Search

To review the literature for randomized control trials (RCTs) and prospective cohort studies investigating the safety and efficacy of tirofiban and eptifibatide in patients with acute ischemic stroke (AIS). PubMed, Embase, and the Cochrane library were searched for available papers published up to September 2021. The efficacy was evaluated based on the 3-month favorable outcome [modified Rankin scale (mRS) = 0-1], functional outcome (mRS = 0-2), and the last available National Institutes of Health Stroke Scale (NIHSS) score measured in each study. Twelve studies (two RCTs and 10 prospective cohorts) and 2926 patients were included. Treatment with tirofiban or eptifibatide had no effects on the favorable outcome (RR = 1.09, 95% CI 0.89-1.35, P = 0.411), functional outcome (RR = 1.12, 95% CI 0.98-1.28, P = 0.010), and last available NIHSS (WMD = - 2.32, 95% CI - 5.14 to 0.50, P = 0.106), but might increase mortality (RR = 0.84, 95% CI 0.71-0.99, P = 0.121). The sensitivity analyses showed that the meta-analyses were robust. There was no significant publication bias. Tirofiban did not increase the risk of ICH (P = 0. 423) and sICH (P = 0. 990) but increased the risk of fatal ICH (RR = 3.59, 95% CI 1.62-7.96, P = 0.002). Thrombolysis/thrombectomy did not influence any of the outcomes. Adding tirofiban or eptifibatide to thrombolysis/thrombectomy was not significantly associated with a favorable outcome (mRS = 0-1) nor functional outcome (mRS = 0-2) in patients with AIS at 3 months, but might be associated with mortality, possibly due to fatal ICH. The NIHSS was also not significantly different between the intervention and control groups after treatments.

Eptifibatide is an antiplatelet drug used for the treatment of thrombosis. However, as a result of its accumulation in non-targeted tissues and short half-life, it has a limited efficacy. In this study, RGD-modified nano-liposomes (RGD-MNL) were prepared as carriers for the targeted delivery of eptifibatide to activated platelets. The nano-liposomes were about 90 ± 10 nm in size, with an encapsulation efficiency of 37 ± 5 % and a good stability during 21 days, with a negligible change in the size of nanoliosomes. The in vitro cytotoxicity of nanoliposomes was examined using MTT assay. The results obtained from the ex vivo study showed that the antiplatelet activity of eptifibatide encapsulated nanoliposomes was higher in comparison with the free drug (81.63 vs. 46.17 % for RGD-MNL) and (66.67 vs. 46.17 % for UNL), and this increase was more significant for nanoliposomes targeted with RGD peptide (81.63 %; p

A 75-year old woman with a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) 8 years ago and a repeat one-vessel CABG 2 years ago in the setting of aortic valve replacement with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis presented with two to three weeks of progressive dyspnea and increasing substernal chest discomfort. Echocardiography revealed a gradient to 31 mmHg across her aortic valve, increased from a baseline of 13 mmHg five months previously. Fluoroscopy revealed thrombosis of her mechanical aortic valve. She was not a candidate for surgery given her multiple comorbidities, and fibrinolysis was contraindicated given a recent subdural hematoma 1 year prior to presentation. She was treated with heparin and eptifibatide and subsequently demonstrated resolution of her aortic valve thrombosis. We report the first described successful use of eptifibatide in addition to unfractionated heparin for the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis.

A 71-year old female patient with inferior ST-elevation myocardial infarction underwent primary percutaneous coronary intervention (PCI) within 3 h of symptom onset. She was preloaded with 300 mg aspirin and 600 mg clopidogrel before PCI. Coronary angiogram showed occlusion of the right coronary artery. During PCI, eptifibatide was initiated due to the large thrombus burden. Few hours after the procedure, on eptifibatide infusion, a severe drop in platelet count was observed (from 210,000/μl to 35,000/μl) and the infusion was discontinued. One hour later, still under eptifibatide effect and with severe thrombocytopenia, acute stent thrombosis developed. Lack of prior heparin exposure, quick onset of thrombocytopenia made heparin induced thrombocytopenia improbable that was later excluded by specific immunoassay. However, platelet function testing suggested that eptifibatide induced thrombocytopenia was mediated by activating autoantibodies since platelet reactivity was paradoxically very high at the time of stent thrombosis but decreased radically with eptifibatide washout. The patient was successfully managed without further complications on the basis of platelet function data obtained in the subsequent days. This rare subtype of thrombocytopenia highlights that not only platelet count but also platelet function should be closely monitored in case of severe thrombocytopenia to better balance bleeding and thrombosis.

Antiplatelet use for treatment of coronary artery disease (CAD) is common amongst thoracic surgery patients. Perioperative management of antiplatelet agents requires balancing the opposing risks of myocardial ischemia and excessive bleeding. Perioperative bridging with short-acting intravenous antiplatelet agents has shown promise in preventing myocardial ischemia, but may increase bleeding. We sought to determine whether perioperative bridging with eptifibatide increased bleeding associated with thoracic surgery. After Institutional Review Board approval, we identified thoracic surgery patients receiving eptifibatide at our institution (n = 30). These patients were matched 1:2 with control patients with CAD who did not receive eptifibatide from an institutional database of general thoracic surgery patients. The primary endpoint for our study was the number of units of blood transfused perioperatively. There were no differences in our primary endpoint, number of units of blood products transfused. There were also no differences noted between groups in intraoperative blood loss, chest tube duration, or postoperative length of stay (LOS). While there were no difference noted in overall complications, including our outcome of perioperative MI or death, composite cardiovascular events were more common in the eptifibatide group. In our retrospective exploratory analysis, eptifibatide bridging in patients with high-risk or recent PCI was not associated with an increased need for perioperative transfusion, bleeding, or increased LOS. In addition, we found a similar rate of perioperative mortality or myocardial infarction in both groups, though the ability of eptifibatide to protect against perioperative myocardial ischemia is unclear given different baseline CAD characteristics.

