgent coronary stenting. This trial was terminated early for efficacy in February 2000.15 Final analysis of the primary composite end point—death, MI, need for urgent target vessel revascularization, or crossover to Gp IIb/IIIa inhibitor therapy for thrombosis within 48 hours—showed a 37% relative risk reduction with treatment (10.5% with placebo vs 6.6% with eptifibatide; P = .002). At 30 days, the key secondary composite end point of death, MI, or urgent target vessel revascularization was reduced by a relative 35% (10.4% vs 6.8%; P = .003).15 The purpose of the present analysis was to determine whether these benefits continued at 6 months for patients enrolled in the ESPRIT trial.

Patients

The design and methods of the ESPRIT trial have been described.15,16 Briefly, 92 centers in the United States and Canada enrolled patients who were scheduled to undergo nonurgent coronary stenting. Enrollment of 2064 patients occurred from June 1999 through February 2000. The primary inclusion criterion was intent to treat a native coronary artery with stent implantation without planned use of a Gp IIb/IIIa inhibitor. Exclusion criteria included MI within 24 hours before randomization and ongoing chest pain precipitating urgent referral for PCI. Other exclusion criteria included PCI within the previous 90 days, previous stent implantation at the target location, staged PCI anticipated less than 30 days after randomization, treatment with a Gp IIb/IIIa inhibitor or a thienopyridine within 30 days before randomization, stroke or transient ischemic attack within 30 days before randomization, history of hemorrhagic stroke, history of bleeding diathesis or evidence of abnormal bleeding within 30 days before randomization, major surgery within the previous 6 weeks, uncontrolled hypertension (>200/100 mm Hg), documented thrombocytopenia (platelet count <100 × 103/µL), or a serum creatinine level of more than 4.0 mg/dL (350 µmol/L).

Treatments

Patients were randomized in a 1:1 ratio to receive either placebo or eptifibatide (Integrilin, COR Therapeutics, South San Francisco, Calif, and Schering-Plough Research Institute, Kenilworth, NJ), started immediately prior to PCI. The randomization allocation code was generated using random permuted blocks within each investigative site. Each site kept a randomization schedule unique to that site. Study drug kits were prepared only after the guiding scout images had been obtained in the catheterization laboratory in preparation for intervention. Patients were considered randomized at the time of any administration of study drug. If the clinician decided not to give the study drug for any reason, the patient was not randomized and was not considered part of the study. If a kit was prepared but not used, unblinding did not occur and replacement kits were used to reestablish the correct sequence in the randomization list for the next eligible patient. Once study drug was given, a patient's participation in the study was communicated to the coordinating center within 30 minutes of randomization. This strategy served to minimize the number of patients randomized but not actually treated in ESPRIT.

Study drug kits were packaged to be indistinguishable, regardless of content. Any drug kit that became unusable was replaced with another uniquely numbered kit of the same treatment. This kit then was given to the next patient enrolled at that site. Eptifibatide was given as two 180-µg/kg boluses 10 minutes apart and as a continuous infusion of 2.0 µg/kg per minute (1.0 µg/kg per minute in patients with a serum creatinine level >2.0 mg/dL [177 µmol/L]) started with the first bolus and continued for 18 to 24 hours. All patients received concomitant aspirin, and a weight-adjusted heparin regimen was recommended (initial bolus of 60 U/kg), with a target activated clotting time of 200 to 300 seconds. Treatment with ticlopidine or clopidogrel was permitted on the day of the procedure but not beforehand; the choice of loading dose was decided by the treating physician. The PCI was performed according to local standards, and any approved stent could be implanted.

To provide emergency, open-label Gp IIb/IIIa inhibitor therapy (for direct treatment of abrupt closure, no reflow, coronary thrombosis, or similar complications of PCI), "bailout" kits were supplied to the sites. These kits contained 2 bolus vials of either eptifibatide (for patients allocated to the placebo group) or placebo (for patients allocated to the eptifibatide group). Once the bolus bailout treatment had begun, the study drug infusion was discontinued and open-label eptifibatide infusion was initiated. Bailout use of Gp IIb/IIIa inhibition did not result in unblinding of treatment assignment.

The protocol was approved by the institutional review board at each clinical site, and patients gave informed consent for participation in the trial and follow-up for 1 year. Masking of study drug allocation was maintained through 1 year of follow-up.

