Platelet glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and tirofiban have been studied extensively as short-term adjuncts to short-term heparin and indefinite aspirin in patients with acute coronary syndrome or undergoing percutaneous coronary interventions on native vessels. The drugs provide a small advantage in the composite endpoint of death, myocardial infarction, and need for revascularization at 30 days (1-2% of treated patients) at the expense of an increase in major and potentially fatal bleeding complications (1% of treated patients over heparin plus aspirin alone). Highest-risk patients appear to benefit the most; clopidogrel should also be considered in these patients. Patients undergoing percutaneous interventions on bypass grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another is incompletely clarified. Abciximab causes severe immune-mediated thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary syndrome and percutaneous coronary interventions requires discerning clinical judgment. The value of GP IIb/IIIa inhibitors is not established in other forms of vascular disease.     

Safety of glycoprotein IIb/IIIa inhibitors in urgent or emergency coronary artery bypass graft surgery

Approximately 2% to 4% of patients undergo urgent or emergency coronary artery bypass grafting (CABG) for complications of percutaneous coronary intervention (PCI) after treatment with glycoprotein (GP) IIb/IIIa inhibitors. The pharmacokinetic and pharmacodynamic properties of GP IIb/IIIa inhibitors play a large role in determining the safety of their use in the setting of urgent or emergency CABG procedures. Emergency or urgent CABG after treatment with the GP IIb/IIIa inhibitor, abciximab, may be associated with increased risk of hemorrhage and the requirement of platelet transfusions if surgery is performed within 12 h of abciximab discontinuation. Eptifibatide is associated with a similar risk compared with placebo, even when surgery is performed within 2 h of eptifibatide cessation. Limited data for tirofiban show that bleeding is not increased when compared with acetylsalicylic acid or heparin. Eptifibatide and tirofiban appear to have favourable safety profiles compared with abciximab in the setting of emergency or urgent CABG after failed PCI.     

In vivo demonstration of an antithrombin effect of abciximab

Abciximab prolonged the activated clotting time (ACT) in a post hoc analysis from the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications trial and an in vitro study has suggested an antithrombin effect of platelet glycoprotein IIb/IIIa inhibition. The purpose of this study was to evaluate the in vivo effects of abciximab on ACT and thrombin generation. In 46 patients undergoing coronary intervention, 24 received heparin and abciximab (group I), whereas 22 received heparin alone (group II). All received the same dose (70 U/kg) of heparin. Heparin was given after a baseline ACT, and in group I, abciximab was administered after the 5-minute ACT. Serial ACTs were recorded at baseline, 5, 10, 20, and every 30 minutes thereafter and at the procedure's end. No intervention including balloon angioplasty was performed until after the 20-minute ACT. The prothrombin fragment F1.2 (Nm/L) was measured at baseline, 20 minutes, and at the end of the procedure. Before (baseline) heparin and at 5 minutes, ACTs were similar. Abciximab prolonged ACT by a mean of 34 to 64 seconds starting with the 10-minute ACT and extending to the 50-minute ACT (all p <0.01 vs heparin alone). There was a progressive decrease in the F1.2 with abciximab, and baseline minus end F1.2 was 0.12 +/- 0.02 in group I versus 0.05 +/- 0.04 in group II, p <0.05. These data indicate a significant in vivo effect of abciximab plus heparin in increasing ACT and decreasing F1.2, results that are consistent with an effect on reducing thrombin generation.     

Effects of tirofiban plus heparin versus heparin alone on troponin I levels in patients with acute coronary syndromes