Selecting appropriate antiplatelet therapy requires close attention to the delicate balance between reducing risk of ischemic events while minimizing bleeding risk. The broad range of available agents, while permitting tailoring of pharmacotherapy to individual patients, also complicates selection of optimal regimens. Platelet physiology provides an underpinning for the rationale behind pharmacotherapeutic strategies for patients with non-ST-segment elevated acute coronary syndromes (NSTE ACS) undergoing percutaneous coronary intervention (PCI). The same mechanisms of action that confer anti-ischemic benefit with antiplatelet agents may also be associated with increased risk. In the context of ACS and PCI, antiplatelet agents are used in complex strategies and combinations with other pharmacotherapies targeted at alleviating ischemic symptoms and reducing ischemic risk. Accounting for individual patient risk factors, timing of treatment, and dosage of antiplatelet medications minimizes risk while optimizing outcomes. This review examines results from clinical trials of thienopyridines (clopidogrel, ticlopidine, and the newer prasugrel), the new P2Y(12) antagonists ticagrelor and cangrelor, glycoprotein IIb-IIIa inhibitors (abciximab, eptifibatide, tirofiban), and the direct thrombin inhibitor bivalirudin. Recommendations include clopidogrel for use upstream if discontinued 5 days before coronary angiographic bypass graft. Bivalirudin remains a reasonable treatment choice in patients at low to moderate risk; and glycoprotein IIb-IIIa inhibitors confer anti-ischemic benefit with little incremental bleeding risk when individual patient factors are taken into account for their dosing. Increased awareness of the factors contributing to risks and benefits associated with the available antiplatelet agents will help guide physicians in choosing optimal regimens for all patients.

Background Platelets are involved in inflammatory reactions which play an important role in the development of atherosclerosis and its acute complications. The objective of this study was to test the ability of glycoprotein (GP) IIb-IIIa antagonist eptifibatide to suppress the increase of inflammatory markers in non-ST-segment elevation acute coronary syndrome (ACS). Methods Twenty-five patients with unstable angina and non-ST-segment elevation myocardial infarction received eptifibatide on admission (two 180 μg/kg boluses followed by infusion at 2.0 and 1.3 μg/kg/min for 24 and 48 h, respectively) and 25 were treated without GP IIb-IIIa antagonists. Plasma von Willebrand factor (vWF) and soluble P-selectin were determined at baseline, 48 h and 2 weeks after onset of ACS, and were also measured in a group of healthy volunteers. Serum C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), and interleukin 6 (IL6) were measured at baseline, 48 h, 2 weeks and 6 months. Results P-selectin was increased at baseline and vWF at baseline, 48 h and 2 weeks in comparison with healthy donors. CRP, TNFα, but not IL6 were increased at baseline, 48 h and 2 weeks in comparison with their levels at 6 months. Maximal values of CRP, TNFα and vWF were detected at 48 h. At any time point eptifibatide failed to decrease the levels of all tested markers. Conclusion Eptifibatide does not suppress elevated levels of inflammatory markers in patients with non-ST-segment elevation ACS.

Glycoprotein (GP) IIb/IIIa inhibitors have been shown to reduce morbidity and mortality in patients with acute coronary syndromes undergoing percutaneous coronary interventions (PCI). With their widespread use, there is a growing body of literature describing adverse outcomes, including severe thrombocytopenia. Here we report a case of a 75-year-old man who presented with an ST-elevation myocardial infarction, underwent primary PCI and stenting, and subsequently developed profound thrombocytopenia and thrombosis after eptifibatide administration. This report adds to the literature regarding eptifibatide-induced thrombocytopenia and also raises the possibility of a new syndrome of eptifibatide-induced thrombosis. A case is made to examine available databases for thrombosis after administration of eptifibatide and other GPIIb/IIIa inhibitors.

Antithrombotic drugs including glycoprotein (GP) IIb IIIa receptor inhibitors have significantly reduced ischaemic events in coronary disease. Variability in the response to GP receptor inhibitors has been observed both with healthy individuals and in clinical studies. One single nucleotide polymorphism on GP IIIa (PI(A1/A2)) correlates with increased risk for cardiovascular events in many studies. In this study we investigated whether this polymorphism associates with individual differences in the response to GP IIb IIIa receptor inhibitors in healthy individuals. Fresh blood samples were collected randomly from individuals without a history of coronary disease. Blood samples were anticoagulated with either sodium citrate or with PPACK. The ability of different GP IIb IIIa receptor inhibitors (tirofiban, eptifibatide and abciximab) to inhibit platelet aggregation was investigated using a commercial PFA-100 analyser. At baseline, the function of platelets with different PI(A) genotypes did not differ from each other. With sodium citrate anticoagulated samples, tirofiban prolonged the closure time slightly more rapidly when platelets with PI(A 2 A 2) genotype were used than with other genotypes (p0.05) both on epinephrine-collagen and ADP-collagen coated membranes. With eptifibatide or abciximab no differences were observed. If an anticoagulant not affecting Ca(2+) concentration (PPACK) was used, no differences were observed between different GP IIIa genotypes and the ability of any of the GP IIb IIIa receptor inhibitors to prolong the closure time. The effect of tirofiban and eptifibatide was significantly affected by the anticoagulant used (p0.001), whereas abciximab functioned equally regardless of the anticoagulant. Glycoprotein IIIa PI(A2) allele has been found in many studies to associate with risk of thrombosis. In healthy controls the function of GP IIb IIIa receptor inhibitors on platelets with different PI(A) genotypes was modified by anticoagulants used. PI(A) polymorphism does not explain the interindividual variance in the response to GP IIb IIIa receptor inhibitors in healthy individuals. The study, however, demonstrates the importance of the anticoagulant used in in vitro studies and the important role of Ca(2+) concentration with tirofiban and eptifibatide, but not with abciximab.