Definitions

Outcomes at 6 months, including death, MI, and target vessel revascularization, were prospectively defined secondary end points of the trial. Target vessel revascularization was defined as coronary artery bypass grafting or a second PCI deemed by the site investigator to involve the original target vessel. All other revascularizations were reviewed by a clinical events committee (CEC) to determine whether the procedure met the criteria for target vessel revascularization.

An end-point MI could occur by 1 of 2 criteria. The first criterion was elevation of the creatine kinase–MB isoenzyme (CK-MB), assessed by the enzymatic core laboratory in at least 2 samples, to at least 3 times the upper limit of normal within 24 hours after PCI. The other criterion included MIs reported by an investigator and adjudicated as end-point MIs by the CEC. This required corroboration in the form of a clinical syndrome consistent with MI (symptoms and signs of cardiac chest pain, other anginal equivalent, or acute shortness of breath with features of new-onset pulmonary edema or hypotension) and supportive electrocardiographic (ECG) or cardiac marker data. Supportive ECG findings included development of Q waves (≥0.04 seconds) in at least 2 contiguous leads or new left bundle-branch block. Supportive cardiac marker findings included (in order of precedence and to the exclusion of the next value) an elevated level of CK-MB, troponin I, or troponin T; or a total CK level elevated to at least twice the upper limit of normal. In cases of repeat PCI or bypass surgery, cardiac marker elevations to at least 3 times or 5 times the upper limit of normal were required, respectively.

Statistical Analyses

The sample size for ESPRIT was calculated based on both the projected reduction in the rate of a key secondary composite end point (death, MI, or target vessel revascularization at 30 days) and the reduction in the rate of the primary composite end point (death, MI, urgent target vessel revascularization, or bailout Gp IIb/IIIa inhibitor use at 48 hours). The secondary end point was used for power calculations because of its application in other trials of Gp IIb/IIIa inhibitors in this setting. We expected a rate of the secondary end point of 11% in the placebo group, reduced by 33% with treatment. With 86% power and a 2-tailed α level of .05, the projected sample size for the study was 2400 patients.

An independent board monitored the safety of the trial. There was no plan for interim analyses of efficacy because recruitment was anticipated to be complete within 6 months. When enrollment continued beyond 8 months, however, the board independently elected to evaluate both safety and efficacy, using a prespecified criterion of P<.005 for the reduction in death or MI at 48 hours for early termination of the trial.

Study coordinators collected data on case report forms at the sites. All analyses were performed according to the intention-to-treat principle (all randomized patients, as randomized). Survival analysis methods were used for the 6-month analyses. Pairwise comparisons between the 2 treatment groups were made using the log-rank test, with event rates calculated by the Kaplan-Meier method. Two-sided P values are reported. Time to first occurrence of any component of the composite end point is shown by Kaplan-Meier survival curves. Treatment effects by subgroups are reported as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using a Cox proportional hazards model.

The 6-month follow-up database was locked on January 5, 2001. Follow-up of all end-point clinical events, obtained by telephone contact or clinic visit at 6 months after randomization, was available for 988 of 1040 patients assigned to receive eptifibatide (95.0%) and 977 of 1024 patients assigned to receive placebo (95.4%); mortality status was available for 1023 (98.4%) and 1010 (98.6%), respectively (Figure 1).

Figure 1. Flow of Patients Through the ESPRIT Trial
Graphic Jump Location
ESPRIT indicates Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy.

Among the 2064 patients enrolled in the study, baseline demographic and angiographic characteristics were balanced and did not differ significantly between treatment groups.15 The cohort had a median age of 62 years, about 73% were male, 20% had diabetes, 23% were current smokers, about one third had had a prior MI, and slightly more than half of the patients in both treatment groups had hypertension and hyperlipidemia. Almost 20% of patients had an acute coronary syndrome within 48 hours or acute ST-segment elevation MI within 7 days before intervention. More than 98% of patients randomized into the trial underwent PCI, at least 1 stent was placed in 97.2% of patients who underwent PCI, and more than 97% of patients received a thienopyridine, predominantly clopidogrel.15

The 6-month composite end point of death or MI occurred in 11.5% of placebo-treated patients and in 7.5% of eptifibatide-treated patients (HR, 0.63; 95% CI, 0.47-0.84; P = .002; Figure 2A; Table 1). There was consistency in the direction of treatment effect of eptifibatide with regard to this end point across patient subgroups defined by age, weight, sex, presence or absence of diabetes, and clinical condition (Figure 3). However, as can be seen from the wide CIs in some of the analyses in Figure 3, the study did not have power to test the treatment effect in these predefined subgroups. In additional analyses that tested for treatment-by-subgroup interactions, an increased benefit of eptifibatide was seen with increasing age (P = .03). The composite end point of death, MI, or target vessel revascularization at 6 months also differed significantly between treatment groups (Figure 2B). The incidence of the individual components varied. The only significant effect was observed in reduction of MI. Mortality was reduced, but not to a significant extent. Finally, target vessel revascularization was not substantially affected (Table 1).

