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

Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI (STEMI).     

Eptifibatide: a potent inhibitor of the platelet receptor integrin glycoprotein IIb/IIIa

The platelet glycoprotein (GP) IIb/IIIa integrin plays a key role in mediating platelet aggregation. Blockade of the platelet GP IIb/IIIa receptor prevents arterial thrombosis in animal models much better than does aspirin. Among the most specific inhibitors in this class of drugs is eptifibatide (Integrilin(TM), Millennium Pharmaceuticals, Inc.), a cyclic heptapeptide based on a peptide recognition sequence found in snake venom. Peptide inhibitors, such as eptifibatide, bind competitively to GP IIb/IIIa and have a short half-life, allowing the effect to be rapidly reversible and providing a favourable overall safety profile. Eptifibatide has been studied in a broad range of ischaemic coronary conditions including percutaneous coronary intervention (PCI), ST-segment and non-ST-segment acute myocardial infarction (MI) and unstable angina. In PCI and non-ST-segment MI, therapy with eptifibatide has been shown to reduce acute ischaemic complications without any increased risk of life-threatening adverse events. In the recently reported Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, two 180 microg/kg boluses of eptifibatide, 10 min apart, followed by an 18 - 24 h infusion at 2 microg/kg/min given as adjunctive therapy in non-urgent PCI reduced the 30-day composite of death, MI and need for urgent target vessel revascularisation from 10.4 to 6.8% compared with placebo. These results were achieved under conditions of typical contemporary PCI, namely the implantation of second- and third-generation stents deployed at high balloon pressures along with modern adjunctive pharmacological treatment, particularly the universal use of thienopyridines and lower-dose heparin. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative clinical applications and combinations with other therapies to further improve cardiovascular outcomes.     

依替巴肽与替罗非班在ACS介入治疗中有效性和安全性

目的 探讨依替巴肽与替罗非班在急性冠状动脉综合征(ACS)介入治疗中的临床疗效和安全性.方法 ACS中不稳定型心绞痛及非ST段抬高心肌梗死(UA/NSTEMI)28例,按就诊顺序随机分为依替巴肽(受试)组和替罗非班(对照)组,在常规予抗血小板及抗凝治疗基础上,经皮冠状动脉介入治疗(PCI)手术开始时即静脉予依替巴肽或替罗非班,观察比较两组住院期间及术后30 d主要不良心脏事件(MACE)、出血情况及血小板减少症.结果 两组住院期间及术后30 d内MACE事件均末发生;24 h心电图缺血导联数与用药及PCI前相比均减少,对照组更明显(P＜0.05);两组均未发生大出血事件,轻微出血发生率受试和对照分别为21.4%和28.6%.结论 两种血小板膜糖蛋白受体拈抗剂在ACS介入治疗中均能起到辅助作用,且安全性好,但长期疗效及毒副作用有待进一步研究观察.     

Eptifibatide: a potent inhibitor of the platelet receptor integrin glycoprotein IIb/IIIa

The platelet glycoprotein (GP) IIb/IIIa integrin plays a key role in mediating platelet aggregation. Blockade of the platelet GP IIb/IIIa receptor prevents arterial thrombosis in animal models much better than does aspirin. Among the most specific inhibitors in this class of drugs is eptifibatide (Integrilin^TMMillennium Pharmaceuticals, Inc.), a cyclic heptapeptide based on a peptide recognition sequence found in snake venom. Peptide inhibitors, such as eptifibatide, bind competitively to GP IIb/IIIa and have a short half-life, allowing the effect to be rapidly reversible and providing a favourable overall safety profile. Eptifibatide has been studied in a broad range of ischaemic coronary conditions including percutaneous coronary intervention (PCI), ST-segment and non-ST-segment acute myocardial infarction (MI) and unstable angina. In PCI and non-ST-segment MI, therapy with eptifibatide has been shown to reduce acute ischaemic complications without any increased risk of life-threatening adverse events. In the recently reported Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, two 180 μg/kg boluses of eptifibatide, 10 min apart, followed by an 18 – 24 h infusion at 2 μg/kg/min given as adjunctive therapy in non-urgent PCI reduced the 30-day composite of death, MI and need for urgent target vessel revascularisation from 10.4 to 6.8% compared with placebo. These results were achieved under conditions of typical contemporary PCI, namely the implantation of second- and third-generation stents deployed at high balloon pressures along with modern adjunctive pharmacological treatment, particularly the universal use of thienopyridines and lower-dose heparin. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative clinical applications and combinations with other therapies to further improve cardiovascular outcomes.     