Elevated serum troponins following an acute coronary syndrome (ACS) predict a poor clinical outcome. Glycoprotein (GP) IIb/IIIa inhibitors reduce adverse clinical outcomes in patients with ACS, although their effect on serum troponin I (TnI) in this setting has not been described. We therefore studied the effects of the GP IIb/IIIa inhibitor tirofiban on serum TnI levels in a group of patients in the Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Serial blood samples were obtained in 53 patients receiving the combination therapy of tirofiban/heparin and in 52 receiving heparin alone, and were analyzed for baseline, peak, and mean concentrations of TnI. Baseline TnI levels were not different between the combination therapy and heparin-only groups (1.6 +/- 3.0 vs 3.1 +/- 6.7 ng/ml, p = 0.15). The peak TnI level was significantly lower in the combination therapy group than in the heparin group (5.2 +/- 8.3 vs 15.5 +/- 29.1 ng/ml, p = 0.017), and mean levels over the initial 24-hour period were also significantly lower in the combination therapy group (3.2 +/- 5.0 vs 8.5 +/- 14.8 ng/ml, p = 0.016). In univariate analysis, combination therapy was associated with lower TnI levels, whereas in a multivariate model, the lower peak and mean TnI levels as a consequence of tirofiban/heparin compared with heparin monotherapy remained significant (peak, p = 0.029; mean, p = 0.035). Among patients with negative TnI at baseline, treatment with the combination of tirofiban/heparin compared with heparin monotherapy still resulted in significantly lower peak (2.5 +/- 5.4 vs 14.6 +/- 32.8 ng/ml, p = 0.024) and mean (1.2 +/- 2.6 vs 6.9 +/- 15.8 ng/ml, p = 0.029) TnI levels. In patients with ACS, therapy with the combination of tirofiban and heparin (compared with heparin treatment alone) resulted in lower serum TnI levels, suggesting reduced myocardial injury.     

Differential Effects of Citrate Versus PPACK Anticoagulation on Measured Platelet Inhibition by Abciximab, Eptifibatide and Tirofiban

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.Conclusion: Accurate assessment and comparison of platelet inhibition by GP IIb/IIIa inhibitors may require avoidance of calcium chelating anticoagulants.     

Update on Glycoprotein IIb/IIIa Blockade in Endovascular Interventions

Platelet aggregation plays a central role in the ischemic complications of percutaneous coronary interventions (PCI) and the acute coronary syndromes (ACS). Although aspirin and heparin have been effective at decreasing adverse events in these settings, the perceived need for more potent inhibition of platelet aggregation has led to targeting of the platelet surface membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Several agents have been developed; four: abciximab, tirofiban, eptifibatide, and lamifiban have been tested in clinical trials. Overall, the positive findings of these studies have supported the hypothesis that enhanced platelet blockade leads to improved clinical outcomes in the settings of PCI and ACS. In this article, an overview of the various GP IIb/IIIa receptor inhibitors is presented. The clinical trials of these agents as adjunctive therapy for patients undergoing PCI and in treatment of acute myocardial infarction are reviewed. Practical considerations relating to clinical efficacy, drug safety, and economic issues are discussed.     

GP IIb/IIIa inhibitors during primary percutaneous coronary intervention for STEMI: New trial and registry data

Primary percutaneous coronary intervention (PCI) with adjunctive glycoprotein (GP) IIb/IIIa receptor inhibitor therapy administered in the cardiac catheterization laboratory is the optimal reperfusion strategy for patients with ST-elevation myocardial infarction. Most available data regarding these agents are from trials comparing abciximab to placebo alone. Noninferiority trials comparing small-molecule GP IIb/IIIa receptor inhibitors, such as tirofiban and eptifibatide with abciximab, have used markers for myocardial reperfusion as primary end points but are underpowered to detect significant differences in hard clinical outcomes. Such a trial would need to enroll a very large number of patients and thus make it practically impossible to perform. Registry data reveal that most patients undergoing primary PCI are treated with small-molecule GP IIb/IIIa receptor inhibitors in clinical practice, and no observed difference is observed in safety and efficacy when compared with patients treated with abciximab therapy.     

A randomized two‐by‐two comparison of high‐dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: The tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial

Background : In the absence of high‐dose thienopyridines, placebo‐controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head‐to‐head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Methods and Results : Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high‐dose bolus (25 μg/kg) plus 12‐hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30‐day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. Conclusion : With limited assessment, this direct comparison of high‐dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. © 2010 Wiley‐Liss, Inc.     

Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial

OBJECTIVES: The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition. BACKGROUND: Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown. METHODS: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations. RESULTS: Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient). CONCLUSIONS: Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.     

