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PubMed2005

Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study.

BACKGROUND: Pretreatment is not the most common strategy practiced for clopidogrel administration in elective coronary stenting. Moreover, limited information is available on the antiplatelet pharmacodynamics of a 300-mg versus a 600-mg clopidogrel loading dose, and the comparative effect of eptifibatide with these regimens is unknown. METHODS AND RESULTS: Patients undergoing elective stenting (n=120) were enrolled in a 2x2 factorial study (300 mg clopidogrel with or without eptifibatide; 600 mg clopidogrel with or without eptifibatide) (Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets [CLEAR PLATELETS] Study). Clopidogrel was administered immediately after stenting. Aggregometry and flow cytometry were used to assess platelet reactivity. Eptifibatide added a > or =2-fold increase in platelet inhibition to 600 mg clopidogrel alone at 3, 8, and 18 to 24 hours after stenting as measured by 5 micromol/L ADP-induced aggregation (P<0.001). Without eptifibatide, 600 mg clopidogrel produced better inhibition than 300 mg clopidogrel at all time points (P<0.001). Glycoprotein IIb/IIIa (GPIIb/IIIa) blockade was associated with lower cardiac marker release. Active GPIIb/IIIa expression was inhibited most in the groups treated with eptifibatide (P<0.05). CONCLUSIONS: In elective stenting without clopidogrel pretreatment, use of a GPIIb/IIIa inhibitor produces superior platelet inhibition and lower myocardial necrosis compared with high-dose (600 mg) or standard-dose (300 mg) clopidogrel loading alone. In the absence of a GPIIb/IIIa inhibitor, 600 mg clopidogrel provides better platelet inhibition than the standard 300-mg dose. These results require confirmation in a large-scale clinical trial.

Adult↗
PubMed2004

Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study.

OBJECTIVES: The present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non-ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention. BACKGROUND: Although thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear. METHOD: Thirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load. RESULTS: After platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion. CONCLUSIONS: The activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect.

Aged↗
PubMed2002

Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide.

BACKGROUND: The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS: We randomized 70 acute coronary syndrome patients undergoing percutaneous coronary intervention to receive abciximab, eptifibatide, or tirofiban at doses used in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), Platelet glycoprotein IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)/Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials, respectively. Platelet aggregation (PA) in response to 20 micro mol/L of adenosine diphosphate was measured with turbidimetric aggregometry in both D-phenylalanyl-L-prolyl-L-arginine chloromethylketone and citrate-anticoagulated blood early (15 and 30 minutes) and late (4, 12, and 18 to 24 hours) after drug initiation. At 15 and 30 minutes, PA was significantly less inhibited by the tirofiban-RESTORE regimen compared with abciximab (P=0.028) and eptifibatide regimens (P=0.0001). The abciximab regimen, however, showed increasingly varied anti-aggregatory effects during continued infusion for > or =4 hours. Citrate exaggerated ex vivo platelet inhibition after eptifibatide and tirofiban, but had the opposite effect on abciximab. Of all regimens evaluated, the eptifibatide regimen inhibited PA most consistently throughout both the early and late periods. CONCLUSIONS: Currently recommended drug regimens to inhibit the platelet glycoprotein IIb/IIIa receptor have distinct pharmacodynamic profiles that might affect their relative efficacy in acute coronary syndromes and percutaneous coronary intervention.

Abciximab↗
PubMed2004

Therapeutic use of intravenous eptifibatide in patients undergoing percutaneous coronary intervention: acute coronary syndromes and elective stenting.