Bivalirudin: a review of its potential place in the management of acute coronary syndromes

Bivalirudin, a synthetic analogue of hirudin, is a specific and reversible inhibitor of thrombin which binds directly with both fluid-phase and clot-bound thrombin. In patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), results from a large well designed study and its reanalysis (n = 4312) indicate that bivalirudin is more effective than heparin in the prevention of ischaemic complications for up to 90 days after the start of treatment. In addition, among patients undergoing PTCA for post myocardial infarction (MI) bivalirudin may be more effective than heparin in preventing ischaemic complications for up to 180 days after treatment was started. Data from dose-finding studies indicate bivalirudin has potential in the treatment of patients with unstable angina not undergoing percutaneous coronary intervention (PCI); however, well designed comparative studies are needed before firm conclusions can be made. Among patients with acute ST elevation MI, randomised trials have demonstrated bivalirudin to be significantly more effective than heparin in improving early patency in patients receiving thrombolytic therapy with streptokinase. Data from the Hirulog and Early Reperfusion/Occlusion (HERO)-1 trial (n = 412) indicate that bivalirudin recipients were significantly more likely to have Thrombin Inhibition in Myocardial Ischaemia (TIMI) grade 3 flow at 90 to 120 minutes than heparin recipients. In addition, data from the HERO-2 trial (n = 17 073) show bivalirudin was significantly more effective than heparin in reducing adjudicated 96-hour reinfarction and 30-day investigator-reported death/reinfarction than heparin. Bivalirudin was as effective as heparin in reducing 30-day mortality. Data from a meta-analysis of four randomised trials among patients undergoing PTCA or treatment for acute coronary syndromes indicate that, at after 30 to 50 days of follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined endpoint of death or nonfatal MI. The most significant adverse events associated with bivalirudin are bleeding complications. In individual trials, bivalirudin was as well tolerated as heparin with, in general, a reduced incidence of bleeding complications. Additionally, bivalirudin provides a more consistent, predictable anticoagulant response. In 4312 patients with unstable angina undergoing PTCA the incidence of retroperitoneal bleeding, blood transfusion and major haemorrhage was significantly lower in bivalirudin than heparin recipients. Data from the HERO-2 trial in patients with acute MI indicate that although bivalirudin recipients had a significantly higher incidence of mild or moderate bleeding than heparin recipients, there was no difference in intracranial haemorrhage, severe bleeding or transfusions. Data from a meta-analysis among 5674 patients with ischaemic heart disease show bivalirudin recipients were at a significantly lower risk of haemorrhagic events than heparin recipients. CONCLUSIONS: Bivalirudin is an effective alternative to heparin in the prevention of ischaemic complications in patients with unstable angina undergoing PTCA. In addition, the drug has shown potential in the treatment of patients with unstable angina not undergoing PCI. For patients with MI, it is clear that bivalirudin can replace heparin in the management of MI where streptokinase is used as the thrombolytic agent. Further data are required on the efficacy of bivalirudin in patients undergoing thrombolysis with newer thrombolytics.     