Figure 2. Cumulative Incidence of Study End Points Among Patients Treated With Eptifibatide or Placebo
Graphic Jump Location
MI indicates myocardial infarction. For the composite end point of death or MI, hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P = .002. For the composite end point of death, MI, or target vessel revascularization, HR, 0.75; 95% CI, 0.60-0.93; P = .008. For the end point of death, HR, 0.56; 95% CI, 0.24-1.34; P = .19.
Table Graphic Jump LocationTable 1. Kaplan-Meier Event Rates for Study End Points at 6 Months, by Treatment
Figure 3. Hazard Ratios and 95% CIs for Risk of Death or MI at 6 Months With Eptifibatide vs Placebo Treatment, by Subgroup
Graphic Jump Location
CI indicates confidence interval; MI, myocardial infarction; and ACS, acute coronary syndrome.

Event rates for the composite end point of death, MI, or target vessel revascularization and selected individual end points at 48 hours, 30 days, and 6 months are shown in Table 2. About 83% of the 4.1% benefit of eptifibatide in reducing this end point at 6 months was achieved in the first 48 hours, during which an absolute reduction of 3.4% occurred. However, an additional 17% of the absolute difference between groups at 6 months was manifested after the first 48 hours.

Table Graphic Jump LocationTable 2. Kaplan-Meier Event Rates at 48 Hours, 30 Days, and 6 Months, by Treatment

For mortality, the rate of death between 30 days and 6 months with placebo was nearly twice that with eptifibatide treatment (1.4% vs 0.8%; P = .19). Furthermore, the Kaplan-Meier curves continued to separate over time; about two thirds of the absolute difference accrued between 30 days and 6 months (Figure 2C). However, only 14 and 8 deaths had occurred by 6 months in the placebo and eptifibatide groups, respectively, and this difference was not statistically significant. The rate of target vessel revascularization also was lower in the eptifibatide group, but the difference was small and not significant at any of the time points. The absolute treatment benefit for the composite end point of MI and death also showed that most of the benefit accrued early and was at least maintained over the ensuing 6 months.

The acute benefits of eptifibatide have been established in several settings, including treatment of patients with acute coronary syndromes and as adjunctive therapy for patients undergoing PCI. The 6-month follow-up of patients in the ESPRIT trial shows the efficacy of eptifibatide in coronary stenting to be clinically relevant, statistically significant, and durable over time. Adjunctive treatment with eptifibatide had the greatest effect on MI and reduced the composite incidence of death or MI, as well as its components, and that of death, MI, and target vessel revascularization. Of interest, benefit continued to accrue between 48 hours and 6 months, well beyond the 18 to 24 hours of initial treatment. The suggestion that treatment with eptifibatide may be associated with lower mortality at 6 months (a nonsignificant 44% reduction in this study) supports the concept of the complementary effects of stenting and Gp IIb/IIIa inhibition in improving this fundamental adverse outcome in patients with ischemic heart disease.17

Until this report, abciximab had been the only Gp IIb/IIIa inhibitor shown to reduce ischemic complications of PCI over the long term.17 Accordingly, much of the discussion of putative mechanisms by which abciximab improves long-term outcomes compared with smaller, competitive Gp IIb/IIIa inhibitors (such as eptifibatide) had focused on the unique pharmacodynamic and pharmacokinetic properties of abciximab. The avid binding of abciximab to platelets for up to 2 weeks after administration and its cross-reactivity with other receptors, including ανβ3 (vitronectin) and Mac-1, were forwarded as hypotheses to explain the differences observed in clinical trials.1720 The ESPRIT results suggest that long-term benefits can be explained more simply by appropriate use of high-level inhibitors of platelet Gp IIb/IIIa integrin during PCI. In the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT-II) study, a 135-µg/kg bolus and either a 0.5- or 0.75-µg/kg-per-minute infusion were studied in coronary intervention. There was only a borderline significant 16% to 22% reduction in the composite end point of death, MI, or urgent target vessel revascularization at 30 days with eptifibatide treatment, with maintenance (but not augmentation) of the results at 6 months.12 The results of the ESPRIT study, which used a dose of eptifibatide some 3 to 4 times higher than that studied in IMPACT-II, lend credence to the need for greater inhibition of platelet aggregation during PCI to maximize both short- and long-term outcomes.

