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Background: Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel., Methods: PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours., Results: A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05)., Conclusions: In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mortality and morbidity in acute coronary syndromes (ACSs), caused principally by plaque erosion or rupture leading to thrombus formation and myocardial ischemia, have been reduced by a combination of antithrombotic agents (antiplatelet drugs and anticoagulants) and early revascularization. Aspirin is the foundation antiplatelet agent. New P2Y12 receptor inhibitors (prasugrel and ticagrelor) have clear benefits compared with clopidogrel for dual antiplatelet therapy, and cangrelor or vorapaxar, a thrombin receptor inhibitor, may be of value in specific settings. Anticoagulation uses 1 of 4 choices: bivalirudin, unfractionated heparin, enoxaparin, and fondaparinux. Moreover, some patients (such as those who have chronic atrial fibrillation) require triple therapy with aspirin, clopidogrel, plus an anticoagulant, frequently a vitamin K antagonist. New oral anticoagulants have been shown to be at least as effective as vitamin K antagonists in atrial fibrillation and led to fewer bleeding complications. Finally, the combination of aspirin, clopidogrel, and low-dose rivaroxaban has recently been approved by the European Medicines Agency (but not the Food and Drug Administration) for secondary prevention after ACS. Several strategies have been developed to balance the potential benefit of antithrombotic therapy against the risk of bleeding complications, for example, radial access in coronary angiography or restricted use of combination therapy, and others are under investigation, such as discontinuation of aspirin. This overview summarizes the current status of antithrombotic therapy in ACS and describes strategies currently explored to optimize its benefit/risk ratio., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Tirofiban and eptifibatide are both small-molecule, competitive glycoprotein IIb/IIIa receptor inhibitors (GPIs) that are guideline-supported for upstream therapy in acute coronary syndromes (ACS). This study sought to compare the efficacy and safety of tirofiban and eptifibatide in patients with ACS., Methods: Within the ACUITY trial, 4,323 patients with moderate- and high-risk ACS received upstream, adjunctive GPI (tirofiban or eptifibatide) in addition to an antithrombin. Primary outcomes included 30-day rates of composite major adverse cardiac events (MACE), major bleeding (not related to coronary artery bypass grafting), and composite net adverse clinical events (NACE). The outcomes were compared based on the upstream GPI administered., Results: There were significant differences in the baseline characteristics of patients treated with tirofiban vs eptifibatide, particularly related to country/region. In unadjusted analyses, treatment with upstream tirofiban vs eptifibatide was associated with similar rates of major bleeding (5.8% vs 6.5%, P = .39) and nonsignificantly lower rates of MACE (6.1% vs 7.6%, P = .06) and NACE (10.6% vs 12.6%, P = .06). After propensity-based multivariable adjustment, there were no significant differences between tirofiban and eptifibatide with respect to 30-day major bleeding, MACE, or NACE., Conclusions: Among more than 4,000 patients with moderate- and high-risk ACS treated with upstream GPI as part of an early invasive management strategy, the use of tirofiban and eptifibatide resulted in similar clinical outcomes. These data suggest equivalence of these 2 agents for upstream use, while highlighting some of the difficulties of nonrandomized comparative effectiveness analyses, specifically the difficulty in addressing geographic differences in the use of nonrandomized treatments., (© 2014.)

Background: Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population., Methods: We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds., Results: Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P < .01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI 3.9-8.8) than among women (odds ratio 1.5, 95% CI 0.8-2.9; sex * bleeding interaction P < .01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors., Conclusions: In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women., (© 2013.)