The role of eptifibatide in patients undergoing percutaneous coronary intervention

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. They have been extensively studied in patients undergoing percutaneous coronary intervention (PCI). Eptifibatide, one of the approved GP IIb/IIIa inhibitors, is a small heptapeptide that is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical studies, concomitant administration of eptifibatide in patients undergoing elective PCI reduced thrombotic complications in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II) and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) trials. In the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial, which included 10,948 patients with non-ST-elevation acute coronary syndromes, eptifibatide significantly reduced the primary end point of death and non-fatal myocardial infarction at 30 days compared with placebo. In patients with ST-segment elevation myocardial infarction (STEMI), eptifibatide has been studied as adjunct to primary PCI and improved epicardial flow and tissue reperfusion. Studies are now evaluating eptifibatide in high-risk patients with non-ST elevation acute coronary syndromes (NSTE-ACS) and a planned early invasive strategy in the EARLY-ACS (Eptifibatide Administration prior to Diagnostic Catherization and Revascularization to Limit Myocardial Necrosis in Acute Coronary Syndrome) trial and in patients with primary PCI for STEMI in comparison to abciximab in the EVA-AMI (Eptifibatide versus Abciximab in Primary PCI for Acute Myocardial Infarction) trial. After the completion of these trials, the value of eptifibatide in patients undergoing PCI in different indications can be determined.     

Eptifibatide: a pharmacoeconomic review of its use in percutaneous coronary intervention and acute coronary syndromes

Eptifibatide (Integrilin) is a selective inhibitor of platelet glycoprotein (GP) IIb/IIIa receptors used as adjunctive therapy for patients undergoing percutaneous coronary intervention (PCI) and for patients with acute coronary syndromes (ACS), particularly those requiring PCI. Most economic analyses of eptifibatide have incorporated clinical and healthcare resource use data from either the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) study in low- to moderate-risk patients undergoing selective PCI with stent implantation or the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial in patients with ACS. Eptifibatide achieved statistically significant reductions in combined endpoints of death and ischaemic complications in both of these large multicentre clinical trials, in which patients were randomised to receive intravenous eptifibatide or placebo as adjunctive therapy to heparin and aspirin (plus a thienopyridine in ESPRIT). In US economic analyses using ESPRIT trial data, approximately 40% and 70% of the acquisition cost of eptifibatide was offset by reduced medical resource consumption during the initial hospitalisation period and over a 1-year period, respectively. Eptifibatide was associated with a favourable cost-effectiveness ratio of $US1407 (year 2000 costs) per life-year gained (LYG) in a retrospective US cost-effectiveness analysis that incorporated data from the ESPRIT trial and modelled life expectancy using a large cardiovascular database.Several cost-effectiveness analyses used prospectively collected data from the PURSUIT trial and modelled survival projections using similar methods. These analyses, conducted in the US, Canada and Western Europe, also showed favourable results ($US3761-$US18 774 per LYG; various years of costing). Cost-utility ratios reported in US analyses varied somewhat, but remained <$US20 000 per quality-adjusted life-year gained (1996 values) when clinical efficacy data were derived from the US cohort of PURSUIT. CONCLUSION: Significant clinical benefits have been demonstrated with eptifibatide as adjunctive therapy in patients undergoing selective PCI with stent implantation in the ESPRIT trial and in patients with ACS in the PURSUIT trial. Pharmacoeconomic analyses using data from either ESPRIT or PURSUIT have demonstrated favourable cost-effectiveness ratios for both indications in various countries. ESPRIT-based results from the limited number of available economic analyses are particularly favourable. The cost-effectiveness of eptifibatide in ACS (i.e. PURSUIT-based results) may be further improved by targeting the drug for patients in whom catheterisation and PCI are planned, although further analyses are required to confirm this.     

The role of eptifibatide in patients undergoing percutaneous coronary intervention