Ability of anti-glycoprotein IIb/IIIa agents to dissolve platelet thrombi formed on a collagen surface under blood flow conditions

OBJECTIVES: We examined the lytic effects of anti-glycoprotein (GP) IIb/IIIa agents on platelet thrombi formed on the collagen surface under blood flow conditions. BACKGROUND: Anti-GP IIb/IIIa agents may influence platelet thrombi already formed. METHODS: Blood samples were anticoagulated either by the specific antithrombin Argatroban (100 microM) or by unfractionated heparin (0.1 U/ml). After platelet thrombi were formed on a collagen surface following 6-min perfusion of whole blood obtained from eight adult donors containing fluorescinated platelets at a wall shear rate of 1,500 s(-1), additional blood samples from the same donors either containing or not containing anti-GP IIb/IIIa agents (abciximab, eptifibatide, or tirofiban) were perfused on these thrombi. The three-dimensional structures of the platelet thrombi were continuously observed by laser confocal microscopy equipped with a piezo-electric motor control unit and recorded. RESULTS: The platelet thrombi started to dissolve after perfusion of blood containing the anti-GP IIb/IIIa agents, whereas their growth resumed after subsequent perfusion of control blood. Only a single layer of platelets having heights of 3 +/- 1 microm, 3 +/- 2 microm, and 3 +/- 1 microm, respectively, could be seen after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, whereas the initial height of the platelet thrombi of 8 +/- 2 microm increased to 11 +/- 4 microm after subsequent perfusion of control blood (n = 8). The volume of the platelet thrombi, which was 3,352 +/- 1,045 microm(3) before starting the second perfusion, was reduced to 778 +/- 102 microm(3), 812 +/- 122 microm(3), and 856 +/- 144 microm(3) after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, respectively. CONCLUSIONS: We have shown in this study that anti-GP IIb/IIIa agents possess the ability to dissolve platelet thrombi.     

Profound thrombocytopenia associated with tirofiban: case report and review of literature

Platelet glycoprotein (GP)IIb/IIIa inhibitors prevent fibrinogen binding and platelet aggregation. Inhibition of platelet activity at the injured coronary plaque is a target for novel therapeutic strategies. They decrease ischemic complications associated with non-ST-segment elevation acute coronary syndromes and percutaneous coronary intervention. Thrombocytopenia is a serious complication well described with the use of the prototype GP IIb/IIIa inhibitor abciximab. Its association with other agents of this class has been underemphasized. It is important to monitor platelet counts closely after initiation of GP IIb/IIIa inhibitor therapy, not only for abciximab, but also for small molecule inhibitors such as eptifibatide and tirofiban. Monitoring of platelet counts at 2 to 6 hours and 24 hours will detect most cases of acute thrombocytopenia. Adverse events may be prevented by prompt discontinuation of GP IIb/IIIa inhibitor therapy. The authors present a case of profound thrombocytopenia after the administration of tirofiban in the treatment of a patient with an acute coronary syndrome.     

Antithrombotic effects of abciximab

The observation that platelet-platelet interaction and thrombosis are ultimately regulated by the glycoprotein (GP) IIb/IIIa receptor complex, triggered the development of agents capable of interfering with this platelet receptor complex. Several large clinical trials have demonstrated the effectiveness of this class of agents. The first of these agents to show beneficial effects after coronary interventions was the mouse/human chimeric Fab fragment antibody c7E3 (abciximab; ReoPro). This study analyzes whether the addition of heparin to the GP IIb/IIIa antagonist abciximab would enhance the antithrombotic effect. Blood drawn directly from patients on aspirin who underwent interventional procedures perfused an ex vivo perfusion chamber containing a severely injured arterial wall at local rheologic conditions of a mildly stenosed coronary artery. Blood was perfused directly from patients at baseline and following administration of heparin, abciximab, or both. The antithrombotic effects of the 3 treatments were assessed by reduction of the thrombus formation on the perfused specimens. Thrombus formation at baseline was not significantly modified by the administration of heparin (13,897 +/- 1,316 vs 11,917 +/- 1,519 microm(2)). Abciximab produced a 58% reduction in thrombus formation (11,631 +/- 861 vs 4, 925 +/- 585 microm(2); p <0.001). The addition of heparin to abciximab did not further reduce thrombus area versus abciximab alone (5,651 +/- 581 vs 4,925 +/- 585 microm(2)). Thus, our data show that abciximab dramatically decreases mural thrombus formation and that combining heparin with abciximab did not add any additional antithrombotic effect to abciximab alone.     