Objective: To evaluate a newly modified rapid platelet function analysis system (ICHOR/ Plateletworks®) and to compare the results obtained with those of traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Background: Anti-platelet therapy is standard of care for patients as an adjunct to percutaneous coronary intervention (PCI) or for medical management of non-ST elevation acute coronary syndromes (NSTE ACS). Recent clinical trial results suggest that the three currently approved platelet GPIIb-IIIa receptor antagonists, eptifibatide, tirofiban and abciximab, may vary in extent of inhibition of platelet aggregation (IPA) at the approved doses. Thus, pharmacodynamic evaluations of these agents to determine the extent of platelet function inhibition, especially during the periprocedural time of a cardiac intervention, are necessary. A rapid measurement method as a surrogate for LTA, the current gold standard, would be ideal in order to have the option for dose monitoring or adjustment prior to or during an intervention. The Helena ICHOR/ Plateletworks® may be useful for point of care testing. Methods: Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Results: This study demonstrated that platelet inhibition measured by the ICHOR/Plateletworks® mirrored the level of IPA obtained with LTA. In contrast, the Ultegra® system had less correlation when compared to LTA at inhibition levels < 90%. Conclusions: Based on these data, the ICHOR/ Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary. A rapid platelet function measurement method as a surrogate for light transmission aggregometry (LTA), the current gold standard, is ideal in order to have the option for GPIIb-IIIa antagonist dose monitoring or adjustment prior to or during a coronary intervention. A newly modified rapid platelet function analysis system (ICHOR/Plateletworks® was evaluated and compared to the results obtained with traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Based on these data, the ICHOR/Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary.

The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS.We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/2.0) [DOSAGE ERROR CORRECTED] and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 microM ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients.Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%.These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used.

Background: Argatroban, a direct thrombin inhibitor, blocks clot-bound thrombin more effectively than does heparin. This multicenter, prospective pilot study evaluated the efficacy and safety of argatroban in combination with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. Methods: Patients (N = 152) received argatroban as a 250- or 300-μg/kg bolus, followed by a 15-μg/kg/min infusion during percutaneous coronary intervention. An additional 150-μg/kg bolus was administered if activated clotting times 5–15 min after initiating argatroban were

Widespread adoption of the antiplatelet agents into everyday clinical practice has revolutionized contemporary care of the cardiovascular patient. Major adverse cardiovascular events including death, myocardial infarction, stroke, and recurrent angina have all been shown to be significantly decreased when these agents are employed in the treatment of coronary atherosclerosis, acute coronary syndromes, myocardial infarction, and in the setting of percutaneous coronary intervention. As a growing number of patients on antiplatelet therapy are undergoing various surgical procedures, the potential risks and benefits these drugs pose perioperatively will become increasingly important. Available data indicate that, when used appropriately, these drugs can be used safely prior to surgery. Efficacy in improving surgical outcomes and in preventing adverse cardiovascular events postoperatively has also been demonstrated. The purpose of this review is to examine the perioperative safety and efficacy of the most widely used antiplatelet agents: aspirin; the thienopyridine clopidogrel; and the glycoprotein (GP) IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban. This information, coupled with emerging platelet monitoring techniques, may help provide additional assistance to the clinician to manage therapy and guide appropriate timing of both cardiac and noncardiac surgery.

Background: Previous studies have demonstrated a prolongation of activated clotting times (ACT) with abciximab administration during percutaneous coronary interventions (PCI). The impact of the short acting glycoprotein (GP) IIb-IIIa inhibitor, eptifibatide, on ACT measurements has not been studied.

Background: Tirofiban and eptifibatide are currently approved for the medical stabilization of non-ST segment elevation acute coronary syndromes. In patients undergoing percutaneous coronary intervention (PCI) during infusion of these drugs, conversion to abciximab, which has long term proven clinical efficacy and cost-effectiveness, following PCI may be desirable. The purpose of this study was to determine if the binding or pharmacodynamics of abciximab is affected by a prior infusion of either tirofiban or eptifibatide.

Background: Receptors other than GP IIb/IIIa may mediate leukocyte-platelet-endothelial interactions that obstruct the microvasculature in acute coronary syndromes (ACS) and cause microinfarcts. The effect of eptifibatide on these receptors was investigated in a substudy of the EARLY Trial. Methods: Patients received early (in the Emergency Department, n = 27) or late (12–24 h, n = 28) eptifibatide. Ten platelet receptors by flow cytometry and platelet aggregation (10 μmol/L ADP) were measured serially at baseline, and at 3, 6, 12 and 24 h after randomization. Results: Platelet aggregation was rapidly inhibited by early eptifibatide therapy (baseline, 72 +/− 20%; 3 h post, 7 +/− 9%; p < 0.001). No significant differences were seen in either group for CD 31, CD 63, CD 107a, CD 107b, CD 41 (GPIIb/IIIa expression), or CD 62p. Leukocyte-platelet aggregate formation (mean fluorescense intensity) trended upward after presentation (early baseline, 43.1 +/− 26.0 versus 65.8 +/− 35.6, p = .09). PAC-1 (GP IIb/IIIa activity), CD 51/61 (vitronectin receptor) and CD 42b (GP Ib) were inhibited by eptifibatide (p < .05). Conclusions: In Emergency Department patients with unstable angina, early eptifibatide rapidly and profoundly inhibits platelet aggregation and reduces GP IIb/IIIa activity and the expression of CD51/61 and CD 42b; the latter two effects may also contribute to the drug's anti-thrombotic effect. However, platelet-leukocyte aggregate formation, a marker of platelet activity rises within 24 h after presentation despite eptifibatide therapy and is a potential mechanism for microvascular obstruction.