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. They have been extensively studied in patients undergoing percutaneous coronary intervention (PCI). Eptifibatide, one of the approved GP IIb/IIIa inhibitors, is a small heptapeptide that is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical studies, concomitant administration of eptifibatide in patients undergoing elective PCI reduced thrombotic complications in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II) and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) trials. In the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial, which included 10,948 patients with non-ST-elevation acute coronary syndromes, eptifibatide significantly reduced the primary end point of death and non-fatal myocardial infarction at 30 days compared with placebo. In patients with ST-segment elevation myocardial infarction (STEMI), eptifibatide has been studied as adjunct to primary PCI and improved epicardial flow and tissue reperfusion. Studies are now evaluating eptifibatide in high-risk patients with non-ST elevation acute coronary syndromes (NSTE-ACS) and a planned early invasive strategy in the EARLY-ACS (Eptifibatide Administration prior to Diagnostic Catherization and Revascularization to Limit Myocardial Necrosis in Acute Coronary Syndrome) trial and in patients with primary PCI for STEMI in comparison to abciximab in the EVA-AMI (Eptifibatide versus Abciximab in Primary PCI for Acute Myocardial Infarction) trial. After the completion of these trials, the value of etifibatide in patients undergoing PCI in different indications can be determined.     

Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions

Heparin is a commonly used anticoagulant in patients with coronary artery disease but its use does not always result in low rates of ischaemic and bleeding events, so the search for new anticoagulants continues. Thrombin plays a key role in both thrombosis and haemostasis and direct thrombin inhibitors modelled on the hirudin molecule found in the saliva of the medicinal leech, Hirudo medicinalis, have recently been developed. To date, the only direct thrombin inhibitor shown to reduce both the ischaemic and the bleeding complications associated with percutaneous coronary intervention (PCI) is bivalirudin, which is approved for this indication in the US and New Zealand. This agent is currently being studied in patients undergoing PCI with or without glycoprotein IIb/IIIa inhibitors and stenting. Bivalirudin has been shown to significantly reduce the risk of reinfarction in patients with acute myocardial infarction (MI) treated with streptokinase, but its use for this indication is not approved in the US. It may also prove to be beneficial in patients with acute MI treated with other fibrinolytic regimens or with primary or facilitated PCI. Bivalirudin is suitable for use as an alternative to heparin in the majority of patients undergoing PCI and in patients receiving streptokinase for acute MI.     

Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions

Heparin is a commonly used anticoagulant in patients with coronary artery disease but its use does not always result in low rates of ischaemic and bleeding events, so the search for new anticoagulants continues. Thrombin plays a key role in both thrombosis and haemostasis and direct thrombin inhibitors modelled on the hirudin molecule found in the saliva of the medicinal leech, Hirudo medicinalis, have recently been developed. To date, the only direct thrombin inhibitor shown to reduce both the ischaemic and the bleeding complications associated with percutaneous coronary intervention (PCI) is bivalirudin, which is approved for this indication in the US and New Zealand. This agent is currently being studied in patients undergoing PCI with or without glycoprotein IIb/IIIa inhibitors and stenting. Bivalirudin has been shown to significantly reduce the risk of reinfarction in patients with acute myocardial infarction (MI) treated with streptokinase, but its use for this indication is not approved in the US. It may also prove to be beneficial in patients with acute MI treated with other fibrinolytic regimens or with primary or facilitated PCI. Bivalirudin is suitable for use as an alternative to heparin in the majority of patients undergoing PCI and in patients receiving streptokinase for acute MI.     

Protection rénale: données récentes en faveur d’une nouvelle approche — l’étude PREMIER

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 μg/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 μg/kg bolus followed by an infusion of either 1.3 μg/kg/min or 2 μg/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/μL) 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.     

Eptifibatide: a potent inhibitor of the platelet receptor integrin, glycoprotein IIb/IIIa

Platelet aggregation is intimately involved in the pathophysiology of acute coronary syndromes. Blockade of the platelet glycoprotein IIb/IIIa receptor, the mediator of platelet aggregation induced by all physiologic agonists, prevents arterial thrombosis in animal models far more effectively than aspirin. Eptifibatide (Integrilintrade mark) is a rapidly reversible competitive inhibitor of glycoprotein IIb/IIIa studied in a broad range of ischaemic coronary conditions, including percutaneous coronary intervention, ST-segment and non-ST-segment acute myocardial infarction and unstable angina. In each case, therapy with eptifibatide has reduced acute ischaemic complications without any increased risk of life-threatening bleeding or adverse events. Based on data from the Integrelin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II study, a salutary benefit in the range of a 20 - 25% reduction in adverse clinical events can be expected in patients undergoing coronary intervention. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative doses, infusion regimens and combinations with other therapies to improve further cardiovascular outcomes.     