Aims: In the EARLY ACS trial, routine early eptifibatide was not superior to delayed provisional use at percutaneous coronary intervention (PCI); however, among PCI-treated patients, numerically fewer ischemic end points occurred in the upstream eptifibatide group. We sought to further explore this finding using methods for examination of treatment effect in this postrandomization subgroup., Methods and Results: Of 9,406 patients in the EARLY ACS primary analysis cohort, 9,166 (97.4%) underwent coronary angiography. We used Cox proportional hazards regression modeling, with PCI as a time-dependent covariate, to examine the effect of routine early versus delayed provisional eptifibatide among 5,541 patients undergoing PCI and to explore the interaction between treatment with PCI and randomized treatment strategy. After multivariable adjustment, compared with delayed provisional use, routine early eptifibatide was associated with lower rate of 30-day death or myocardial infarction (MI) after PCI (hazard ratio [HR] 0.80, 95% CI 0.68-0.95) but not with medical management (HR 0.97, 95% CI 0.74-1.29); PCI × randomized treatment interaction term P = .24. Excluding PCI-related MI, the adjusted HR for 30-day death or MI for routine early eptifibatide versus delayed provisional use was 0.80 (95% CI 0.60-1.08) for post-PCI treatment and 1.01 (95% CI 0.79-1.34) for medical management; PCI × randomized treatment interaction term P = .28., Conclusions: Consistent with previous literature, upstream treatment with eptifibatide was associated with improved outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients treated with PCI; however, a nonsignificant interaction term precludes a definite conclusion., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Bleeding is a major limitation of antithrombotic therapy among invasively managed non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients; therefore, we examined the use of radial access and its association with outcomes among NSTE-ACS patients., Methods: Clinical characteristics and geographic variation in radial access were examined, as well as its association with bleeding, red blood cell transfusion and ischemic outcomes (96-hour death/myocardial infarction/recurrent ischemic/thrombotic bailout; 30-day death/myocardial infarction; 1-year death) in the EARLY versus delayed, provisional eptifibatide in acute coronary syndromes trial., Results: Of 9126 patients, 13.5% underwent radial-access catheterization. Female sex, age, weight, and prior revascularization were inversely associated with radial access, and its use varied widely by country (2%-97%). There were fewer GUSTO severe/moderate bleeds and red blood cell transfusions in the radial access group; however, it was attenuated after adjustment (odds ratio 0.73, 95% confidence intervals [CI] [0.50-1.06], P = .094 and 1.00 [0.71-1.40] P = .991). Ischemic outcomes did not differ by access site., Conclusions: In this post hoc analysis of a large clinical trial, there was significant international variation in use of radial access for NSTE-ACS patients undergoing invasive management, and it was preferentially used in those at lower risk for bleeding. Radial approach was not associated with a significant reduction in either bleeding or ischemic outcomes. Further study is needed to determine whether wider application of radial approach to acute coronary syndrome patients at high risk for bleeding improves overall outcomes., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset/offset, linear kinetics, and no significant renal elimination. A phase II trial in acute coronary syndromes (ACS) showed a marked reduction in the combined end point of death or myocardial infarction (MI) and similar bleeding rates with otamixaban at midrange doses, compared with unfractionated heparin (UFH) and eptifibatide., Design: The TAO trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy of otamixaban over UFH plus eptifibatide in patients with non-ST-segment elevation ACS to be treated with dual oral antiplatelet therapy and an invasive strategy. Approximately 13,220 patients in 55 countries will be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started pre-percutaneous coronary intervention and continued per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). An interim analysis was performed after ≥1,969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected 1 otamixaban dose (blinded to investigators) to be carried forward using a prespecified algorithm. The primary efficacy outcome is the composite of all-cause mortality or new MI through day 7. The primary safety outcome is thrombolysis in MI major or minor bleeding through day 7. Secondary outcomes include all-cause mortality, recurrent ischemia/infarction resulting in prolonged/recurrent hospitalization, periprocedural angiographic complications, and pharmacokinetic data in 6,000 patients., Conclusions: The TAO trial will assess the clinical efficacy and safety of otamixaban in non-ST-segment elevation ACS with planned invasive strategy., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: The optimal antiplatelet regimen in elective patients undergoing complex percutaneous coronary interventions (PCIs) is uncertain. We aimed to assess the impact of glycoprotein IIb/IIIa (GpIIb/IIIa) inhibition with eptifibatide in clinically stable subjects with diffuse coronary lesions., Methods: Patients with stable coronary artery disease undergoing PCI by means of implantation of >33 mm of drug-eluting stent were single-blindedly randomized to heparin plus eptifibatide versus heparin alone. The primary end point was the rate of abnormal post-PCI creatine kinase-MB mass values. Secondary end points were major adverse cardiovascular events (MACEs) (ie, cardiac death, myocardial infarction, or urgent revascularization) and MACE plus bailout GpIIb/IIIa inhibitor use., Results: The study was stopped for slow enrollment and funding issues after including a total of 91 patients: 44 were randomized to heparin plus eptifibatide, and 47, to heparin alone. Analysis for the primary end point showed a trend toward lower rates of abnormal post-PCI creatine kinase-MB mass values in the heparin-plus-eptifibatide group (18 [41%]) versus the heparin-alone group (26 [55%], relative risk 0.74 [95% CI 0.48-1.15], P = .169). Similar nonstatistically significant trends were found for rates of MACE, their components, or MACE plus bailout GpIIb/IIIa inhibitors (all P > .05). Notably, heparin plus eptifibatide proved remarkably safe because major bleedings or minor bleeding was uncommon and nonsignificantly different in both groups (all P > .05)., Conclusions: Given its lack of statistical power, the INSTANT study cannot definitively provide evidence against or in favor of routine eptifibatide administration in stable patients undergoing implantation of multiple drug-eluting stent for diffuse coronary disease. However, the favorable trend evident for the primary end point warrants further larger randomized studies., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: KILO tested 2 novel weight-based eptifibatide dosing strategies compared with standard dosing in obese patients undergoing elective percutaneous coronary intervention (PCI). Eptifibatide dosing is weight adjusted for patients up to 121 kg. Patients above this weight receive the same maximal dose, although it is unknown if this provides adequate eptifibatide concentration or platelet inhibition., Methods: Sixty-seven patients weighing ≥125 kg undergoing elective PCI were randomized to 1 of 3 eptifibatide dosing regimens: standard dosing using a weight of 121 kg, actual body weight (ABW)-based dosing with no upper limit, or ideal body weight (IBW)-based dosing. Boluses of 180 μg/kg were given 10 minutes apart, followed by a 2.0 μg/kg per minute infusion. Plasma eptifibatide concentrations were drawn at 12 to 18 hours after initiating the infusion. Platelet aggregation was assessed at baseline and 10 minutes after the second bolus., Results: Sixty-seven patients were randomized to standard (n = 22), ABW (n = 23), or IBW (n = 22) dosing. The median (25th, 75th) steady-state plasma eptifibatide concentrations were 1,740 ng/mL (1,350, 2,350), 1,780 ng/mL (1,510, 2,350), and 1,055 ng/mL (738, 1,405), respectively (P < .001). Ten-minute median (25th, 75th) platelet aggregation units were 7 (0, 21), 2 (0, 8), and 14 (8, 20), respectively (P = .001)., Conclusions: Actual body weight eptifibatide dosing leads to higher plasma concentrations and greater platelet inhibition than standard or IBW dosing in obese patients undergoing PCI. Current recommendations for eptifibatide dosing may be inadequate in patients >121 kg. Further study is warranted to define the optimal dosing of eptifibatide and other medications in obese patients., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy., Methods: Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 μg/kg/min; estimated creatinine clearance [eCrCl] ≥50 ml/min), adjusted dose (1 μg/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 μg/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI)., Results: Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy., Conclusion: Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency., (Copyright © 2011 Mosby, Inc. All rights reserved.)

We present a 56-year-old man who developed acute transient phlebitis of the right cephalic vein during an intravenous injection of eptifibatide (Integrilin, Schering Plough, Kenilworth, NJ). The eptifibatide injections were discontinued, and signs of phlebitis disappeared within minutes. The patient's course was uneventful, and he was discharged home after 8 days. As far as we know, this is the first report of acute transient phlebitis during intravenous eptifibatide injections in the English-language medical literature., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: The study aimed to determine the impact on eptifibatide-associated bleeding by implementing a computerized dosing algorithm in the cardiac catheterization suite., Background: Excessive dosing of eptifibatide is associated with increased bleeding rates and hospital mortality. Although dosing adjustments based on renal function has been recommended, its implementation and clinical impact have not been assessed in daily practice., Methods: A computerized algorithm was implemented in January 2006 to calculate appropriate eptifibatide infusion dose (1 microg kg(-1) min(-1) for creatinine clearance <50 mL/min or 2 microg kg(-1) min(-1) for creatinine clearance >or=50 mL/min) using the Cockroft-Gault formula. All patients had hemoglobin measured before and the day after the procedure. Bleeding within 24 hours and mortality during hospitalization were compared in consecutive patients before and after implementation of the algorithm., Results: A total of 334 patients qualified for inclusion (pre-algorithm n = 91, post-algorithm n = 243). There was an increase in the proportion of patients receiving recommended doses of eptifibatide dosing (74.7% pre-algorithm vs 97.5% post-algorithm, P

Background: Bleeding is associated with adverse outcome in acute coronary syndromes. However, the precise pathophysiologic mechanisms have not been elucidated. We sought to determine the relationship between bleeding and myocardial ischemia detected by concurrent continuous electrocardiogram (ECG) monitoring and their independent long-term prognostic significance., Methods: The INTERACT trial was a randomized controlled trial of enoxaparin versus unfractionated heparin in patients with high-risk non-ST-elevation acute coronary syndromes. Continuous ECG monitoring, performed after enrollment up to 96 hours, was analyzed by an automated algorithm and reviewed by a blinded cardiologist. We centrally adjudicated all bleeding and clinical events in a blinded fashion and calculated the Global Registry of Acute Coronary Events risk score (a validated predictor of mortality) for each patient., Results: Of the 746 patients enrolled, 34 (4.6%) developed major bleeding within 96 hours. After a median follow-up of 2.4 years, patients with bleeding had a higher risk of death (28.4% vs 7.3%, P < .001) and death/myocardial infarction (38.0% vs 12.9%, P < .001) compared with those without bleeding. Overall, 619 patients survived the first 96 hours with complete data on continuous ECG monitoring. Bleeding was associated with the simultaneous presence of ST-segment shifts on continuous ECG monitoring (P = .03). After adjusting for Global Registry of Acute Coronary Events risk score and myocardial ischemia detected by continuous ECG monitoring, major bleeding remained an independent predictor of death (adjusted hazard ratio = 3.48, 95% confidence interval 1.51-8.03, P = .003) and death/myocardial infarction (adjusted hazard ratio = 2.85, 95% confidence interval 1.40-5.78, P = .004)., Conclusions: Bleeding is a powerful independent predictor of poor long-term outcome, even after adjusting for other associated prognostic factors such as advanced age and renal dysfunction. Although bleeding is associated with concurrent myocardial ischemia, its adverse prognostic impact may be mediated by complex pathophysiologic mechanisms rather than myocardial ischemia alone. Our findings suggest that future investigations should focus on other biologically plausible mechanisms.