Background: High levels of glycoprotein (GP) IIb/IIIa receptor inhibition are required to prevent arterial thrombosis following percutaneous coronary intervention. Ex-vivo turbidometric platelet aggregation in citrate anticoagulated blood samples has been the primary method previously utilized to derive dose regimens for administering platelet GP IIb/IIIa inhibitors. Enhanced GP IIb/IIIa binding and inhibition of platelet aggregation for eptifibatide secondary to citrate induced reduction of ionized plasma calcium concentrations has been reported. Methods/Results: We evaluated the differential effects of citrate versus PPACK anticoagulation on turbidometric platelet inhibition in normal volunteers by eptifibatide, tirofiban or abciximab. The decrease in ionized calcium afforded by citrate was associated with enhanced in vitro platelet inhibition for all three GP IIb/IIIa inhibitors, including abciximab. The magnitude of citrate effect was greatest for eptifibatide. Both tirofiban and abciximab have similar citrate calcium chelation associated enhancement of measured platelet inhibition.

Background: GP IIb/IIIa inhibitors have primarily been used short-term e.g., during PTCA. They failed to show clinical benefit during long-term therapy. One reason might be the absence of a method to monitor inhibitor activity. This study compared platelet aggregometry, the rapid platelet function analyzer (RPFA) test, single platelet counting, and flow cytometric determination of receptor occupancy to measure GP IIb/IIIa-receptor inhibitor activity. Methods: Increasing doses of abciximab, tirofiban, and eptifibatide were added to whole blood in vitro. Whole blood was used for the RPFA, for single platelet counting and flow cytometry. Platelet rich plasma was prepared for aggregometry. Results: The correlation between aggregometry and RPFA results was linear for abciximab and eptifibatide. Tirofiban was a stronger inhibitor with the RPFA (IC50 7.7[emsp4 ]nM) than with aggregometry (IC50 19.6[emsp4 ]nM). The single platelet counting technique showed that even supratherapeutic concentrations of all three inhibitors could not completely suppress microaggregation. Abciximab concentrations that were equipotent to tirofiban with aggregometry were less potent with regards to the inhibition of microaggregation. This difference was more pronounced with TRAP induced microaggregation than with ADP. The flow cytometric receptor occupancy test showed that occupancy was 95[emsp4 ]% with 5[emsp4 ]μg/ml abciximab and almost 97[emsp4 ]% with 10[emsp4 ]μg/ml. Tirofiban reached a maximum receptor occupancy of 56[emsp4 ]%, eptifibatide 64[emsp4 ]%. Conclusions: While aggregometry is time consuming the RPFA provides results fast and with little variability. There is still a discrepancy between aggregometry and RPFA results for tirofiban. The single platelet counting technique detects the inhibition of microaggregation the relevance of which for the clinical outcome is not known. The flow cytometric receptor occupancy assay is best suited for abciximab.

Background:Platelet glycoprotein (GP) IIb/IIIa antagonists reduce the occurrence of death, myocardial infarction (MI) and urgent revascularization among patients undergoing percutaneous coronary intervention (PCI). Despite a similar mechanism of platelet inhibition, the three currently approved agents vary widely in cost. Purpose: The purpose of this prospectively designed, retrospective analysis was to determine clinical outcomes for patients receiving abciximab, tirofiban or eptifibatide as adjunctive therapy during PCI at a single center. We hypothesized that there would be no difference in outcomes during hospitalization following PCI in patients receiving tirofiban or eptifibatide compared with those patients who received abciximab. Outcomes examined included in-hospital mortality, hemorrhagic procedural complications, need for recatheterization, peak creatine kinase following intervention and length of hospital stay (LOS). Results: Two hundred and sixty seven consecutive patients in whom GP IIb/IIIa antagonist therapy was initiated in the catheterization laboratory for PCI were analyzed. Abciximab-treated patients were more likely to be undergoing primary (p

Fibrinolytic drugs given within 6-12 h of onset of symptoms have reduced mortality by approximately 30%. However, even the most efficacious regimens are associated with only a 55% reperfusion rate at 90 min. In contrast, primary angioplasty (without fibrinolysis) yields to reperfusion in 75-95% of cases. This therapy, when compared with fibrinolysis, is associated with lower early mortality and reinfarction rates. Therefore, there is a need to find a therapy that would have the speed and ease of administration of intravenous lysis and the efficacy of primary angioplasty in re-establishing normal myocardial tissue perfusion. This article will review the rationale for the use of partial-dose lytic agents combined with platelet glycoprotein IIb/IIIa inhibitors for the treatment of acute myocardial infarction. The available and upcoming data on this subject will also be reviewed.