Eptifibatide: a potent inhibitor of the platelet receptor integrin,glycoprotein IIb/IIIa

Platelet aggregation is intimately involved in the pathophysiology of acute coronary syndromes. Blockade of the platelet glycoprotein IIb/IIIa receptor, the mediator of platelet aggregation induced by all physiologic agonists, prevents arterial thrombosis in animal models far more effectively than aspirin. Eptifibatide (Integrilin ?) is a rapidly reversible competitive inhibitor of glycoprotein IIb/IIIa studied in a broad range of ischaemic coronary conditions, including percutaneous coronary intervention, ST-segment and non-ST-segment acute myocardial infarction and unstable angina. In each case, therapy with eptifibatide has reduced acute ischaemic complications without any increased risk of life-threatening bleeding or adverse events. Based on data from the Integrelin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II study, a salutary benefit in the range of a 20 - 25% reduction in adverse clinical events can be expected in patients undergoing coronary intervention. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative doses, infusion regimens and combinations with other therapies to improve further cardiovascular outcomes.     

Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation

Abciximab (Reopro) is an antibody fragment that dose-dependently inhibits platelet aggregation and leucocyte adhesion by binding to the glycoprotein (GP) IIb/IIIa, vitronectin and Mac-1 receptors.Abciximab (0.25 mg/kg bolus plus infusion of 0.125 micro g/kg/min for 12 hours) showed greater efficacy than tirofiban in reducing the 30-day composite endpoint of death, nonfatal myocardial infarction (MI) or urgent target-vessel revascularisation in the randomised, double-blind TARGET study in patients scheduled for stent placement. In addition, the beneficial effects of treatment with abciximab previously observed in the randomised, multicentre, placebo-controlled EPILOG and EPISTENT studies have been maintained to 1 year, with a significantly reduced incidence of ischaemic complications relative to placebo consistently observed across a range of subgroups including age, sex, bodyweight and indication for revascularisation.The incidence of the composite endpoint was reduced in patients presenting with acute MI of <48 hours' duration in comparison with either fibrinolytic therapy or stenting alone in the randomised STOPAMI and ADMIRAL trials, primarily because of a reduced requirement for urgent repeat revascularisation and reduced incidence of mortality. In the randomised, nonblind, multicentre CADILLAC trial in patients with acute myocardial infarction (MI), stenting alone was superior to percutaneous transluminal coronary angioplasty (PTCA) and stenting alone was not inferior to PTCA plus abciximab.Recent large randomised, multicentre studies (ASSENT-3 and GUSTO-V) have shown higher efficacy (on various ischaemic endpoints) of abciximab in combination with either a reduced dose of tenecteplase or reteplase compared with the fibrinolytic drug alone. TIMI grade 3 flow rates at 60 and 90 minutes in the TIMI-14 and SPEED trials were higher in patients who received abciximab in combination with either alteplase or reteplase than abciximab alone and were similar to that seen with the full-dose fibrinolytic alone.In the randomised, multicentre GUSTO IV-ACS study, no significant differences in any of the ischaemic endpoints at either 7 or 30 days in patients with acute coronary syndromes who were not scheduled to undergo early revascularisation (within 12 hours of end of infusion) were apparent between those who received abciximab (bolus and either 24- or 48-hour infusion) and those who received placebo in addition to aspirin and heparin. The most common adverse events associated with the use of abciximab are bleeding complications and thrombocytopenia, although the risk of major bleeding can be limited through adhering to current administration protocols.Treatment costs are generally higher in both stent plus abciximab and angioplasty plus abciximab groups than stent plus placebo, primarily because of the acquisition cost of abciximab. Abciximab appeared most cost beneficial in high-risk patients undergoing elective percutaneous coronary revascularisation; among lower risk patients, abciximab therapy has been associated with higher total in-hospital and 6-month medical costs than eptifibatide. CONCLUSION: The GP IIb/IIIa receptor antagonist abciximab, when used with aspirin and heparin, has demonstrated efficacy in reducing the short- and long-term risk of ischaemic complications in patients with ischaemic heart disease undergoing percutaneous coronary intervention, when used with aspirin and heparin. High-risk patients (including those with diabetes mellitus) derive particular benefits from abciximab treatment. Abciximab remains an important therapeutic option for the prevention of complications in patients with ischaemic heart disease.     