That benefits continued to accrue over time is a provocative and unexplained observation. Although eptifibatide treatment reduced epicardial thrombosis resulting in abrupt closure and urgent target vessel revascularization within the first 48 hours, this phenomenon accounted for only a small proportion of the long-term benefit. In particular, the treatment effect on mortality appears to be a delayed phenomenon—the difference in mortality between the placebo and eptifibatide groups tripled, from 0.2% to 0.6%, between 30 days and 6 months. Clearly, these numbers are small (and the differences are not statistically significant); there were only 22 deaths across both treatment arms at 6 months, and the outcomes of patients lost to follow-up in the 2 treatment arms are unknown. Nevertheless, these data are consistent with the observations for mortality at the same follow-up point in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC),18 Evaluation in PTCA to Improve Long-term Outcomes with abciximab Gp IIb/IIIa blockade (EPILOG),19 and the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trials of abciximab.20

Recent studies have suggested additional mechanisms by which platelet Gp IIb/IIIa blockade might indirectly improve long-term outcomes. Periprocedural MI, as evidenced by increases in CK-MB levels, long has been associated with increased mortality and other adverse cardiac events.21,22 In an angiographic substudy of the ESPRIT trial, Gibson et al23 found that eptifibatide administration was associated with significantly increased coronary flow reserve and a trend toward increased microvascular perfusion after stent placement. In that study, poor myocardial perfusion was the strongest predictor of release of CK-MB. Reductions in release of inflammatory factors, such as CD-40 ligand (David Phillips, PhD, written communication, March 2001), and of vascular mediators, such as platelet-derived growth factor and transforming growth factor β, by Gp IIb/IIIa inhibition is another possible mechanism that might improve long-term vascular responses.

In summary, these data, particularly when coupled with the antecedent clinical trials of Gp IIb/IIIa inhibition in PCI, argue strongly that all patients undergoing PCI should be considered for treatment with an inhibitor of the platelet Gp IIb/IIIa integrin. Across a series of randomized trials involving different intravenous Gp IIb/IIIa antagonists, benefits have been observed among patients of all risk categories and with all approved interventional devices. The strategy of maximal inhibition beginning just before the procedure and maintained throughout the infusion, especially in the early hours immediately after PCI, appears to be critical to imparting long-term benefits. This study adds to the evidence that outcomes of PCI can be improved through inhibition of the platelet Gp IIb/IIIa integrin.

Fuster V, Adams PC, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med.1992;326:242-250.
Roe MT, Ohman EM, Maas AC.  et al.  Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion.  J Am Coll Cardiol.2001;37:9-18.
Madan M, Berkowitz SD, Tcheng JE. Glycoprotein IIb/IIIa integrin blockade.  Circulation.1998;98:2629-2635.
Kong DF, Califf RM, Miller DP.  et al.  Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease.  Circulation.1998;98:2829-2835.
Hynes RO. Integrins: a family of cell surface receptors.  Cell.1987;48:549-554.
Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion.  Cell.1992;69:11-25.
Jang U, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease.  J Am Coll Cardiol.1994;24:1591-1601.
Phillips DR, Charo IF, Parisi LV, Fitzgerald LA. The platelet membrane glycoprotein IIb/IIIa complex.  Blood.1988;71:831-843.
Phillips DR, Charo IF, Scarborough RM. GP IIb-IIIa: the responsive integrin.  Cell.1991;65:359-362.
Charo IF, Kieffer N, Phillips DR. Platelet membrane glycoproteins. In: Colman RW, ed. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: JB Lippincott; 1994:489-507.
Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.  N Engl J Med.1995;332:1553-1559.
The IMPACT-II Investigators.  Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II.  Lancet.1997;349:1422-1428.
Ohman EM, Kleiman NS, Gacioch G.  et al. for the IMPACT-AMI Investigators.  Combined accelerated tissue-plasminogen activator and glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: results of a randomized, placebo-controlled dose ranging trial.  Circulation.1997;95:846-854.
The PURSUIT Trial Investigators.  Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med.1998;339:436-443.
The ESPRIT Investigators.  Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial.  Lancet.2000;356:2037-2044.
O'Shea JC, Madan M, Cantor WJ.  et al.  Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention.  Am Heart J.2000;140:834-839.
Topol EJ, Mark DB, Lincoff AM.  et al. for the EPISTENT Investigators.  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.
The 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.
The EPILOG Investigators.  Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization.  N Engl J Med.1997;336:1689-1696.
The 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.
Abdelmeguid AE, Topol EJ. The myth of the myocardial ‘infarctlet' during percutaneous coronary revascularization procedures.  Circulation.1996;94:3369-3375.
Califf RM, Abdelmeguid AE, Kuntz RE.  et al.  Myonecrosis after revascularization procedures.  J Am Coll Cardiol.1998;31:241-251.
Gibson C, Cohen D, Cohen E.  et al.  Eptifibatide improves coronary flow reserve following stent placement: an ESPRIT substudy [abstract].  Circulation.2000;102:II-366.