Background: The present study was done to analyze if glycoprotein IIb/IIIa inhibitors (GPI) bolus-only will reduce vascular/bleeding complications and cost with similar major adverse cardiac events (MACE) when compared with GPI bolus + infusion. Evidence-based therapy of GPI inhibitors during percutaneous coronary intervention (PCI) incorporates intravenous bolus followed by 12 to 18 hours of infusion. However, GPI bolus + infusion may increase vascular/bleeding complications and may not reduce MACE when compared with GPI bolus-only., Methods: From January 1, 2003, to December 31, 2004, 2,629 consecutive patients received GPI during PCI at a single center. Of these, 1,064 patients received GPI bolus + infusion in 2003 and were compared with 1,565 patients that received GPI bolus-only in 2004. Baseline characteristics were similar in both groups., Results: Patients receiving GPI bolus-only had reduced vascular/bleeding complications when compared with bolus + infusion (4.9% vs 7%, P < .05, odds ratio 0.62, 95% confidence interval 0.45-0.89). Furthermore, ischemic complications were similar in both groups, including periprocedural creatine kinase-MB enzyme release (12.8% vs 15.3%, P = NS), MACE at 30 days (3.2% vs 3%, P = NS), and death and myocardial infarction at 1 year (7.1% vs 7.8%, P = NS). In addition, GPI bolus-only reduced cost in US dollars ($323 vs $706, P < .001) and increased ambulatory PCI (13.1% vs 3.2%, P < .01), with reduced length of stay (1.1 vs 1.6 days, P < .01), when compared with GPI bolus + infusion., Conclusions: Glycoprotein inhibitor bolus-only reduces vascular/bleeding complications with similar MACE and reduced cost when compared with GPI bolus + infusion. In addition, GPI bolus-only improved ambulatory PCI and reduced length of stay. These results are consistent with a safer and cost-effective strategy for bolus-only when GPI therapy is considered during PCI.

Background: Optimal inhibition of platelet aggregation (IPA) may afford greater protection against ischemic events during percutaneous coronary intervention (PCI). The objective of this study was to test several antiplatelet regimens in elective high-risk PCI patients by comparing different combinations of glycoprotein IIb/IIIa inhibitors and clopidogrel., Methods: The study was a randomized open-label study at 3 heart centers in India. One hundred twenty patients were enrolled between July 2006 and September 2006. Patients were randomized to 1 of the 4 groups: group A--tirofiban, group B--eptifibatide, group C--tirofiban + clopidogrel 600-mg loading dose, and group D--eptifibatide + clopidogrel 600-mg loading dose. All patients received a clopidogrel maintenance dose after PCI. The primary outcome measure was the IPA assessed at 10 minutes, at 6 to 8 hours, and at 24 hours., Results: The IPA was higher with high-dose tirofiban compared with eptifibatide at 10 minutes (95.88 +/- 5.85% vs 91.22 +/- 7.52%, P = .003) and at 6 to 8 hours (93.11 +/- 7.6% vs 85.45 +/- 11.03, P < .001). Significantly more patients achieved >95% IPA with the high-dose tirofiban regimen., Conclusions: This head-to-head study comparing high-dose tirofiban with double-bolus eptifibatide demonstrated higher degree of platelet inhibition with high-dose tirofiban at 10 minutes and at 6 to 8 hours in patients undergoing elective high-risk PCI. The addition of clopidogrel did not acutely extend the IPA from intravenous glycoprotein IIb/IIIa inhibitors, but did so at 24 hours.

Background: This study evaluated the immediate and intermediate results of intracoronary (i.c.) eptifibatide administration during percutaneous coronary intervention (PCI). Several studies tested intravenous (i.v.) bolus and continuous administration of eptifibatide during PCI. However, limited data are available regarding giving eptifibatide as i.c. bolus alone during PCI., Methods: We studied clinical outcomes of 376 patients who received coronary stent(s) and eptifibatide by 3 applications during PCI and were followed up over 24 months. Group A (119 patients) had i.c. eptifibatide bolus only, group B (119 patients) had i.c. bolus and i.v. infusion, and group C (138 patients) had i.v. bolus and infusion. The standard 2 boluses of eptifibatide 180 microg/kg were given either via i.c. or i.v. route, and only groups B and C received i.v. infusion at 2 microcg x kg(-1) x min(-1) for 18 to 24 hours., Results: There were 256 males and 120 females, with a mean age of 57 +/- 11 years. Among them, 52% were diabetic. The 6-, 12-, and 24-month cumulative composite end point of death and myocardial infraction was lower in group A (2.5%) compared with group C (10.8%, odds ratio [OR] 4.3, P = .029) and group B (5.8%, OR 2.6, P = .17). Compared with group A, target vessel revascularization was 3-fold in group C (OR 3.3, P = .001) and 2-fold in group B (OR 2.0, P = .061). Bleeding was significantly higher in group C (OR 5.4, P < .0001) and group B (OR 3.4, P = .007) compared with group A. Rehospitalization was significantly lower in group A (10.9%) compared with group B (16.8%) and group C (28%) (P = .0009)., Conclusion: The i.c.-bolus-alone application of eptifibatide may be safer and superior to the i.v. route, and continuous infusion may not be necessary. Large-scale prospective randomized trials are needed to further validate these findings.

Background: Early restoration of epicardial flow before primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) has been associated with improved clinical outcomes., Methods: We hypothesized that early administration of the glycoprotein IIb/IIIa inhibitor eptifibatide in the emergency department (ED) would yield superior epicardial flow and myocardial perfusion before primary PCI compared with initiating eptifibatide after diagnostic angiography in the cardiac catheterization laboratory (CCL). Three hundred forty-three patients with STEMI were randomized to either early ED eptifibatide (n = 180) or CCL eptifibatide (n = 163)., Results: The primary end point (pre-PCI corrected TIMI frame count) was significantly lower (faster flow) with early eptifibatide (77.5 +/- 32.2 vs 84.3 +/- 30.7, P = .049). The incidence of normal pre-PCI TIMI myocardial perfusion was increased among patients treated in the ED versus CCL (24% vs 14%, P = .026). There was no excess of TIMI major or minor bleeding among patients treated in the ED versus CCL (6.9% [12/174] vs 7.8% [11/142], P = NS)., Conclusion: A strategy of early initiation of eptifibatide in the ED before primary PCI for STEMI yields superior pre-PCI TIMI frame counts, reflecting epicardial flow, and superior TIMI myocardial perfusion compared with a strategy of initiating eptifibatide in the CCL without an increase in bleeding risk.