Bivalirudin: a review of its use in patients undergoing percutaneous coronary intervention

Bivalirudin (Angiox, Angiomax) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI. Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.     

Eptifibatide and tirofiban: new preparations. Limited benefit

(1) Two antiplatelet drugs, eptifibatide and tirofiban, are licensed for the prevention of early myocardial infarction in patients with unstable angina or non Q-wave myocardial infarction. (2) These drugs appear to have a mechanism similar to that of abciximab. Abciximab reduced the incidence of myocardial infarction during the month following administration to patients with unstable angina who were scheduled for a percutaneous coronary procedure. (3) The clinical assessment files on eptifibatide and tirofiban are both centred on a large double-blind, placebo-controlled trial. (4) In patients with unstable angina or non Q-wave myocardial infarction, the PURSUIT trial, involving 10,948 patients, showed a lower incidence, at one month, of a combined end point (death or non fatal myocardial infarction) in patients on the eptifibatide + heparin + aspirin combination than in patients on the heparin + aspirin + placebo combination. A retrospective subgroup analysis raised the hypothesis that eptifibatide would be most beneficial in patients who had had coronary interventions. (5) In patients with unstable angina or non Q-wave myocardial infarction, the patients with unstable angina or non Q-wave myocardial infarction, the PRISM-PLUS trial, involving 1,915 patients, showed a reduction in the risk of myocardial infarction at 7 days in patients on the tirofiban + heparin + aspirin combination compared with those on the heparin +aspirin combination. Here too a retrospective subgroup analysis suggested that tirofiban would be most beneficial in patients who had had coronary intervention. (6) On the whole, these three antiplatelet drugs appear to benefit the same type of patient at high risk of myocardial infarction, but abciximab has been more thoroughly assessed than eptifibatide and tirofiban. Neither eptifibatide nor tirofiban (which were developed simultaneously) has been directly compared with abciximab. The value of antiplatelet drugs in patients treated with a low-molecular-weight heparin + aspirin combination is unknown. (7) These antiplatelet drugs carry a risk of haemorrhage and thrombocytopenia. On treatment cessation, coagulation function appears to normalise slightly more rapidly with eptifibatide (approximately 6 hours) and tirofiban (approximately 8 hours) than with abciximab (approximately 12 hours).     

Clinical trials with glycoprotein IIb/IIIa antagonists - No benefit without bleeding?

As the glycoprotein GPIIb/IIIa receptor is the final common pathway in platelet aggregation, antagonists of this receptor cause a profound inhibition of aggregation induced by any agonist. The short-term efficacy and safety of GPIIb/IIIa antagonists in patients undergoing coronary angioplasty was demonstrated with murine 7E3 Fab, but this antibody was immunogenic. Abciximab is a chimeric human-mouse monoclonal antibody that is less immunogenic. The first major trial with a GPIIb/IIIa antagonist was the EPIC trial with abciximab, which showed that abciximab reduced the ischemic complications of coronary balloon angioplasty and atherectomy in high-risk patients, but increased the risk of bleeding. Subsequent studies showed that using less concurrent heparin reduced bleeding. Abciximab also reduced the rate of revascularization. Further studies have shown that the benefits of abciximab extended to all patients undergoing angioplasty (EPILOG), including patients with unstable angina (CAPTURE) and acute myocardial infarction (RAPPORT). Clinical trials with eptifibatide and tirofiban have failed to demonstrate benefit, at the doses used, in angioplasty. Abciximab and eptifibatide, but not oral xemilofiban, improve the safety of the coronary stenting procedure. Short-term intravenous treatment with lamifiban, eptifibatide or tirofiban is beneficial in acute coronary syndromes (unstable angina, non-Q wave myocardial infarction). Orally active GPIIb/IIIa antagonists are being developed for use in acute coronary syndromes and myocardial infarction. However, no benefit has been shown with lefradafiban in acute coronary syndromes and sibrafiban and orbofiban are harmful. Eptifibatide, lamifiban and abciximab improve coronary patency in myocardial infarction, and long- term trials of GPIIb/IIIa antagonists are being conducted in acute myocardial infarction. Abciximab can cause thrombocytopenia, and all the GPIIb/ IIIa antagonists increase the incidence of bleeding, but there is no excess of intracranial hemorrhage. (c) 2001 Prous Science. All rights reserved.     