Eptifibatide, a molecule isolated from the venom of the southeastern pygmy rattlesnake, selectively inhibits the platelet receptor IIb/IIIa. The safety and clinical efficacy of eptifibatide in patients undergoing percutaneous coronary intervention (PCI) was first evaluated in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) trial. In this study, the primary combined endpoint (composite of death, myocardial infarction [MI] or target vessel revascularization [TVR] at 30 days) occurred in 9.6% of the patients assigned to eptifibatide bolus followed by the 4-hour infusion versus 12.2% in the placebo group (p = 0.67). In the IMPACT-II trial, two different eptifibatide dosages were studied in 4011 patients undergoing elective PCI. The primary endpoint (death, MI, TVR or stent placement for threatened vessel closure at 30 days) occurred in 11.6% in the placebo group versus 9.1% in the 135/0.5 eptifibatide group (p = 0.035) and 10% in the 135/0.75 eptifibatide group (p = 0.18). The Enhanced Suppression of Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial studied a dose of eptifibatide 3- to 4-fold higher than that used in IMPACT II trial in patients undergoing non-emergent coronary artery stenting (two 180 microg/kg bolus doses 10 minutes apart). The 6-month composite endpoint (death, MI, TVR and 'bailout' eptifibatide use) occurred in 18.3% of patients in the placebo group versus 14.2% in the eptifibatide group (p = 0.008) and was maintained at 12 months (22.1% in the placebo group vs 17.5% in the eptifibatide group, p = 0.0068). The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) study in 10 948 patients was designed to study the effect of eptifibatide in the treatment of acute coronary syndromes (ACS) using two different dosages (180 microg/kg bolus followed by an infusion of either 1.3 microg/kg/min or 2 microg/kg/min. The primary endpoint, a composite of death or MI at 30 days, occurred in 15.7% of placebo-treated patients and 14.2% of eptifibatide-treated patients (p = 0.042). This difference was maintained at 7 days (11.6% in the placebo group vs 10.1% in the eptifibatide group, p = 0.016) and at 30 days (15.7% in the placebo group vs 14.2% in the eptifibatide group). In the eptifibatide studies, the rates of major bleeding were 0.7% (0.5% in the control group) in ESPRIT and 2.1% (1.3% in the placebo group) in PURSUIT. The incidence of intracranial bleeding was 0.2% in ESPRIT (0.1% in the placebo group) and 0.7% in PURSUIT (0.8% in the placebo group). Significant thrombocytopenia (platelet count <20 000/microL) was reported in 0.2% of the patients receiving eptifibatide in the ESPRIT trial (0% in the placebo group) and in <1% in PURSUIT (<1% in the placebo group). In summary, several clinical trials have demonstrated a clear-cut reduction in a variety of ischemic events in patients receiving eptifibatide as adjunctive pharmacotherapy during PCI.

Acute Disease↗
PubMed2004

Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function.

BACKGROUND: Previous studies of the glycoprotein IIb-IIIa inhibitor eptifibatide have included patients with moderate renal impairment (serum creatinine concentrations, 2.0-4.0 mg/dL). In these patients, adjustment of the standard infusion dose (2.0 microg/kg.min) to 1.0 microg/kg.min was recommended on empiric grounds because approximately 50% of eptifibatide is cleared renally. OBJECTIVE: The present study was designed to assess teh pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with various levels of creatinine clearance (CrCl), a parameter that is a more accurate indicator of renal function than serum creatinine concentration to determine the appropriate dose adjustment in patients with reduced renal function. A secondary objective was to determine the tolerability of eptifibatide when administered to patients with decreased renal function. METHODS: This open-label study was concluded at 3 US sites experienced in conducting similar studies. Subjects with differing renal function (normal [group 1, CrCl > 80 mL/min], mild renal impairment [group 2, CrCl 51-80 mL/min], moderate renal impairment [group 3, CrCl 30-50 mL/min], or severe renal impairment [group 4, CrCl <30 mL/min]) received a 24-hour eptifibatide infusion of 2.0 microg/kg.min (groups 1, 2, and 3) or 1.0 microg/kg.min (group 4). The primary end point was the eptifibatide steady-state plasma concentration; the secondary end points included inhibition of platelet aggregation and eptifibatide clearance, terminal plasma half-life, and area under the plasma concentration-time curve. In addition to analyses performed for each group, pharmacokinetic models were estimated and eptifibatide clearance was related to CrCl as a continuous variable by linear regression. All adverse events were recorded, with particular attention to bleeding. RESULTS: Thirty-one subjects (21 men, 10 women; mean age, 58.5 years [range, 44-73 years]; mean body weight, 81.6 kg [range, 51.5-105.1 kg]; mean height, 162.9 cm [range, 150-183 cm]) were included in the study. A strong correlation was found between eptifibatide clearance and CrCl. A tree-based analytic model indicated that the optimal discrete break point for the purpose of dose adjustment was a CrCl of 55.85 mL/min, which was rounded to 50 mL/min for practical clinical reasons. In patients with moderate or severe renal impairment (CrCl < or = 50 mL/min), clearance rates and steady-state concentrations of eptifibatide were approximately 50% lower and almost 2-fold higher, respectively, than in patients with normal renal function or mild renal impairment (CrCl > 50 mL/min). Inhibition of platelet aggregation exceeded the clinically significant threshold of 80% in all groups. Five subjects had a mild bleeding event and 4 subjects experienced mild to moderate nonbleeding events, 2 of which were considered drug-related by the investigator. None of the events required intervention. CONCLUSIONS: In this study, moderate to severe renal impairment was associated with an approximately 50% reduction in total eptifibatide clearance and a corresponding doubling of plasma eptifibatide concentration. Based on these findings, in patients with moderately or severely impaired renal function (calculated CrCl < or =50 mL/min) who are scheduled for percutaneous coronary intervention or who have non-ST-segment elevation acute coronary syndromes, it is appropriate to reduce the infusion dose of eptifibatide by 50% (from 2 to 1 microg/kg.min). Because the bolus dose(s) is (are) used to establish the initial targeted plasma eptifibatide concentrations, which are independent of clearance, and given that the volume of distribution did not correlate with renal function, no adjustment of the bolus dose(s) is required.