Background: Patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) benefit from the early administration of aspirin, a small molecule glycoprotein IIb/IIIa inhibitor such as eptifibatide, and heparin. The INTERACT trial demonstrated that in high-risk patients with ACS receiving aspirin and eptifibatide, the use of enoxaparin compared with unfractionated heparin (UFH) was associated with less bleeding, less early myocardial ischemia, and improved 30-day outcomes., Objective: The aim of our study was to determine whether the short-term benefits of enoxaparin compared with UFH observed in high-risk patients with NSTE ACS are maintained over a prolonged period of follow-up., Methods: Six hundred thirty-nine patients that were representative of the total population of subjects in the INTERACT trial were followed up for a median period of 2.5 years., Results: In this group, the early benefit of enoxaparin was maintained. The incidence of death or myocardial infarction at the time of long-term follow-up was 39% lower in patients receiving enoxaparin compared with those who received UFH (8.9% vs 14.7%, P = .024). There was no difference in the frequency of cardiac catheterization in the groups receiving either enoxaparin or UFH., Conclusions: The early treatment of high-risk patients with NSTE ACS receiving aspirin and eptifibatide with enoxaparin is associated with early outcome benefits that are sustained over a prolonged follow-up period. This trial supports the concept that early treatment directed against platelet and thrombin formation is associated with better short- and long-term outcomes.

Background: Despite meticulous investigation of bypass techniques for deep hypothermic circulatory arrest, unfavorable long-term neurologic deficits have been well documented. Our aim was to improve brain perfusion by reducing platelet plugging with a glycoprotein IIb/IIIa inhibitor (eptifibatide) in an experimental model of deep hypothermic circulatory arrest-reperfusion in pigs., Methods: Two groups of 12 piglets each (eptifibatide group [eptifibatide + unfractionated heparin] vs UFH group [only unfractionated heparin]) underwent 10 minutes of normothermic bypass, 40 minutes of cooling during cardiopulmonary bypass (hematocrit, 30%; cardiopulmonary bypass flow, 100 mL x kg(-1) x min(-1)), 60 minutes of circulatory arrest at 15 degrees C, and a 40-minute rewarming period. Intravital fluorescence microscopy of pial vessels at set intervals was performed., Results: During the cooling period, there was a tendency toward reduced functional capillary density values without statistical significance in both groups. During reperfusion, the eptifibatide group demonstrated a significantly decreased platelet adhesion and aggregation (at 30 minutes of reperfusion: functional capillary density, 104% +/- 3% vs 77% +/- 4% relative to baseline, P = .02; red blood cell velocity, 0.65 vs 0.30 mm/s, P < .004). A more rapid recovery of tissue oxygenation (P < .001) was documented. Furthermore, a significant microvascular permeability reduction was achieved compared with that seen in the UFH group (P < .02). The use of eptifibatide resulted in fewer ultrastructural changes in hippocampal tissue, which is demonstrated by histologic examination., Conclusions: Platelet plugging reduction with the glycoprotein IIb/IIIa inhibitor eptifibatide improves cerebral capillary blood flow and reduces cerebral ischemia in the setting of deep hypothermic circulatory arrest. Furthermore, significant endothelial cell injury and perivascular edema reduction can be achieved.

Background: Facilitated percutaneous coronary intervention (PCI)--simultaneous administration of glycoprotein IIb/IIIa inhibitors and reduced-dose fibrinolytics before primary PCI for ST-segment elevation myocardial infarction (STEMI)--may be a promising reperfusion strategy., Methods: The ADVANCE MI trial was intended to evaluate facilitated PCI in 5640 STEMI patients but was prematurely terminated as a result of slow recruitment over 12 months at 30 centers in the United States. Patients with STEMI with planned primary PCI were randomly assigned to receive eptifibatide + 50% of standard-dose tenecteplase (which equated to 0.25 mg/kg intravenous bolus) or eptifibatide + placebo before PCI and randomized in a 2 x 2 factorial design to unfractionated heparin or enoxaparin., Results: A total of 148 patients were randomized (74 patients in each treatment arm) and formed the "as-randomized" intention-to-treat population. However, only 69 patients actually received eptifibatide + tenecteplase, and 77 actually received eptifibatide + placebo (2 patients did not receive eptifibatide and 4 patients randomized to tenecteplase did not receive this therapy)--these 146 patients formed the "as-treated" population. Among both populations, epicardial infarct artery patency and myocardial tissue perfusion on pre-PCI angiography were improved in the tenecteplase group, but ST-segment resolution at 60 minutes was similar. The frequency of the primary end point of death or new/worsening severe heart failure at 30 days was higher among patients treated with eptifibatide + tenecteplase in the "as-treated" (10% vs 3%, P = .09) and the "as-randomized" (11% vs 1%, P = .02) populations. Bleeding complications were 2-fold higher with eptifibatide + tenecteplase. Analysis of the results by treatment with unfractionated heparin versus enoxaparin demonstrated similar findings., Conclusions: Although definitive conclusions cannot be made as a result of the small sample size and premature study termination, facilitated PCI with eptifibatide + reduced-dose tenecteplase was associated with improved angiographic flow patterns, increases in adverse clinical outcomes, and higher bleeding rates compared with eptifibatide + placebo administered before primary PCI for STEMI.

Background: The recent North American and European practice guidelines in patients with non-ST-segment elevation acute coronary syndrome (nSTE ACS) recommend glycoprotein IIb/IIIa (GpIIb-IIIa) inhibition in patients undergoing an early invasive treatment strategy. However, the guidelines are not explicit regarding the timing of initiation of GpIIb-IIIa antagonists, and there is marked variation in clinical practice regarding their use., Study Design: The EARLY ACS trial will enroll 10,500 patients in a prospective, randomized, double blind, international, multicenter investigation of early eptifibatide compared with placebo (with provisional eptifibatide in the catheterization laboratory) in patients with high-risk nSTE ACS in whom an invasive strategy is planned no sooner than the next calendar day. The primary efficacy end point is the 96-hour composite of all-cause mortality, nonfatal myocardial infarction, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout with GpIIb-IIIa inhibitor during percutaneous coronary intervention. The key secondary end point is the composite of death or nonfatal myocardial infarction within 30 days of enrollment., Implications: The EARLY ACS trial will be the largest study to date to evaluate the utility of early GpIIb-IIIa inhibition in patients with nSTE ACS in whom an invasive approach is planned. This trial will provide important evidence regarding the benefit of initiating eptifibatide early after presentation with high-risk ACS versus delayed provisional use after coronary angiography. Furthermore, it will explore the ability of biomarkers to identify high-risk patients who may benefit from such an early aggressive approach.

Background: Unfractionated heparin (UFH) has been considered the standard anticoagulant for patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS), yet it has limitations, including an unpredictable dose-response and intravenous administration. Enoxaparin was shown to be more effective than UFH in two large, randomized trials, ESSENCE and TIMI 11B. These trials were conducted before the widespread use of glycoprotein (GP) IIb/IIIa inhibitors, clopidogrel, and an early invasive management strategy, leaving questions concerning whether and how newer agents should be used in combination., Methods: The INTERACT trial compared the efficacy and safety of enoxaparin, relative to UFH, in high-risk NSTE ACS patients receiving aspirin and the GP IIb/IIIa inhibitor eptifibatide. The design and primary results of INTERACT are reviewed and compared with similar trials of combination therapy and with observational studies., Results: In INTERACT, enoxaparin was associated with significant reductions in recurrent ischemia during the first 4 days, death or myocardial infarction at 30 days, and non-coronary artery bypass grafting-related major bleeding at 4 days relative to UFH. Recent trials of enoxaparin in NSTE ACS patients have differed in the use of concomitant medications, the timing and frequency of invasive procedures, and end point definitions. The results from INTERACT are consistent with the results of ESSENCE and TIMI 11B and with "real-world" data from the CRUSADE and GRACE registries., Conclusions: In high-risk patients with NSTE ACS, strong consideration should be given to initiation of therapy with aspirin, enoxaparin, a GP IIb/IIIa inhibitor, and clopidogrel while pursuing an early invasive approach.