Adjuvant antithrombotic therapy in ST-elevation myocardial infarction: A narrative review

This article reviews the major pharmacologic features of, and clinical evidence on, adjuvant medical therapy in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. These drugs include oral antiplatelets (aspirin and P2Y₁₂ inhibitors such as clopidogrel, prasugrel and ticagrelor), intravenous antiplatelet agents (the P2Y₁₂ inhibitor cangrelor, GP IIb/IIIa inhibitors such as abciximab, eptifibatide and tirofiban), and intravenous anticoagulant agents (unfractionated heparin, low molecular weight heparin and bivalirudin).     

Platelet glycoprotein IIb/IIIa inhibitor use during percutaneous coronary intervention: IIb or Not IIb,what is the question?

Over the past decade, numerous placebo-controlled randomized clinical trials have documented robust clinical benefits of intravenous platelet glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI). This evidence has led to U.S. Food and Drug Administration approval and indication for use of two GP IIb/IIIa inhibitors at the time of PCI, namely, the chimeric monoclonal antibody fragment abciximab (ReoPro, Centocor, Inc. and Eli Lilly & Company) and the cyclic heptapeptide small molecule eptifibatide (Integrilin, COR Therapeutics and Key Pharmaceuticals). Currently, another small molecule GP IIb/IIIa inhibitor, tirofiban (Aggrastat, Merck & Company), which (similar to eptifibatide) is approved for the medical therapy of patients with non-ST segment elevation acute coronary syndromes (ACS), has not received indication for use in the PCI setting. Although the clinical benefits of both abciximab and eptifibatide administered at the time of PCI have been proven in randomized clinical trials, only abciximab has demonstrated a late survival advantage in patients following PCI. Evidence in support of the presence, magnitude and possible mechanisms for abciximab survival advantage is herein reviewed.     

Effect of tirofiban therapy on ST segment resolution and clinical outcomes in patients with ST segment elevated acute myocardial infarction undergoing primary angioplasty

BACKGROUND: In our study, we assessed the effect of glycoprotein (GP) IIb/IIIa receptor inhibition on microvascular flow after acute coronary occlusion using the early sum of ST segment resolution in electrocardiography. Platelets may play a major role in the dissociation of epicardial artery recanalization and tissue level reperfusion, referred to as the 'no-reflow phenomenon'. Therefore, GP IIb/IIIa receptor inhibition might improve myocardial reperfusion, distinct from its effects on epicardial patency. METHODS AND RESULTS: One hundred and fifteen patients (mean age 57.7 +/- 12.2 years, 96 males, 19 females) with < or = 12-hour acute ST segment elevation myocardial infarction who underwent successful primary percutaneous coronary intervention were retrospectively enrolled into the study. Patients were grouped according to whether they received tirofiban therapy or not. Clinical and electrocardiographic parameters were evaluated. The first sum of ST segment elevation amounts in millimeters was obtained immediately before angioplasty and the second 60 min after restoration of thrombolysis in myocardial infarction III flow. The difference between the two measurements was accepted as resolution of the sum of ST segment elevation and expressed as SigmaSTR. There were no significant differences between the groups regarding age, gender, cardiovascular risk factors, and laboratory parameters, duration from angina onset to the emergency unit, and from door to angioplasty. SigmaSTR was higher in patients who received tirofiban than in those who did not (7.2 +/- 2.8 and 4.2 +/- 2.6 mm, respectively; p < 0.001). There was a significant and positive correlation between GP IIb/IIIa inhibition and SigmaSTR (r = 0.336, p < 0.001), as well as between ejection fraction and SigmaSTR (r = 0.310, p < 0.001). GP IIb/IIIa inhibition was the only independent determinant of SigmaSTR in a multivariate linear regression model which contains 10 variables (p < 0.001). The incidence of in-hospital post-myocardial infarction refractory angina, reinfarction, and heart failure was significantly lower in the tirofiban group (p < 0.05, p < 0.05, and p < 0.05, respectively). Additionally, after 30 days, reinfarction and heart failure were lower in the tirofiban group (p < 0.05 and p < 0.05, respectively). CONCLUSIONS: It is well known that SigmaSTR determines microvascular perfusion. This study shows that GP IIb/IIIa inhibition with tirofiban is of value in preserving microvascular perfusion after restoring coronary thrombolysis in myocardial infarction III flow.     

Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting

OBJECTIVES: We sought to investigate whether abciximab, tirofiban and eptifibatide achieve comparable antiplatelet effects with coronary stenting. BACKGROUND: The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban and eptifibatide differ in chemical structure, binding site and pharmacokinetics. METHODS: Sixty patients undergoing coronary stenting were randomly assigned to abciximab (bolus 0.25 mg/kg body weight, infusion 10 microg per min for 12 h), tirofiban (bolus 10 microg/kg, infusion 0.15 microg/kg per min for 72 h) or eptifibatide (bolus 180 microg/kg, infusion 2 microg/kg per min for 72 h). We took serial blood samples to analyze platelet function by using flow cytometry, turbidimetric aggregometry and the rapid platelet-function assay (RPFA). RESULTS: As assessed by RPFA, platelet aggregation after 2 h of infusion was reduced to 5.9 +/- 7.8% (mean +/- SD) of baseline by abciximab, to 5.0 +/- 5.4% by tirofiban and to 7.8 +/- 7.1% by eptifibatide (p = 0.42). Turbidimetric aggregometry with adenosine diphosphate stimulation yielded similar results, whereas percent inhibition of platelet aggregation after thrombin receptor stimulation was 45.8 +/- 16.8% with abciximab, 51.3 +/- 17.6% with tirofiban and 52.9 +/- 14.8% with eptifibatide (p = 0.37). Tirofiban and eptifibatide maintained their level of platelet inhibition during infusion. Flow cytometry revealed that the reduction in the monocyte-platelet interaction by abciximab, tirofiban and eptifibatide was not significantly different (20.0 +/- 21.9%, 23.8 +/- 18.2% and 21.0 +/- 19.8%, respectively; p = 0.87). CONCLUSIONS: Abciximab, tirofiban and eptifibatide, at currently recommended doses, achieved similar levels of inhibition of platelet aggregation and a similar reduction in the platelet-monocyte interaction.     

Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina

OBJECTIVES: We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature. BACKGROUND: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined. METHODS: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty. RESULTS: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration. CONCLUSIONS: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.     

The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial

OBJECTIVES: We sought to determine the safety and efficacy of high-dose bolus (HDB) tirofiban in high-risk patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The use of HDB tirofiban in the catheterization laboratory is controversial. In particular, in patients with acute coronary syndromes undergoing PCI, there is no evidence that tirofiban administered in the catheterization laboratory is superior to heparin alone. This finding probably reflects the suboptimal platelet inhibition when tirofiban is employed at RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) regimen. METHODS: A total of 202 patients (mean age 69 +/- 8 years; 137 males [68%]) undergoing high-risk PCI, pretreated with thienopyridines, were consecutively randomized to HDB tirofiban (25 microg/kg/3 min, and infusion of 0.15 microg/kg/min for 24 to 48 h) or placebo immediately before the procedure and then followed for a median time of 185 days (range 45 to 324 days) for the occurrence of the primary composite end point of death, myocardial infarction, target vessel revascularization (TVR), and bailout use of glycoprotein (GP) IIb/IIIa inhibitors. RESULTS: The cumulative incidence of the primary end point was 35% and 20% in placebo and HDB tirofiban groups, respectively (hazard ratio 0.51, 95% confidence interval 0.29 to 0.88; p = 0.01). This difference was mainly due to the reduction of myocardial infarction and bailout use of GP IIb/IIIa inhibitors, with no significant effect on TVR or death. The safety profile did not differ between tirofiban and placebo. CONCLUSIONS: The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.     