Adult↗
PubMed2001

Effect of eptifibatide on angiographic complications during percutaneous coronary intervention in the IMPACT--(Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) II Trial.

We sought to determine whether eptifibatide reduces elevation of creatine kinase (CK)-MB isoenzyme release during coronary intervention by preventing angiographic complications, by minimizing the sequelae of angiographic complications once they occur, or by other mechanisms. In the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis trial, patients underwent coronary intervention during treatment with placebo versus the glycoprotein IIb/IIIa receptor inhibitor eptifibatide. Eptifibatide decreased ischemic complications at 24 hours and 30 days. CK-MB elevations and in-laboratory angiographic complications (including major dissection, distal embolization, residual thrombus, abrupt closure, residual stenosis >50%, and side branch occlusion) were prospectively recorded. The incidence of any angiographic complication was lower in eptifibatide-treated patients (33%) than in placebo-treated patients (38%, p = 0.019). For patients with angiographic complications, there was a trend toward a reduced incidence of any elevation in CK-MB in the first 24 hours (29%, 135/0.75 eptifibatide dose; 33%, 135/0.5 eptifibatide dose; 37%, placebo). Among patients without angiographic complications, there was a similar trend toward fewer abnormal CK-MB levels in patients receiving eptifibatide (17% and 18% in eptifibatide arms vs 21% placebo). Thus, eptifibatide reduces angiographically evident complications during coronary intervention, but this effect accounts for only 1/3 of the reduced frequency of CK-MB elevations observed with eptifibatide. When angiographic complications occur, eptifibatide reduces rates of subsequent CK-MB elevation, accounting for another 1/3 of the reduction in CK-MB elevations. Finally, eptifibatide reduces the incidence of periprocedural CK-MB elevations in patients without angiographically evident complications, accounting for 1/3 of eptifibatide's overall effect in reducing of CK-MB elevations in patients undergoing percutanous coronary intervention.

Angioplasty, Balloon, Coronary↗
PubMed1999

Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention.