Clopidogrel for the secondary prevention of stroke

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.     

阿司匹林抵抗的急性冠脉综合征患者加用替罗非班治疗的疗效及安全性探讨

目的评价血小板糖蛋白Ⅱb／Ⅲa（GPⅡb／Ⅲa）受体拈抗剂替罗非班应用于阿司匹林抵抗（AR）的急性冠脉综合征（ACS）患者的疗效及安全性。方法128例AR的ACS（包括不稳定性心绞痛和非Q波心肌梗塞）随机分为替罗非班组和对照组,对照组常规联合应用阿司匹林和氯吡格雷治疗,替罗非班组加用替罗非班治疗。观察用药后36小时和30天的不良心血管事件及副反应的发生情况。结果用药后36小时两组患者均未出现死亡及靶血管再次重建。用药后36小时实验组未出现心绞痛及心梗,对照组2例出现心绞痛,无心梗发生。用药后30天实验组无心绞痛发作,无心梗发作,对照组5例出现心绞痛,2例出现心梗。用药后36小时,替罗非班组出现2例牙龈出血,对照组无出血事件发生。用药后30天两组均无出血事件发生。两组均无颅内出血及消化道大出血,无血小板减少发生。两组的出血事件及血小板减少的副反应发生率无统计学意义（P〉0．05）。结论阿司匹林抵抗的急性冠脉综合征患者加用替罗非班治疗可明显降低心绞痛及心梗的发生率,并不增加急性冠脉综合征患者出血及血小板减少的发生率．值得临床推广应用。     

Drug treatment of elderly patients with acute myocardial infarction: practical recommendations.

Aspirin (acetylsalicylic acid) should be administered to patients on day 1 of an acute myocardial infarction (MI) and continued indefinitely. Early intravenous beta-blockade should be used during acute MI. beta-blockers should be continued indefinitely. Angiotensin-converting enzyme (ACE) inhibitors should be used in patients with acute MI with ST-segment elevation in two or more anterior precordial leads. ACE inhibitors should be used during and after acute MI in patients with chronic heart failure (CHF) or with a left ventricular ejection fraction < or =40%. There are no class I indications for using calcium channel antagonists during and after acute MI. Intravenous heparin should be used in patients with acute MI undergoing coronary revascularisation and in patients at high risk for systemic embolisation. Enoxaparin should be used in patients with non-Q-wave MI. Thrombolytic therapy should be considered in patients with acute MI with ST-segment elevation in contiguous leads of a 12-lead electrocardiogram or with left bundle branch block. Platelet glycoprotein IIb/IIIa inhibitors should be administered intravenously as an adjunct to heparin and aspirin in patients with non-Q-wave MI. Intravenous nitroglycerin should be used: (i) for the first 24 to 48 hours in patients with acute MI and CHF, large anterior MI, persistent ischaemia or hypertension; and (ii) continued beyond 48 hours in patients with recurrent angina pectoris or persistent pulmonary congestion. Long-acting nitrates should be given after MI, along with beta-blockers, to patients with angina pectoris. There are no class I indications for using intravenous magnesium during acute MI. The routine use of antiarrhythmic drugs other than beta-blockers during and after acute MI is not recommended.