Effects of Different Thrombolytic Treatment Regimen with Abciximab and Tirofiban on Platelet Aggregation and Platelet-Leukocyte Interactions: A Subgroup Analysis from the GUSTO V and FASTER Trials

Background: Due to considerably high rates of reocclusion under standard thrombolytic therapy GP IIb/IIIa inhibitors have been combined with thrombolytics to improve therapeutic outcomes. Potential reasons for arterial reocclusion may be increased platelet activation, interaction of platelets with other cell types such as leukocytes and inadequate drug dosing due to lack of ideal platelet monitoring. We compared combination therapy regimens consisting of GP IIb/IIIa inhibitors and thrombolytics with respect to platelet inhibition and platelet-leukocyte interactions. Methods and results: From the GUSTO V trial (standard rPA vs. reduced dose rPA and abciximab) and the FASTER trial (standard TNK-tPA vs. reduced dose TNK-tPA and tirofiban) 15 patients were monitored by platelet aggregometry, rapid platelet function assay (RPFA) and flow cytometry (FC). rPA alone (n = 5) caused initial increases in platelet aggregation. However, platelet aggregation was significantly (p < 0.05) and sufficiently (>80%) inhibited by abciximab/rPA (n = 5) and tirofiban/TNK-tPA (n = 5). The platelet inhibitory effect of tirofiban/TNK-tPA was more pronounced compared to abciximab/rPA with a significant difference after 2 h (p < 0.05). Tirofiban/TNK-tPA and abciximab/rPA caused decreases in platelet-leukocyte aggregates as well as in binding of specific antibodies to the platelet vitronectin receptor and P-selectin (p < 0.05, respect.). No differences among the treatment groups were seen with respect to antibody binding to MAC-1 and CD154/CD40 ligand. Conclusions: Taken together, GP IIb/IIIa inhibitors overcome the platelet activating effect of thrombolytics resulting in sufficient platelet inhibition. RPFA is a suitable monitoring tool to accurately assess platelet inhibition. Within the given combination treatment regimen tirofiban appears to be more effective compared to abciximab and to exert effects beyond the inhibition of GP IIb/IIIa.     

Drip and Ship: A New Strategy for the Treatment of Acute Coronary Syndromes

Glycoprotein (GP) IIb/IIIa inhibitors block the final common pathway of platelet aggregation by preventing fibrinogen from binding to the GP IIb/IIIa platelet receptor. In patients with unstable angina (UA) or a non–Q wave myocardial infarction (NQWMI), including those with UA refractory to medical therapy, these agents decrease the risk of death, myocardial infarction (MI), and recurrent ischemia. Most patients with acute coronary syndromes are managed in hospitals without on-site angioplasty capabilities and often require transfer for an interventional procedure. We propose that GP IIb/IIIa inhibitors can be safely initiated at the referring hospital. We studied 20 patients with UA/NQWMI in whom therapy with a GP IIb/IIIa inhibitor, in addition to standard medical therapy, was initiated prior to transfer for an urgent percutaneous coronary intervention (PCI) (drip and ship). The primary end point was a composite of death, MI, and recurrent ischemia at 30 days. Twelve patients were treated with abciximab, 5 patients were treated with tirofiban, and 3 patients initially treated with tirofiban were converted to abciximab. Procedural success occurred in 33 out of 36 (92%) lesions and 18 out of 20 (90%) patients. At 30 days, 4 out of 20 (20%) patients had recurrent ischemia. The PTCA sites were widely patent in the 3 patients who underwent repeat angiography. The fourth patient had an unsuccessful PCI and was referred for coronary artery bypass surgery. There were no MIs or deaths. Patients who require transfer for an urgent PCI can be managed safely and efficaciously by initiating a GP IIb/IIIa inhibitor, in addition to standard medical therapy, prior to transfer.