UNLABELLED: Eptifibatide, a cyclic peptide, is a highly specific, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist. By preventing fibrinogen binding to the GP IIb/IIIa receptor, eptifibatide inhibits platelet aggregation and prevents thrombus formation. Clinically, the drug is used as an adjunct to heparin and aspirin. The PURSUIT trial, conducted in >10,000 patients with unstable angina or non-Q-wave myocardial infarction (MI), showed that eptifibatide (180 microg/kg bolus then 2 microg/kg/min infusion for < or =72 hours) reduces the 30-day risk of death or nonfatal MI, with this benefit apparent at 96 hours. The absolute reduction in this end-point of 1.5% persisted at 6 months. The drug is effective in patients undergoing percutaneous coronary intervention (PCI), and, as shown in the North American subgroup, in patients in whom medical management is appropriate. Eptifibatide is also beneficial in patients undergoing PCI, whether or not they have unstable angina or non-Q-wave MI. In a dosage of 135 microg/kg then 0.5 microg/kg/min for 24 hours, eptifibatide reduced the 30-day risk of a combined end-point (death, nonfatal MI and urgent or emergency coronary interventions) by 2.5% (absolute reduction) in patients undergoing PCI in the IMPACT-II trial, when measured by per-protocol (patients treated), but not intent-to-treat, analysis. The drug also decreased the incidence of abrupt vessel closure and ischaemic cardiovascular complications in the first 24 hours (the period of greatest risk). Bleeding episodes are the most common adverse event associated with eptifibatide therapy. Although the incidence of major bleeding is increased with eptifibatide, most bleeding episodes are minor and occur at the vascular access site. The drug is not associated with an excess of intracranial bleeds, stroke or thrombocytopenia, does not appear to increase bleeding risk in patients undergoing coronary artery bypass graft (CABG), and does not cause antibody formation. Limited data suggest that eptifibatide may improve coronary flow when combined with alteplase in patients with acute Q-wave MI, but the possibility of increased bleeding with eptifibatide plus thrombolytics should be borne in mind. CONCLUSIONS: Intravenous eptifibatide, when combined with aspirin and heparin, reduces the 30-day risk of ischaemic events in patients with unstable angina and non-Q-wave MI and decreases ischaemic cardiovascular complications at the time of greatest risk in patients undergoing PCI. With its acceptable tolerability profile eptifibatide is a suitable option as a short term adjunct in these clinical settings. Whether eptifibatide in combination with fibrolysis may improve outcome in patients with acute Q-wave MI has yet to be determined.

Angina, Unstable↗
PubMed1997

Clinical pharmacology of eptifibatide.

Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common pathway to platelet aggregation. Platelet aggregates provide the structural basis for coronary thrombosis, a major cause of ischemic heart disease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor function has emerged as a promising new therapeutic strategy for management of acute ischemic coronary syndromes and acute ischemic complications of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa inhibitor from the venom of the southeastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. Preclinical pharmacologic studies have established that eptifibatide can inhibit thrombosis effectively, with only modest effects on bleeding time measurements. Pharmacokinetic and pharmacodynamic studies in both animal models and humans have shown that the antiplatelet effect of eptifibatide has a rapid onset of action and that the drug has a short plasma half-life. Furthermore, the rapid reversibility of action of eptifibatide, exemplified by an antihemostatic effect limited to the period of drug administration, was apparent in both healthy volunteers and patients with ischemic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have led to the evaluation of eptifibatide in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, which enrolled 4,010 patients undergoing coronary angioplasty. The combination of a bolus plus either of 2 infusion doses of eptifibatide reduced the incidence of ischemic complications without increasing the risk of bleeding or other complications. Recent pharmacodynamic studies have established that more aggressive dosing of eptifibatide provides greater inhibition of ex vivo platelet aggregation and more robust antithrombotic activity. Higher doses of eptifibatide were therefore selected for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The available data suggest that eptifibatide may represent a useful clinical alternative to existing antiplatelet therapies.

Animals↗
PubMed2000

Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: results from PURSUIT. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy.

BACKGROUND: The platelet GP IIb/IIIa inhibitor eptifibatide improves outcomes in patients with acute coronary syndromes. Patients requiring emergent coronary artery bypass grafting, however, may be at increased risk for bleeding if exposed to eptifibatide. Data from the PURSUIT trial were reviewed to assess this risk in patients undergoing coronary surgery immediately after exposure to eptifibatide. METHODS: In PURSUIT, 10,948 patients who presented with non-ST segment elevation acute coronary syndromes were prospectively randomized to receive eptifibatide (180 microg/kg bolus plus 2 microg/kg/min infusion) or placebo. A total of 78 patients underwent immediate coronary artery bypass surgery within 2 hours of cessation of study drug (placebo, n = 46; eptifibatide, n = 32). Clinical outcome, bleeding, and transfusion requirements within this subset were examined. RESULTS: Major bleeding was not different between groups, occurring in 64% of patients receiving placebo and 63% of patients receiving eptifibatide. The incidence of blood transfusion was similar as well (57% vs 59%). Postoperative thrombocytopenia occurred less often after eptifibatide exposure. Perioperative myocardial infarction was significantly reduced in patients who received eptifibatide (46% vs 22%, p < 0.05). There was no difference in perioperative stroke (2.2% vs 6.3%) or mortality (6.3% vs 6.5%). CONCLUSIONS: Patients may safely undergo coronary artery bypass surgery within 2 hours of discontinuation of eptifibatide. Eptifibatide infusion in the immediate preoperative period had no adverse clinical effects, but did significantly decrease the incidence of perioperative myocardial infarction. Additionally, platelet counts after surgery were higher in the group of patients who received eptifibatide, perhaps indicative of a platelet-sparing effect during cardiopulmonary bypass.