Inhibitors of the platelet receptor glycoprotein (GP) IIb--IIIa are a novel and potent class of antithrombotic drugs for the management of patients with non-ST-segment elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Pharmacodynamic studies with three currently approved agents in this class (abciximab [ReoPro, Centocor, Inc., Malvern, Pennsylvania, and Eli Lilly & Company, Indianapolis, Indiana]; eptifibatide [INTEGRILIN, COR Therapeutics, Inc., South San Francisco, California, and Key Pharmaceuticals, Inc., Kenilworth, New Jersey]; and tirofiban HCI [Aggrastat, Merck & Co., Inc., Whitehouse Station, New Jersey]) all sought to identify dosing regimens that would establish and maintain >80 % inhibition of ex vivo platelet aggregation throughout the duration of intravenous infusion. Direct comparison of these prior studies is difficult, however, because the assays used different anticoagulants (sodium citrate [abciximab, tirofiban HCI] or D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone [PPACK] [eptifibatide]) and different concentrations of the platelet agonist adenosine diphosphate (ADP) (5 micromol [tirofiban HCI] or 20 micromol [abciximab, eptifibatide]). More recent work has attempted to overcome these limitations by using similar assay conditions for all GP IIb--IIIa inhibitors. These studies have indicated that the concentrations of all three agents required to provide the targeted effect for platelet inhibition are considerably higher in the presence of an anticoagulant that does not chelate calcium ions (e.g., heparin or PPACK) than in the presence of calcium-chelating anticoagulant (i.e., sodium citrate). Of the three currently approved GP IIb--IIIa inhibitors, eptifibatide is the only agent whose approved dosing is based on an ex vivo platelet aggregation assay that uses such an anticoagulant. Additionally, Kereiakes et al. have recently reported that the high levels of platelet inhibition (>80 %), using PPACK as an anticoagulant and ADP (20 micromol) as an agonist, are more consistently achieved with the approved dosing regimen of eptifibatide. The antiplatelet effect of abciximab showed more interpatient variability, whereas the median inhibition of ex vivo platelet aggregation with the approved dosing regimen for tirofiban HCl was

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.

We evaluated the differential effect of platelet count in platelet-rich plasma (PRP) on the level of ex vivo inhibition of platelet aggregation provided by abciximab, eptifibatide, and tirofiban as part of a randomized, comparative trial of these agents on platelet function in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Platelet count

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

Glycoprotein (GP) IIb/IIIa inhibitors reduce major adverse coronary events in patients with acute coronary syndromes undergoing percutaneous coronary interventions (PCI). Unlike the other GPIIb/IIIa inhibitors, eptifibatide is rarely associated with thrombocytopenia with only a few cases reported in the medical literature. Here we report a case of a 34-year-old man presenting with a non ST-elevation myocardial infarction (NSTEMI) who underwent primary PCI with stenting and developed stent thrombosis 5 days after the procedure. He underwent repeat PCI with readministration of eptifibatide and subsequently developed profound thrombocytopenia within 4 h. This report adds another case of eptifibatide associated thrombocytopenia to the literature and reinforces the importance of platelet count monitoring after therapy with this agent.

Glycoprotein IIb–IIIa (GPIIb–IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus stability. Light transmission aggregometry was used to examine the effects of exposing human platelet aggregates to extremely high local levels of GPIIb–IIIa antagonists versus conventional therapeutic levels in vitro. Freshly-formed or aged platelet aggregates were subjected to GPIIb–IIIa antagonists (abciximab, eptifibatide) or direct thrombin inhibitor bivalirudin at concentrations simulating either conventional intravenous (IV) or LIC administration. The degree of antagonist-induced disaggregation was significantly higher using elevated (LIC) doses versus conventional (IV) doses (60.1 % vs. 7.4 % for abciximab, 41.6 % or 45.3 % vs. 17.6 % for eptifibatide, p

Owing to its beneficial pharmacological profile, the low-molecular-weight heparin (LMWH) enoxaparin is increasingly being taken as an alternative to UFH in the treatment of ACS with an early invasive strategy and in elective percutaneous coronary interventions (PCI). Insufficient anticoagulation increases the risk of catheter thrombus formation during PCI. The aim of the present study was to test in vitro the hypotheses that (i) inhibiting thrombin or thrombin generation by administering LMWH is a critical intervention in preventing catheter thrombus formation and (ii) other LMWH such as certoparin or dalteparin are as effective as enoxaparin. Blood pre-treated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 min or until the catheter became occluded. Overall thrombus weight, anti-Xa activity and electron microscopic features such as deposits of platelets, erythrocytes and fibrin on the catheter surface were quantified as endpoints. All LMWH tested significantly reduced catheter thrombus generation comparable to UFH treatment whereas there was no difference between the specific LMWH with respect to catheter thrombus formation or deposition of platelets, erythrocytes and fibrin. Thrombus generation was found to negatively correlate with anti-Xa activity. The additional use of eptifibatide did not affect thrombus formation. These data suggest that modulating plasmatic coagulation by employing LMWH is critical for preventing catheter thrombus formation and at the same time offer a potential for administering LMWH other than enoxaparin, such as certoparin or dalteparin, in the setting of PCI.

Despite their proven beneficial effects and inclusion in the guidelines, glycoprotein (GP) IIb/IIIA blockers are underused in daily practice in patients with non ST-segment elevation acute coronary syndrome (NSTE ACS). This study combines the data from two randomized controlled trials, comparing routine upstream versus selective down stream use of tirofiban in patients with NSTE ACS. Inclusion criteria for both studies (ELISA-1 and 2) were angina pectoris, with ST depression >1 mm and or a positive cardiac biomarkers. All patients were scheduled for coronary angiography. The primary and secondary end points for both studies were enzymatic infarct size (LDHQ48) and initial TIMI flow of the culprit lesion respectively. From August 2000 to January 2005, 273 patients were randomized to routine upstream tirofiban and 275 patients to selective down stream use of tirofiban. Selective down stream tirofiban was used in 55 patients (20%). Patients in the upstream group more often had a patent culprit lesion (65% vs. 50%, P=0.003) and a significantly smaller enzymatic infarct size, LDHQ48 median (25–75%): 125 (55–309) vs. 189 (68–504) IU/l, P=0.006 as compared to the selective down stream group. Subgroup analysis showed that routine upstream tirofiban was particularly effective in males, patients with a positive troponin on admission and in those not pretreated with clopidogrel. Routine upstream GP IIb/IIIa is mainly effective in patients with elevated troponin on admission and those not pretreated with clopidogrel. Large scale randomized trials are needed to evaluate the effect of GP IIb/IIIa blockers on top of clopidogrel pretreatment on major adverse cardiac events.