Background: Adjunctive pharmacotherapy during percutaneous coronary intervention (PCI) has historically consisted of a regimen of antiplatelet agents accompanied by an antithrombin agent, typically unfractionated heparin. Paradoxically, unfractionated heparin may activate platelets, induce other pro-thrombotic activities, increase bleeding complications, and cause thrombocytopenia. To optimize patient care and avoid the potential risks of unfractionated heparin in patients undergoing elective PCI, one of the authors began to use adjunctive pharmacotherapy consisting of broad-spectrum antiplatelet therapy alone, without scheduled unfractionated heparin or other antithrombin therapy., Methods: Five hundred consecutive patients undergoing scheduled, elective PCI (stent deployment, cutting balloon atherotomy, conventional balloon angioplasty, or high-speed rotational atherectomy) received adjunctive pharmacotherapy consisting of eptifibatide, clopidogrel, and aspirin., Results: The technical success rate was 100%. During the first 24 hours, there were no major adverse clinical events. Non-Q-wave myocardial infarction occurred in 1.6% of patients, major and minor bleeding complications in 0.2% and 0.6%, respectively, and thrombocytopenia in 0.6%. During the first 30 days, there was 1 (0.2%) major adverse clinical event., Conclusions: For elective PCI, adjunctive pharmacotherapy consisting of broad-spectrum antiplatelet therapy alone, without scheduled unfractionated heparin or other antithrombin therapy, appears to be safe and may prove to be efficacious.

Background: More complete ST-segment resolution (ST res) in acute myocardial infarction (MI) has been associated with better epicardial and myocardial reperfusion as assessed with the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and the TIMI myocardial perfusion grade (TMPG), respectively. However, no data exist comparing the speed of ST resolution on continuous electrocardiogram (ECG) monitoring with the TMPG on coronary angiography. We hypothesized that delayed ST res is associated with impaired TMPGs., Methods: Continuous 12-lead ECG recordings and 60-minute angiographic data were analyzed in 120 patients with acute MI who received tenectaplase monotherapy or combination therapy with low-dose tenectaplase and eptifibatide in the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial., Results: More rapid ST res on continuous ECG monitoring was associated with improved TMPGs on coronary angiography performed 60 minutes after study drug administration. For TMPG 3, the median time to ST resolution was 53 minutes. For TMPG 2, 1, and 0, the corresponding times were 64 minutes, 80 minutes, and 106 minutes, respectively (P =.01 for trend). Likewise, more rapid ST res was also associated with faster epicardial flow. For TFG 3, the median time to ST resolution was 46 minutes, compared with 109 minutes for TIMI flow grades 0 to 2 (P =.001). The corresponding times for a corrected TIMI frame count < or =40 versus >40 were 52 minutes and 112 minutes, respectively (P <.001)., Conclusions: Although the static ECG has been associated with epicardial and myocardial blood flow in the past, this study extends these observations to demonstrate that more rapid ST res on continuous ECG monitoring is associated with improved myocardial perfusion after thrombolytic administration.

Background: Glycoprotein (GP) IIb/IIIa antagonists have become a mainstay for the treatment of acute coronary syndromes. Yet, they have rarely been evaluated under relevant pathophysiologic conditions, for example, high shear rates in the presence of physiologic calcium concentrations. We compared the efficacy of eptifibatide and tirofiban versus placebo on high shear-induced platelet plug formation in a model in which healthy subjects exhibit von Willebrand factor concentrations and platelet activation comparable to patients with acute coronary syndromes., Methods: Thirty male volunteers received 2 ng/kg endotoxin and standard doses of eptifibatide, tirofiban, or placebo over a period of 5 hours in a randomized, double-blinded, placebo-controlled, double-dummy parallel-group trial. Platelet inhibition was measured with the Platelet Function Analyzer-100 (PFA-100) and the Ultegra method., Results: Although bolus infusion of both GPIIb/IIIa antagonists inhibited high shear-induced platelet plug formation, continuous infusion of eptifibatide prolonged closure times more effectively than did tirofiban (P <.008). Interestingly, tirofiban had only placebo-like effects on platelet plug formation after 2 hours. However, when additional drug was exogenously added, closure time values were maximally prolonged in all cases., Conclusions: Standard doses, particularly of tirofiban, have limited impact on high shear-induced platelet plug formation at physiologic Ca(2+) concentrations.

Background: We evaluated whether the use of glycoprotein IIb/IIIa receptor inhibitors, in addition to heparin and aspirin, imparts an incremental benefit in a subgroup of patients with acute coronary syndromes (ACS) who had congestive heart failure (CHF) symptoms at presentation., Methods: We analyzed patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized, double-blind, placebo-controlled study evaluating the use of eptifibatide versus placebo for patients with ACS without persistent ST-elevation. We compared the clinical characteristics and 30-day outcomes for 861 patients who had Killip class II or III CHF symptoms with those of 8558 patients who had no CHF symptoms., Results: Odds ratios for the primary end point, 30-day death or non-fatal myocardial infarction, in the placebo group versus the eptifibatide group were similar for patients with and without CHF (odds ratio, 1.11; 95% CI, 0.8-1.5; odds ratio, 1.13; 95% CI, 1.0-1.3). However, adverse events were almost twice as frequent for patients with CHF compared with patients with no CHF (24.5% vs 14%)., Conclusions: Although patients with non-ST-segment elevation ACS who have CHF have markedly worse outcomes than patients without CHF symptoms, we did not find an incremental benefit from the use of eptifibatide in this seriously ill subgroup.

Background: The acute benefits of platelet glycoprotein IIb/IIIa inhibitors for non-ST-segment elevation acute coronary syndromes (NSTE ACS) remain unclear., Methods: In this pilot trial, 311 patients with NSTE ACS were randomly assigned in the emergency department to double-blinded therapy with eptifibatide or placebo for 12 to 24 hours before crossover to open-label eptifibatide. Serial creatine-kinase MB (CK-MB) and quantitative cardiac troponin T levels were collected during the first 24 hours to assess the impact of early platelet glycoprotein IIb/IIIa blockade on infarct size as measured by cardiac markers., Results: Median peak CK-MB (10.3 vs 11.8 ng/mL; P =.71) and peak quantitative cardiac troponin T levels (0.2 vs 0.3 ng/mL; P =.95) were similar between treatment groups, respectively. Median calculated peak CK-MB values (41 vs 40 ng/mL; P =.72) and area under the CK-MB curve measurements (980 vs 764 microg/min/L; P =.68) from curve-fitting analyses that could be performed in 106 of 311 patients were also similar., Conclusions: In this pilot trial, early administration of eptifibatide in the emergency department did not modulate serologic measurements of infarct size in patients with NSTE ACS.

Despite extensive data supporting their use for non-ST-segment elevation acute coronary syndromes, glycoprotein (GP) IIb/IIIa antagonists are underutilized. This is likely the consequence of confusion as to which patients should receive these agents, as well as to the most appropriate timing and venue for their initiation. We will review the advances in the understanding of GP IIb/IIIa antagonist therapy, emphasizing methods of identifying those most likely to benefit from the use of GP IIb/IIIa receptor blockade. In addition, we will consider appropriate methods/venues for use of GP IIb/IIIa receptor antagonism, including its role in an "early invasive" catheterization strategy.