Adult↗
PubMedDate not supplied

Disposition of 14C-eptifibatide after intravenous administration to healthy men.

Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of 14C-eptifibatide in man after a single intravenous (i.v.) bolus dose. 14C-Eptifibatide (approximately 50 microCi) was administered to eight healthy men as a single 135-microgram/kg i.v. bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following 14C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).

Adult↗
PubMed2004

Administration of eptifibatide to acute coronary syndrome patients receiving enoxaparin or unfractionated heparin: effect on platelet function and thrombus formation.

OBJECTIVES: The goal of this study was to compare the antithrombotic effects of enoxaparin versus unfractionated heparin (UFH) when combined with eptifibatide in acute coronary syndrome (ACS) patients. BACKGROUND: An increasing number of high-risk ACS patients are treated with low-molecular-weight heparin and a glycoprotein (GP) IIb/IIIa inhibitor. There is a paucity of data regarding the antithrombotic properties of such a combination as compared with UFH and GP IIb/IIIa inhibitors. METHODS: Twenty-six ACS patients scheduled to undergo coronary angiography were treated with subcutaneous enoxaparin (n = 13) or intravenous UFH (n = 13). All patients received eptifibatide just before coronary angiography. Antithrombotic effects were assessed as changes in platelet-thrombus formation using the Badimon ex vivo perfusion chamber. Perfusions were carried out at a high shear rate (HSR) and a low shear rate (LSR). Patients underwent two perfusion studies: at baseline (under enoxaparin or UFH) and 10 min after the eptifibatide bolus. Platelet function was evaluated by ADP-induced platelet aggregation and the rapid platelet function analyzer. RESULTS: Both therapeutic combinations achieved a marked reduction in platelet aggregation after eptifibatide (83% to 89.7% reduction in the enoxaparin-eptifibatide group and 77.8% to 85.5% reduction in the UFH-eptifibatide group, inter-group differences not significant). Both groups also demonstrated marked reductions in thrombus formation, but the reductions achieved in the enoxaparin-eptifibatide group were significantly higher than those achieved in the UFH-eptifibatide group (HSR: 75.6% reduction vs. 63.9%, respectively, p = 0.01; LSR: 79.7% reduction vs. 66.1%, respectively, p = 0.0001). CONCLUSIONS: The combination of eptifibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptifibatide and UFH in the doses tested.

Anticoagulants↗
PubMed2005

Eptifibatide-associated acute, profound thrombocytopenia.

OBJECTIVE: To describe 3 cases of eptifibatide-associated acute, profound thrombocytopenia. CASE SUMMARIES: A 40-year-old black female received eptifibatide 180-microg/kg double bolus followed by a continuous infusion of 2 microg/kg/min for percutaneous coronary intervention (PCI). The platelet count decreased from 308 x 10(3)/mm3 to 2 x10(3)/mm3 4 hours after initiation of eptifibatide. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma and petechiae. A 67-year-old white female received the same dosage regimen of eptifibatide for PCI with no serious adverse effects, with the treatment repeated one month later. At that time, she developed chest and back pain, dyspnea, wheezing, and hypotension after the first bolus. Her platelet count decreased from 334 x10(3)/mm3 to 6 x10(3)/mm3 24 hours after initiation. Eptifibatide was discontinued and platelets were transfused. The patient died due to shock. A 72-year-old white male received eptifibatide 180-microg/kg double bolus followed by a continuous infusion of 2 microg/kg/min for acute coronary syndrome. His platelet count decreased from 189 x10(3)/mm3 to 17 x10(3)/mm3, and eptifibatide was discontinued. Eptifibatide was readministered with bivalirudin for PCI once the platelet count increased to 94 x10(3)/mm3. Sixteen hours later, the platelet count decreased to 1 x 10(3)/mm3. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma. DISCUSSION: Acute, profound thrombocytopenia is a rare complication of glycoprotein IIb/IIIa inhibitor therapy characterized by a precipitous decline in platelet count to <20 x10(3)/mm3 within 24 hours of therapy. An objective causality assessment revealed that the adverse drug event was probable in 2 cases and possible in the other. CONCLUSIONS: Increasing use of the glycoprotein IIb/IIIa inhibitors and enhanced recognition of the potential for acute, profound thrombocytopenia reinforce the need for more vigilant monitoring and alternative management strategies.