Distal embolization of thrombotic debris may occur during and after percutaneous coronary intervention (PCI) for acute coronary syndromes. This may lead to impaired microvascular perfusion, myocardial infarction and increased morbidity and mortality. In vitro studies suggest that high local concentrations of a glycoprotein IIb/IIIa inhibitor may be effective in disaggregating thrombus and thereby prevent microvascular compromise. We hypothesized that intracoronary (IC) administration of eptifibatide during stent implantation for unstable angina/non ST elevation myocardial infarction (UA/NSTEMI) would be safe and would lead to an acceptable rate of normal myocardial perfusion.In 54 patients with UA/NSTEMI, 2 boluses of 180 mcg/kg of eptifibatide each were administered via the IC route during PCI. Data were retrospectively collected and reviewed by an independent core laboratory.No adverse events including arrhythmias occurred during IC administration of eptifibatide. There were no deaths or urgent revascularizations among patients treated with IC eptifibatide. One patient (2.0%) sustained a post-procedure myocardial infarction. One patient sustained a TIMI major bleeding event due to a gastrointestinal bleed. There were no TIMI minor bleeding events. Normal post PCI TIMI Myocardial Perfusion Grade was observed in 54% of patients.IC bolus administration of eptifibatide was feasible and safe among patients with UA/NSTEMI. Larger prospective and randomized studies are warranted to further explore the efficacy of this strategy. Intracoronary eptifibatide administration during PCI for UA/NSTEMI is feasible and safe.

Background: Aspirin, glycoprotein IIb/IIIa inhibitors and heparin are routinely used in acute coronary syndromes. Previously we showed that there is synergism between ultrasound and heparin and tirofiban in augmenting blood clot disruption. However, there is a little data on a possible synergism of low-frequency ultrasound with aspirin for in-vitro clot dissolution, and especially on the combination of aspirin with heparin and/or glycoprotein IIb/IIIa inhibitors. Materials and Methods: Human blood clots (n = 320) were incubated for 10 or 20 minutes in saline containing aspirin alone or combined with heparin and/or tirofiban and/or eptifibatide. Clots were randomly treated with low-frequency ultrasound (27.3 kHz) or incubation only. The percent clot weight loss and the incremental effect of ultrasound were calculated. Results: The most significant incremental effect of ultrasound on clot weight reduction was detected with aspirin alone (5.2 ± 2.3% and 5.2 ± 2.6% after 10′ and 20′, p = 0.04 and p = 0.06, respectively) and in combination with heparin (8.8 ± 2.5% and 11.5 ± 2.7% after 10′ and 20′, p = 0.01 and p = 0.0001, respectively). The greatest absolute magnitude of clot weight reduction was observed with ultrasound combined with aspirin and heparin (48.5 ± 9.5% after 20′). The addition of tirofiban or eptifibatide to aspirin, heparin and ultrasound did not increase clot lysis. However, eptifibatide had significantly better synergism than tirofiban (p = 0.025 and p = 0.015, after 10 and 20 minutes, respectively). Conclusions: Aspirin alone or in combination with heparin results in significant augmentation of clot lysis and is synergistic with application of low-frequency ultrasound for 10 and 20 minutes only. These results may have important implications for a possible use of low-frequency ultrasound in treatment algorithms of acute coronary syndromes.

GP IIb/IIIa antagonists are qualitatively different from classical antiplatelet agents, such as aspirin or clopidogrel. They do not inhibit platelet activation, i.e. intraplatelet signal generation or conduction but primarily act outside the platelet by competing with ligand (e.g. fibrinogen) binding that is essential for platelet bridging and aggregate formation. Three compounds are in clinical use: abciximab, an antibody fragment and two low-molecular weight compounds, tirofiban and eptifibatide. In comparison to the low-molecular weight compounds, abciximab has a substantially longer platelet half-life (4 h), i.e. slow off-rate and a short plasma half-life (20-30 min) without significant distribution into the extravascular space. The plasma half-life of tirofiban and eptifibatide is about 2 h and parallels the antiplatelet effect. The off-rate from the platelet GP IIb/IIIa receptor is much faster and there is a significant distribution into the extravascular space. These pharmacokinetic variables might influence the competition between the antagonists and fibrinogen for GP IIb/IIIa binding. Other pharmacological variables are a partial agonistic activity, facilitation of thrombolysis, modification of other integrin-related actions, including inflammatory responses, effects on vascular cells and apoptosis. Importantly, GP IIb/IIIa antagonists might also interfere with prothrombin binding to the platelet surface and, thus, might influence the coagulation pathway. There is no clear evidence that the biological activity of the agents is modified by gene polymorphism (HPA-1). All three compounds may cause thrombocytopenia, possibly related to drug-induced antibodies. There is no clear data suggesting that these pharmacological differences transfer into significant differences in clinical outcome, for example in patients with acute coronary syndromes (ACS) subjected to acute percutaneous coronary interventions (PCI). The only head-to-head comparison of all three clinically used parenteral compounds did not demonstrate differences in major adverse cardiac effects (MACE) at 30 days although those have been described in particular with long-term use of oral antagonists. The inherent problems with all GP IIb/IIIa antagonists are the narrow therapeutic range because the same mechanisms are involved in hemostasis and thrombosis and their inability to inhibit platelet activation.