Background: The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) risk score was derived from the PURSUIT trial population for 30-day mortality prediction., Methods: The PURSUIT risk score was calculated for 337 consecutive Olmsted County residents with non-ST-elevation acute myocardial infarction admitted to the coronary care unit of our institution from 1988 through 1998. Predischarge ejection fraction (EF) measurement was available for 246 patients (73%). After excluding patients with prior coronary artery bypass graft surgery (n = 42), 219 patients (65%) had coronary angiography within 30 days of admission. Mortality at 30 days was 8.9%. Among 30-day survivors, mortality at 1 year was 7.9%., Results: Mean age was 70 +/- 13 years, and 37% of patients were women. Mean predischarge EF was 52% +/- 16%. Patients with higher PURSUIT risk score had lower EF (P <.001). Three-vessel (> or =70% stenosis in all 3 coronary arteries) or left main (> or =50% stenosis) coronary artery disease was present in 60 of 219 patients (27%) who had coronary angiography. Higher PURSUIT risk score was associated with greater likelihood of 3-vessel or left main disease (P <.001). The PURSUIT risk score had very good predictive accuracy for both early (30-day, C-statistic = 0.78) and late (30-day to 1-year, C-statistic = 0.77) mortality., Conclusions: The PURSUIT risk score correlates with EF, angiographic severity of coronary artery disease, and short- and long-term mortality of nonselected patients with non-ST-elevation acute myocardial infarction.

Background: In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI)., Methods: The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST-elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia., Results: A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively)., Conclusions: The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.

Background: A simple device to rapidly evaluate platelet function may aid in optimizing glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention (PCI). We prospectively studied platelet function in 250 patients receiving abciximab or eptifibatide during PCI., Methods and Results: The platelet function analyzer PFA-100 (Dade-Behring, Deerfield, Ill) measures platelet function by determining the time to occlusion of an aperture in a biochemically active membrane as whole blood flows under high shear conditions. Platelet aggregation causes aperture occlusion, and results are reported as a closure time (CT). All patients received either abciximab or eptifibatide, along with aspirin and heparin; patients undergoing stent implantation received aspirin and a thienopyridine postprocedure. The CT was measured at baseline and 10 minutes, 4 hours, 12 hours (abciximab-only), and 24 hours after the bolus. Profound inhibition was exhibited in most patients shortly after the platelet inhibitor bolus and during the course of therapy. We observed recovery of platelet function 12 hours after discontinuation of abciximab, with a high degree of interpatient variability, and ongoing profound platelet inhibition 4 to 6 hours after the discontinuation of eptifibatide. Among patients treated with abciximab, patients who were obese recovered from platelet inhibition sooner than patients who were not obese, whereas patients who were elderly had delayed recovery compared with patients who were not elderly. Failure to achieve maximal platelet inhibition (nonclosure) at 10 minutes indicated a possible association with adverse clinical events at the 6-month follow-up examination (60% vs 20%)., Conclusions: PFA-100 is a rapid simple assay used as a means of assessing inhibition of platelet aggregation during PCI performed with glycoprotein IIb/IIIa inhibition. Failure to achieve nonclosure early after the initiation of abciximab therapy warrants further investigation because there may be an association with adverse cardiac events at 6-month follow-up.

Background: Platelet surface glycoprotein IIb/IIIa (alphaIIb/beta3) receptor inhibition, with prevention of fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes., Purpose: Because the currently available, Food and Drug Administration-approved small molecule glycoprotein IIb/IIIa receptor antagonists are considered "competitive" inhibitors and there is limited information on the reversibility of platelet inhibition with fibrinogen or platelet supplementation, the following series of in vitro experiments were performed., Methods and Results: Washed platelets from 24 healthy volunteers were suspended in tyrodes buffer and incubated with achievable (in vivo) concentrations of either tirofiban or eptifibatide before activation with thrombin receptor agonist peptide (15 micromol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved with fibrinogen supplementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with tirofiban (average concentration 9.28 microg/L) and eptifibatide (average concentration 95.4 microg/L). Recovery of platelet aggregation to at least 50% was achieved after the addition of fibrinogen (0.76-0.80 g/L), platelets (2.4 x 10(11)/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen needed to restore platelet aggregability (r = -0.60; P <.01)., Conclusion: The reversibility of glycoprotein IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and intrinsic pharmacodynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet transfusion represents an important and readily available treatment consideration for restoring hemostatic potential and managing major hemorrhagic complications associated with the administration of small-molecule, competitive glycoprotein IIb/IIIa receptor antagonists.

Background: Because of the adverse characteristics associated with heparin, direct antagonists of thrombin have been investigated as anticoagulants during percutaneous coronary interventions. However, the hematologic and clinical interactions between direct thrombin antagonists and inhibitors of platelet glycoprotein IIb-IIIa are incompletely explored., Methods: Forty-two patients who underwent elective percutaneous coronary intervention were randomized to receive a bivalirudin 1.0 mg/kg bolus followed by a 4-hour infusion at 2.5 mg/kg/h; a bivalirudin 0.75 mg/kg bolus followed by a 4-hour infusion at 1.75 mg/kg; or a heparin 60 U/kg bolus. All the patients also received eptifibatide, given as 2 sequential boluses of 180 microg/kg followed by a 2 microg/kg/min infusion for 18 to 24 hours, and aspirin., Results: After the bolus dose of the study drug, turbidimetric platelet aggregation in response to 5 micromol/L adenosine diphosphate increased in patients assigned to heparin but not those assigned to bivalirudin. After eptifibatide, platelet aggregation was eliminated in all 3 treatment groups. The effect of heparin and the effects of both bivalirudin regimens on the formation of thrombin antithrombin complexes and prothrombin fragment 1.2 were comparable. Neither agent affected the formation of platelet-monocyte complexes or expression of CD 63 lysosomal antigen. There were no major bleeding events, and a single non-Q-wave myocardial infarction (MI) occurred in a patient treated with bivalirudin., Conclusion: These findings show the feasibility of combining the direct thrombin antagonist bivalirudin with a potent antagonist of platelet glycoprotein IIb-IIIa. Clinical trials are needed to assess the safety and efficacy of this combination.

Background: The etiology of creatine kinase-myocardial band (CK-MB) release after percutaneous coronary intervention (PCI) remains unclear. The goal of this study was to evaluate the relationship of both epicardial and tissue level perfusion at the completion of stent placement to CK-MB release after the procedure. Given the high rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow after PCI, we hypothesized that abnormalities in tissue level perfusion would instead explain CK-MB release., Methods: Data were drawn from the angiographic substudy of the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trial of eptifibatide versus placebo in patients undergoing planned coronary stent implantation. In the substudy, cinefilms of 65 patients were analyzed by an angiographic core laboratory blinded to enzymatic and clinical outcomes., Results: The release of CK-MB was not associated with TIMI grade 3 flow or the corrected TIMI frame count; 100% of patients had TIMI grade 3 flow at the completion of PCI. In contrast, tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) was related to postintervention CK-MB release: patients with a closed myocardium (TMPG 0/1) or delayed myocardial perfusion (TMPG 2) had an average CK-MB release 2.2 +/- 2.7 times the upper limit of normal (n = 34), whereas those patients with normal myocardial perfusion (TMPG 3, n = 24) had CK-MB 0.8 +/- 0.6 times the upper limit of normal (P =.01). Although no patients with TMPG 3 sustained death/myocardial infarction/urgent target vessel revascularization or thrombotic bailout, 17.7% of patients with TMPG 0/1/2 did by 48 hours (P =.037)., Conclusions: Impaired tissue level perfusion as assessed by the TMPG and not epicardial coronary blood flow is associated with CK-MB elevation after PCI. These data provide a pathophysiologic link between impaired tissue level perfusion, post-PCI infarction, and adverse clinical outcomes.