Figures

Figure 1. Flow of Patients Through the ESPRIT Trial
Graphic Jump Location
ESPRIT indicates Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy.
Figure 2. Cumulative Incidence of Study End Points Among Patients Treated With Eptifibatide or Placebo
Graphic Jump Location
MI indicates myocardial infarction. For the composite end point of death or MI, hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P = .002. For the composite end point of death, MI, or target vessel revascularization, HR, 0.75; 95% CI, 0.60-0.93; P = .008. For the end point of death, HR, 0.56; 95% CI, 0.24-1.34; P = .19.
Figure 3. Hazard Ratios and 95% CIs for Risk of Death or MI at 6 Months With Eptifibatide vs Placebo Treatment, by Subgroup
Graphic Jump Location
CI indicates confidence interval; MI, myocardial infarction; and ACS, acute coronary syndrome.

Tables

Table Graphic Jump LocationTable 1. Kaplan-Meier Event Rates for Study End Points at 6 Months, by Treatment
Table Graphic Jump LocationTable 2. Kaplan-Meier Event Rates at 48 Hours, 30 Days, and 6 Months, by Treatment

References

Fuster V, Adams PC, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med.1992;326:242-250.
Roe MT, Ohman EM, Maas AC.  et al.  Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion.  J Am Coll Cardiol.2001;37:9-18.
Madan M, Berkowitz SD, Tcheng JE. Glycoprotein IIb/IIIa integrin blockade.  Circulation.1998;98:2629-2635.
Kong DF, Califf RM, Miller DP.  et al.  Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease.  Circulation.1998;98:2829-2835.
Hynes RO. Integrins: a family of cell surface receptors.  Cell.1987;48:549-554.
Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion.  Cell.1992;69:11-25.
Jang U, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease.  J Am Coll Cardiol.1994;24:1591-1601.
Phillips DR, Charo IF, Parisi LV, Fitzgerald LA. The platelet membrane glycoprotein IIb/IIIa complex.  Blood.1988;71:831-843.
Phillips DR, Charo IF, Scarborough RM. GP IIb-IIIa: the responsive integrin.  Cell.1991;65:359-362.
Charo IF, Kieffer N, Phillips DR. Platelet membrane glycoproteins. In: Colman RW, ed. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: JB Lippincott; 1994:489-507.
Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.  N Engl J Med.1995;332:1553-1559.
The IMPACT-II Investigators.  Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II.  Lancet.1997;349:1422-1428.
Ohman EM, Kleiman NS, Gacioch G.  et al. for the IMPACT-AMI Investigators.  Combined accelerated tissue-plasminogen activator and glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: results of a randomized, placebo-controlled dose ranging trial.  Circulation.1997;95:846-854.
The PURSUIT Trial Investigators.  Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med.1998;339:436-443.
The ESPRIT Investigators.  Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial.  Lancet.2000;356:2037-2044.
O'Shea JC, Madan M, Cantor WJ.  et al.  Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention.  Am Heart J.2000;140:834-839.
Topol EJ, Mark DB, Lincoff AM.  et al. for the EPISTENT Investigators.  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.
The 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.
The EPILOG Investigators.  Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization.  N Engl J Med.1997;336:1689-1696.
The 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.
Abdelmeguid AE, Topol EJ. The myth of the myocardial ‘infarctlet' during percutaneous coronary revascularization procedures.  Circulation.1996;94:3369-3375.
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