Acute Disease↗
PubMed2001

Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial.

CONTEXT: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial showed the efficacy of adjunctive, double-bolus eptifibatide therapy in reducing ischemic complications of nonurgent coronary stent implantation at 48 hours and at 30 days. OBJECTIVE: To determine whether the beneficial effects of eptifibatide persist at 6 months after treatment. DESIGN: Follow-up study of a randomized, double-blind, placebo-controlled, crossover-permitted trial conducted from June 1999 through February 2000. SETTING: Ninety-two tertiary care centers in the United States and Canada. PARTICIPANTS: A total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation. INTERVENTION: Patients were randomly assigned to receive placebo or eptifibatide (two 180-microg/kg boluses 10 minutes apart and continuous infusion of 2.0 microg/kg per minute), started immediately before stent implantation and continued for 18 to 24 hours. Complete follow-up data were available for 988 (95.0%) of 1040 patients given eptifibatide and 977 (95.4%) of 1024 patients given placebo. MAIN OUTCOME MEASURES: Composite rates of death or myocardial infarction (MI); death, MI, or target vessel revascularization; and their individual components 6 months after enrollment, compared between the 2 groups. RESULTS: By 6 months, the composite end point of death or MI had occurred in 7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P =.002). The composite of death, MI, or target vessel revascularization was 14.2% in eptifibatide-treated patients vs 18.3% in placebo-treated patients (HR, 0.75; 95% CI, 0.60-0.93; P =.008). Most of this benefit accrued early (<48 hours after initiation of therapy) and was maintained through 6 months. Six-month mortality in the eptifibatide group was 0.8% vs 1.4% in the placebo group (HR, 0.56; 95% CI, 0.24-1.34; P =.19) and target vessel revascularization occurred in 8.6% of the eptifibatide group vs 9.4% of the placebo group (HR, 0.91; 95% CI, 0.68-1.22; P =.51). CONCLUSION: Adjunctive eptifibatide therapy during coronary stent implantation provides benefit through 6-month follow-up.

Aged↗
PubMed2005

Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial.

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.

Aged↗
PubMed2001

Prognostic importance of concomitant heparin with eptifibatide in acute coronary syndromes. PURSUIT Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy.

Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

Aged↗
PubMed2002

Activated clotting times in the setting of eptifibatide use during percutaneous coronary intervention.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Angioplasty, Balloon, Coronary↗
PubMed2000

Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting. PURSUIT Investigators.

BACKGROUND: Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. METHODS AND RESULTS: The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7). CONCLUSIONS: Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

Acute Disease↗
PubMed2001

Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT.

BACKGROUND: Platelet deposition and aggregation are central to the pathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects of the platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but not in patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patients enrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy (PURSUIT) trial of ACS. METHODS AND RESULTS: Patients were randomly assigned to an intravenous bolus (180 microgram/kg) and 72-hour infusion of eptifibatide (2.0 microgram/kg per minute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptor occupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hours during treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrate and D-phenylalanyl-L-prolyl-L-arginine chloromethylketone anticoagulants. Although eptifibatide produced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared to recover partially by 4 hours after the bolus. The aggregation response was greater with thrombin receptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in blood samples anticoagulated with citrate versus D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibition of platelet aggregation. CONCLUSIONS: A bolus and infusion of eptifibatide inhibits platelet aggregation profoundly in patients with ACS and is followed by brief, partial recovery. These results enhance our understanding of the relation between pharmacodynamic and clinical effects of eptifibatide in such patients and may have important implications for its use in percutaneous interventions.

Adenosine Diphosphate↗