Recent advances in the understanding of the pathophysiology of thrombus formation and the role of platelet adhesion have led to a new pharmacologic era in cardiology. The advent of the glycoprotein IIb/IIIa inhibitor, primarily used in conjunction with percutaneous coronary intervention, has proved to be beneficial beyond the confines of the cardiac catheterization laboratory. The glycoprotein IIb/IIIa inhibitor has inspired much research in the past few years of its use in the management of acute coronary syndromes. The CAPTURE, PURSUIT, PRISM, and PRISM-PLUS trials have all documented the beneficial effects of glycoprotein IIb/IIIa inhibition that have reduced 2 of the major sequelae of acute coronary syndromes: myocardial infarction and death. Through the implementation of primary research-based data, it is the job of practitioners to appropriately stratify and implement judicious use of glycoprotein IIb/IIIa inhibition with the population affected by acute coronary syndromes.

Background: Platelet surface glycoprotein (GP) IIb/IIIa (alphaIIb/beta(3)) receptor inhibition, by preventing fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes. Because the currently available Food and Drug Administration-approved small molecule GP IIb/IIIa receptor antagonists are considered "competitive" inhibitors and because there is limited information on the reversibility of platelet inhibition by fibrinogen or platelet supplementation, the following series of in vitro experiments were performed., Methods and Results: Washed platelets from 24 healthy volunteers were suspended in Tyrodes buffer and incubated with achievable (in vivo) steady-state concentrations of either tirofiban or eptifibatide before activation with TRAP (thrombin receptor agonist peptide) (15 micromol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved by fibrinogen supplementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with tirofiban (average concentration 9.28 microg/L) and eptifibatide (average concentration 95.4 microg/L). Recovery of platelet aggregation to at least 50% was achieved after the addition of fibrinogen (0.76-0.80 g/L), platelets (2.4 x 10(11)/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen required to restore platelet aggregability (r = -0.60, P <.01)., Conclusions: The reversibility of GP IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and the intrinsic pharmacodynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet transfusion, represents an important and readily available treatment consideration for restoring hemostatic potential and managing major hemorrhagic complications associated with the administration of small molecule competitive GP IIb/IIIa receptor antagonists.

Background: Although more than 9500 patients have been enrolled in major clinical trials in Latin America, practice patterns in this region have rarely been examined. We sought to compare characteristics, resource utilization, and outcomes of patients treated for acute coronary syndromes in Latin America with those in North America., Methods: The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Theraphy Trial (PURSUIT) enrolled 10,948 patients with non-ST-segment elevation acute coronary syndromes, including 585 in Latin America and 4358 in North America. We analyzed regional differences in patient groups, treatment patterns, and outcomes and used logistic regression analysis to identify association of enrollment region and survival., Results: For patients in Latin America, the length of hospital stay was significantly longer (10 [7, 15] days vs 6 [4, 9], P <.001). Angiograms, angioplasty, and bypass surgery were significantly less common in Latin America (46.2%, 17.6%, and 11.3% vs 79.4%, 33.6%, and 19.4%, P <.001). Thirty-day death/myocardial infarction was not significantly higher, although mortality alone was significantly higher (6.8% vs 3.1%, P <.001). After adjustment for baseline characteristics, enrollment in Latin America remained an independent predictor for death at 30 days (odds ratio [OR] [95% confidence interval (CI)] 2.42 [1.60-3.67]) and persisted at 6 months (OR [95% CI] 2.5 [1.8-3.4])., Conclusions: Latin American patients treated for acute coronary syndromes were managed less invasively and were twice as likely as their North American counterparts to die within 6 months. This mortality difference was not explained by imbalances in baseline risk.

Objectives: This study examined the economics, pharmacodynamics, and clinical outcomes among patients randomly assigned to receive either abciximab (ReoPro, Centocor, Inc, Malvern, Pa, and Eli Lilly & Company, Indianapolis, Ind) or eptifibatide (Integrilin, COR Therapeutics, Inc, South San Francisco, Calif, and Key Pharmaceuticals, Inc, Kenilworth, NJ) therapy during elective percutaneous coronary intervention (PCI)., Background: Clinical and safety outcomes after elective PCI with a high-dose eptifibatide treatment strategy have not previously been systematically evaluated. In addition, comparative economic and pharmacodynamic studies of platelet glycoprotein (GP) IIb/IIIa receptor antagonists during PCI are sparse., Methods: This randomized, double-blind study assessed the 30-day economic and clinical outcomes of 320 consecutive patients undergoing elective coronary balloon angioplasty or stent implantation who were randomly assigned to receive adjunct abciximab (n = 163) or eptifibatide (n = 157) therapy. The primary study end point was total in-hospital costs based on an intention-to-treat analysis. A secondary end point included 30-day total hospital costs. A platelet aggregometry substudy was performed on 155 patients (abciximab: n = 74 and eptifibatide: n = 81) with use of the Ultegra Rapid Platelet Function Assay., Results: Baseline demographic, angiographic, and procedural variables were similar between the two treatment groups. The median and interquartile ranges of total in-hospital costs were $8268 ($6505, $9958) and $7207 ($5659, $9307), respectively, between the abciximab- and eptifibatide-treated patients (P =.009). Median total costs at 30 days were $8336 ($6505, $10,126) and $7207 ($5659, $9431), respectively, between the abciximab- and eptifibatide-treated groups (P =.009). The composite secondary clinical end points (death/nonfatal myocardial infarction/urgent revascularization) occurred in 4.9% versus 5.1% of patients, respectively, by hospital discharge (P =.84) and in 5.6% versus 6.3% of patients, respectively, at 30 days (P =.95) in the abciximab and eptifibatide groups. With the eptifibatide dose used, early and more durable platelet inhibition was achieved compared with abciximab (P <.00001)., Conclusion: In drug dosages and patients similar to those enrolled in the current study, eptifibatide achieved durable platelet inhibition throughout drug infusion and was associated with lower in-hospital and 30-day costs compared with abciximab in patients undergoing elective PCI.

Background: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting., Methods and Results: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab., Conclusions: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.