Receptors other than GP IIb/IIIa may mediate leukocyte-platelet-endothelial interactions that obstruct the microvasculature in acute coronary syndromes (ACS) and cause microinfarcts. The effect of eptifibatide on these receptors was investigated in a substudy of the EARLY Trial.Patients received early (in the Emergency Department, n = 27) or late (12-24 h, n = 28) eptifibatide. Ten platelet receptors by flow cytometry and platelet aggregation (10 micromol/L ADP) were measured serially at baseline, and at 3, 6, 12 and 24 h after randomization.Platelet aggregation was rapidly inhibited by early eptifibatide therapy (baseline, 72 +/- 20%; 3 h post, 7 +/- 9%; p0.001). No significant differences were seen in either group for CD 31, CD 63, CD 107a, CD 107b, CD 41 (GPIIb/IIIa expression), or CD 62p. Leukocyte-platelet aggregate formation (mean fluorescense intensity) trended upward after presentation (early baseline, 43.1 +/- 26.0 versus 65.8 +/- 35.6, p =.09). PAC-1 (GP IIb/IIIa activity), CD 51/61 (vitronectin receptor) and CD 42b (GP Ib) were inhibited by eptifibatide (p.05).In Emergency Department patients with unstable angina, early eptifibatide rapidly and profoundly inhibits platelet aggregation and reduces GP IIb/IIIa activity and the expression of CD51/61 and CD 42b; the latter two effects may also contribute to the drug's anti-thrombotic effect. However, platelet-leukocyte aggregate formation, a marker of platelet activity rises within 24 h after presentation despite eptifibatide therapy and is a potential mechanism for microvascular obstruction.

Tirofiban and eptifibatide are currently approved for the medical stabilization of non-ST segment elevation acute coronary syndromes. In patients undergoing percutaneous coronary intervention (PCI) during infusion of these drugs, conversion to abciximab, which has long term proven clinical efficacy and cost-effectiveness, following PCI may be desirable. The purpose of this study was to determine if the binding or pharmacodynamics of abciximab is affected by a prior infusion of either tirofiban or eptifibatide.In vitro binding experiments were performed to determine if prior exposure to tirofiban or eptifibatide altered the affinity and extent of binding of abciximab to GPIIb/IIIa. For in vivo experiments, cynomolgus monkeys were pretreated with a bolus and 18 hour infusion of saline, tirofiban, or eptifibatide. At the end of the initial treatment, a bolus and 12 hr infusion of abciximab was started without delay. Inhibition of platelet aggregation, GPIIb/IIIa receptor blockade and abciximab pharmacokinetics were measured during and after both infusions.Equilibrium binding of abciximab in vitro was unaffected by tirofiban or eptifibatide. The extent and duration of abciximab inhibition of ex vivo platelet aggregation, receptor blockade, and abciximab pharmacokinetics in monkeys during and after the abciximab infusion were not affected by prior infusion of the animals with tirofiban or eptifibatide.In vitro and in vivo studies revealed that the molecular interaction of abciximab with the platelet GPIIb/IIIa receptor is not altered by immediate prior exposure of platelets to small molecule GPIIb/IIIa antagonists. These preclinical studies suggest that the efficacy of abciximab should not be impaired if it is initiated following termination of therapy with small molecule GPIIb/IIIa antagonists.

Previous studies have demonstrated a prolongation of activated clotting times (ACT) with abciximab administration during percutaneous coronary interventions (PCI). The impact of the short acting glycoprotein (GP) IIb-IIIa inhibitor, eptifibatide, on ACT measurements has not been studied.Seventy consecutive patients undergoing PCI in the setting of eptifibatide administration were prospectively enrolled in a single center study. Eptifibatide was administered as two 180 microg/kg boluses 10 minutes apart followed by a continuous infusion of 2.0 microg/kg/min. In 15 patients (Group I), the initial eptifibatide and heparin boluses were separated by 5 minutes, and ACT's were assessed after each bolus as well as at 3 subsequent time points. In 55 patients (Group II), an ACT level was drawn 10 minutes after the initial heparin/eptifibatide bolus and 20 minutes following the second eptifibatide bolus. Two different ACT measuring devices--CoaguChek Pro DM and Hemochron 801--were used to examine the impact of eptifibatide on ACT values.The devices differed in the reproducibility of their measurements, but the overall trends were consistent with both devices. The ACT value was unchanged after the initial eptifibatide bolus (with a delta of 0.6 seconds by CoaguChek Pro DM and 4.2 seconds by Hemochron). While the ACT value rose significantly after the heparin bolus, the second eptifibatide bolus did not result in any further rise in ACT values.Unlike abciximab, eptifibatide does not significantly prolong the ACT in patients undergoing PCI. This may have implications regarding the need for separate heparin dosing algorithms for patients undergoing PCI in the setting of different GPIIb-IIIa inhibitors.

High levels of glycoprotein (GP) IIb/IIIa receptor inhibition are required to prevent arterial thrombosis following percutaneous coronary intervention. Ex-vivo turbidometric platelet aggregation in citrate anticoagulated blood samples has been the primary method previously utilized to derive dose regimens for administering platelet GP IIb/IIIa inhibitors. Enhanced GP IIb/IIIa binding and inhibition of platelet aggregation for eptifibatide secondary to citrate induced reduction of ionized plasma calcium concentrations has been reported.We evaluated the differential effects of citrate versus PPACK anticoagulation on turbidometric platelet inhibition in normal volunteers by eptifibatide, tirofiban or abciximab. The decrease in ionized calcium afforded by citrate was associated with enhanced in vitro platelet inhibition for all three GP IIb/IIIa inhibitors, including abciximab. The magnitude of citrate effect was greatest for eptifibatide. Both tirofiban and abciximab have similar citrate calcium chelation associated enhancement of measured platelet inhibition.Accurate assessment and comparison of platelet inhibition by GP IIb/IIIa inhibitors may require avoidance of calcium chelating anticoagulants.