Background: Despite the increasingly prevalent role of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors in acute coronary syndromes and percutaneous coronary interventions, the incidence and clinical relevance of thrombocytopenia occurring with their use remain unclear., Methods: We identified 8 placebo-controlled, randomized, large trials of GP IIb/IIIa receptor inhibitors reporting the incidence of thrombocytopenia, grouped by severity. The clinical courses of 42 patients with GP IIb/IIIa-related thrombocytopenia in these studies and other case reports were reviewed for bleeding complications., Results: Abciximab increased mild thrombocytopenia compared with placebo (4.2% vs 2.0%; P <.001; odds ratio 2.14) and increased severe thrombocytopenia compared with placebo (1.0% vs 0.4%; P =.01; odds ratio 2.48). Small-molecule IIb/IIIa inhibitors did not significantly increase mild or severe thrombocytopenia compared with placebo. Mild thrombocytopenia occurred more frequently in acute coronary syndrome trials than in coronary intervention trials, even in patients not receiving any IIb/IIIa inhibitors. No major bleeding sequelae were reported in 23 patients with severe thrombocytopenia or in 19 patients with profound thrombocytopenia., Conclusions: Abciximab, but not eptifibatide or tirofiban, increases the incidence of thrombocytopenia compared with placebo in patients also treated with heparin. Thrombocytopenia associated with GP IIb/IIIa inhibition does not routinely lead to severe bleeding complications.

Background: Although age is the most important variable associated with death among patients with persistent ST-segment elevation, its impact on outcome among patients without persistent ST-segment elevation remains unknown. Moreover, the impact of age on the efficacy of antiplatelet therapy with eptifibatide is unknown., Methods: We analyzed the impact of increased age on outcome (death or [re]infarction) among patients enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy), a prospective, randomized study comparing placebo versus eptifibatide therapy in acute coronary syndromes without persistent ST-segment elevation. The 9461 patients were divided into 10-year age groups: <50, 50-59, 60-69, 70-79, and >/=80. In addition, we examined whether age had an impact on the efficacy of eptifibatide therapy., Results: Eptifibatide improved outcome at 30 days (P =.04). There was no interaction among age and treatment (placebo vs eptifibatide) and adjusted outcome (P =.16 for death or [re]infarction at 30 days). Despite their worse clinical profile, older patients were less likely to undergo coronary angiography at 30 days: 936 (71%), 1489 (68%), 1969 (65%), 1357 (57%), and 193 (38%) in the respective age groups. Death or (re)infarction at 30 days occurred in 121 (9%), 255 (12%), 447 (15%), 460 (19%), and 134 (26%) in the respective age groups, and at 6 months in 149 (11%), 301 (14%), 547 (18%), 575 (24%), and 162 (32%). For a 10-year difference in age group, the adjusted odds for death or (re)infarction were greater by 33% within 30 days and by 34% within 6 months. These trends persisted for patients with or without myocardial infarction on presentation., Conclusions: Age did not significantly affect the efficacy of eptifibatide. Older age among patients with acute coronary syndromes was associated with worse baseline characteristics, fewer invasive procedures, and worse outcome.

Background: Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers., Methods: The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain

Randomized clinical trials of glycoprotein IIb/IIIa integrin inhibition during percutaneous coronary intervention and as adjunctive treatment of acute coronary syndromes have shown impressive clinical efficacy in reducing the morbidity and mortality rates of cardiovascular disease. Three agents are currently available in the United States: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). Pharmacodynamic studies show that abciximab is a high-affinity agent with a low dissociation constant; eptifibatide and tirofiban are high-specificity agents with higher dissociation constants and concentration-dependent antiplatelet effects. This article first reviews the relevant pharmacokinetic and pharmacodynamic properties of each of the agents. These principles are then applied to a discussion of the 4 primary clinical issues concerning their use: prevention of untoward bleeding, algorithms for acute reversal, recognition and treatment of thrombocytopenia, and the issue of readministration.

Background: The primary cause of acute coronary syndromes is the development of a thrombus, a pathologic manifestation of platelet aggregation that occurs as part of the normal process of hemostasis. The discovery that the final common step in platelet aggregation, through the binding of fibrinogen to the activated platelet integrin glycoprotein (GP) IIb/IIIa, has opened the door to the development of novel and potentially more effective antithrombotic therapies. Abciximab, a human-murine chimeric Fab fragment of a monoclonal antibody against the GP IIb/IIIa receptor, was the first agent of this class to demonstrate clinical effectiveness. Several of the specific properties of abciximab, such as its long half-life, lack of receptor-blocking specificity, and some tendency for antigenicity, have prompted the development of alternative GP IIb/IIIa inhibitors with distinct pharmacologic profiles., Methods and Results: One of these newer agents is eptifibatide, which was developed by mimicking the GP IIb/IIIa blocker barbourin, found in the venom of the southeastern pigmy rattlesnake. Eptifibatide is a small, cyclic heptapeptide that has shown high specificity and high affinity for GP IIb-IIIa, a short plasma half-life, and rapid onset of antiplatelet action accompanied by a rapid reversibility of platelet inhibition once treatment is stopped., Conclusions: In clinical trials, culminating in the phase III IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) and PURSUIT (Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trials, eptifibatide was found to reduce coronary events significantly in a broad range of low-, medium-, and high-risk patients with acute coronary syndromes without significantly increasing the risk of bleeding or other complications. These results suggest that eptifibatide may prove to be an effective addition to currently available antithrombotic therapies.

Background: Rates of morbidity and mortality after interventional procedures are reported to be inversely associated with institutional volume., Methods: This study assessed both procedural volume and academic status at the 82 US centers that participated in the IMPACT-II trial. Interventional volumes at the sites ranged from 90 to 3300 cases per year. Patients were randomly assigned to a platelet glycoprotein IIb/IIIa inhibitor (eptifibatide) or placebo during procedures done by experienced operators. The primary end point was the composite of death, myocardial infarction, nonelective repeat coronary intervention, or nonelective coronary artery bypass surgery at 30 days, or placement of an intracoronary stent for abrupt closure during the initial procedure., Results: Baseline patient characteristics and median length of stay were similar between the academic and nonacademic centers. In univariable analysis, volume as a continuous variable had a nonlinear relation with the incidence of the composite end point, with better outcomes noted at the highest volume institutions. Academic status did not predict outcome. When added to a predictive model that contained the variables unstable angina, weight, prior coronary artery bypass grafting, heart rate, and platelet count, procedural volume continued to be associated with the composite outcome (P =.04)., Conclusions: We conclude that among hospitals participating in this trial, there is a nonlinear relation between annual interventional volume and outcomes. This relation is complex, involving variations in periprocedural infarction rates and additional, undefined institutional differences (other than academic status) that result in differences in procedural outcome.

Acute coronary syndromes (ACS) are the major cause of mortality and morbidity in Western countries. The primary pathophysiologic mechanism of ACS involves the formation of thrombus in coronary arteries in response to spontaneous or intervention-induced endothelial damage. This leads to myocardial ischemia. The final common pathway to the coronary thrombosis underlying ACS involves the aggregation of platelets mediated by the binding of soluble fibrinogen to the platelet receptor glycoprotein (GP) IIb-IIIa. Several GP IIb-IIIa inhibitors have been developed that promise greater antithrombotic potential than aspirin and heparin alone. Over the past 2 years, 4 major trials involving more than 18,000 patients have evaluated the therapeutic potential of 3 small-molecule, intravenous GP IIb-IIIa inhibitors as a component of first-line management of unstable angina or non-ST-segment elevation myocardial infarction. Results of these studies show that administration of a GP IIb-IIIa inhibitor in combination with aspirin and heparin provides a significant reduction in mortality and morbidity rates compared with aspirin plus heparin alone. Recent approvals of 2 GP IIb-IIIa inhibitors, the peptide eptifibatide and the peptidomimetic tirofiban, mark the beginning of a new era in the management of non-ST-segment elevation ACS.