Platelet glycoprotein (GP) IIb/IIIa antagonists reduce the occurrence of death, myocardial infarction (MI) and urgent revascularization among patients undergoing percutaneous coronary intervention (PCI). Despite a similar mechanism of platelet inhibition, the three currently approved agents vary widely in cost.The purpose of this prospectively designed, retrospective analysis was to determine clinical outcomes for patients receiving abciximab, tirofiban or eptifibatide as adjunctive therapy during PCI at a single center. We hypothesized that there would be no difference in outcomes during hospitalization following PCI in patients receiving tirofiban or eptifibatide compared with those patients who received abciximab. Outcomes examined included in-hospital mortality, hemorrhagic procedural complications, need for recatheterization, peak creatine kinase following intervention and length of hospital stay (LOS).Two hundred and sixty seven consecutive patients in whom GP IIb/IIIa antagonist therapy was initiated in the catheterization laboratory for PCI were analyzed. Abciximab-treated patients were more likely to be undergoing primary (p0.001) and rescue (p=0.022) PCI and to have received fibrinolytic therapy (p=0.013) when compared to patients receiving tirofiban or eptifibatide. There were no significant differences between abciximab- and non abciximab-treated patients in either the primary PCI or non primary PCI groups in any of the studied endpoints. In patients undergoing primary PCI, abciximab-treated patients when compared with non abciximab-treated patients exhibited a trend toward an increase in hospital LOS (7.8+/-7.0 d vs 6.2+/-3.9, p=0.19) and in the frequency of hemorrhagic complications (22.1% vs 5.3%, p=0.11). In patients not receiving fibrinolytic therapy, abciximab-treated patients experienced a trend toward increased hemorrhagic complications following PCI when compared to non abciximab-treated patients (10.2% vs 6.0%, p=0.28). Complications distant from the vascular access site comprised 62.5% of hemorrhagic complications in the abciximab-treated group, but only 20% of the complications in the non-abciximab treated population (p0.001). These data suggest no differences in acute outcomes between groups of patients receiving abciximab or other approved GP IIb/IIIa antagonists highlighting a potential significant cost saving. These data will require interpretation following the publication of comparative trials.

Inhibitors of the platelet receptor glycoprotein (GP) IIb--IIIa are a novel and potent class of antithrombotic drugs for the management of patients with non-ST-segment elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Pharmacodynamic studies with three currently approved agents in this class (abciximab [ReoPro, Centocor, Inc., Malvern, Pennsylvania, and Eli LillyCompany, Indianapolis, Indiana]; eptifibatide [INTEGRILIN, COR Therapeutics, Inc., South San Francisco, California, and Key Pharmaceuticals, Inc., Kenilworth, New Jersey]; and tirofiban HCI [Aggrastat, MerckCo., Inc., Whitehouse Station, New Jersey]) all sought to identify dosing regimens that would establish and maintain80 % inhibition of ex vivo platelet aggregation throughout the duration of intravenous infusion. Direct comparison of these prior studies is difficult, however, because the assays used different anticoagulants (sodium citrate [abciximab, tirofiban HCI] or D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone [PPACK] [eptifibatide]) and different concentrations of the platelet agonist adenosine diphosphate (ADP) (5 micromol [tirofiban HCI] or 20 micromol [abciximab, eptifibatide]). More recent work has attempted to overcome these limitations by using similar assay conditions for all GP IIb--IIIa inhibitors. These studies have indicated that the concentrations of all three agents required to provide the targeted effect for platelet inhibition are considerably higher in the presence of an anticoagulant that does not chelate calcium ions (e.g., heparin or PPACK) than in the presence of calcium-chelating anticoagulant (i.e., sodium citrate). Of the three currently approved GP IIb--IIIa inhibitors, eptifibatide is the only agent whose approved dosing is based on an ex vivo platelet aggregation assay that uses such an anticoagulant. Additionally, Kereiakes et al. have recently reported that the high levels of platelet inhibition (80 %), using PPACK as an anticoagulant and ADP (20 micromol) as an agonist, are more consistently achieved with the approved dosing regimen of eptifibatide. The antiplatelet effect of abciximab showed more interpatient variability, whereas the median inhibition of ex vivo platelet aggregation with the approved dosing regimen for tirofiban HCl was80 % at almost all time points during drug infusion.

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

We evaluated the differential effect of platelet count in platelet-rich plasma (PRP) on the level of ex vivo inhibition of platelet aggregation provided by abciximab, eptifibatide, and tirofiban as part of a randomized, comparative trial of these agents on platelet function in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Platelet count350 K/microL in PRP reduced measured platelet inhibition by abciximab, but not eptifibatide nor tirofiban. This observation suggests the need for standardized, uniform platelet counts in PRP during future comparisons of the degree of platelet inhibition by these agents.

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.

Pharmacological reperfusion therapy for acute myocardial infarction with intravenous fibrinolytic agents improves survival yet fails to achieve early and complete coronary blood flow in nearly half of treated patients. In principle, glycoprotein (GP) IIb/IIIa inhibitors, potent antiplatelet agents, might improve the efficacy and clinical outcomes associated with fibrinolysis. Preclinical research suggests more rapid and effective reperfusion with combined platelet GP IIb/IIIa inhibition and fibrinolysis. Early clinical studies confirm improved early patency and more rapid electrocardiographic resolution, but increased bleeding complications, with the addition of GP IIb/IIIa antagonists to conventional fibrinolysis. Future studies may combine reduced-dose fibrinolytic therapy with GP IIb/IIIa inhibition to optimize efficacy and safety.