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.     

Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.     

Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention.

Adjunctive platelet glycoprotein IIb/IIIa blockade during percutaneous coronary intervention (PCI) reduces platelet-mediated adverse ischemic outcomes. Although abciximab, eptifibatide, and tirofiban have received U.S. Food and Drug Administration approval for use, these agents differ in their pharmacodynamic profiles. Each of these agents has been compared in randomized trials with placebo for patients undergoing PCI, but no randomized comparative studies of these agents have been performed. We compared ex vivo platelet function by both standard light transmission aggregometry and rapid platelet function assay during and after administration of abciximab, eptifibatide, or tirofiban in approved dose regimens on a randomized basis at the time of PCI in patients with unstable angina pectoris. A reduced intensity of platelet inhibition by light transmission aggregometry was observed for tirofiban compared with either eptifibatide or abciximab. In addition, the 30-minute bolus strategy used for tirofiban was associated with delayed onset of maximal platelet inhibition relative to the initiation of bolus infusion. Whether the trends in platelet function observed in this study will be translated into differences in clinical outcomes awaits definition by larger scale randomized clinical trials comparing these platelet glycoprotein IIb/IIIa inhibitors.     

Pharmacodynamic and clinical trials of glycoprotein IIb/IIIa inhibitors and potential relationship of results to dosing

Glycoprotein IIb/IIIa inhibitors have become the standard of care for patients undergoing percutaneous coronary intervention (PCI) and for those presenting with non-ST-segment elevation myocardial infarction (NSTE-ACS). Clinical effects of GP IIb/IIIa inhibitors in PCI and NSTE-ACS strongly correlate with potency, consistency, and durability of platelet aggregation inhibition. Under standardized conditions [light transmission aggregometry (LTA), 20 micromol adenosine diphosphate (ADP) as an agonist, and D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone (PPACK) as an anticoagulant], we demand consistent platelet aggregation inhibition >80% during the time of PCI (initial balloon inflation), and during the entire duration of therapy in NSTE-ACS. The benefit of abciximab (bolus 0.25 mg/kg plus infusion 10 microg/kg/min) correlates with >80% inhibition of platelet aggregation during the intervention (PCI) and immediately thereafter (<6 hours). The absence of a benefit with abciximab in NSTE-ACS is most likely due to <80% inhibition during the major part of the infusion period (>6 hours). Tirofiban does not achieve >80% inhibition at the time of PCI at a dose of 10 microg/kg bolus plus 0.15 microg/kg/min infusion, and at a dose of 0.4 lg/kg/min loading infusion for 30 minutes plus 0.1 microg/kg/min maintenance infusion, the target value is only reached after 18 h. Eptifibatide (double-bolus 180 microg/kg 10 min apart, followed immediately by a 2.0 microg/kg/min infusion) provided an instant, consistent, and durable antiplatelet effect for the entire duration of infusion, and a significant clinical benefit in both PCI (non-ACS patients) and medically managed NSTE-ACS patients.     

Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial)

Limited data are available with regard to the pharmacodynamics and safety of combining enoxaparin with glycoprotein IIb/IIIa inhibition during elective percutaneous coronary interventions (PCIs). We randomized 200 patients to receive open-label enoxaparin (0.75 mg/kg intravenous bolus) or unfractionated heparin (60 U/kg intravenous bolus) and eptifibatide or tirofiban during PCI. This yielded 4 groups of combination therapy (50 patients/group). The first 10 patients per group had anti-Xa activity and inhibition of platelet aggregation measured at baseline, and at 5 minutes, 10 minutes, 4 hours, and 24 hours. All patients received aspirin and clopidogrel therapy before PCI. Patients who received enoxaparin and heparin achieved therapeutic peak anti-Xa activity observed shortly after drug administration. At 4 hours, a differential anticoagulant effect was observed, with patients who received enoxaparin having a more gradual decrease in anti-Xa activity. Patients who received eptifibatide achieved >80% inhibition of platelet aggregation soon after initiation of therapy more often than did those who received tirofiban. Type of heparin did not affect inhibition of platelet aggregation. Compared with patients who received heparin, periprocedural myocardial infarction and bleeding events occurred less frequently among those who received enoxaparin (14% vs 8% and 10% vs 5%); however, these differences were not statistically significant. Three cases of intraprocedural thrombus occurred among patients who received enoxaparin. Two patients received concomitant tirofiban therapy. Compared with unfractionated heparin, similar levels of anticoagulation and platelet inhibition are achieved with enoxaparin when concomitant therapy with eptifibatide or tirofiban is used during elective PCI, without an observed increase in early bleeding events or periprocedural ischemic complications.     

A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban.

Platelet inhibition is central to the efficacy of glycoprotein (GP) IIb-IIIa antagonist therapy, but is not routinely measured during percutaneous coronary intervention (PCI). Data directly comparing the antiplatelet effects of these agents are also limited. Therefore, we compared ex vivo platelet function by standard light transmission aggregometry (LTA) and two automated bedside platelet function assays in 36 patients undergoing PCI with GP IIb-IIIa inhibitors. At baseline and 10 min following clinically recommended bolus and infusion of abciximab (0.25 mg/kg, 0.125 microg/kg/min), eptifibatide (180 microg/kg, 2 microg/kg/min), or tirofiban (10 microg/kg, 0.1 microg/kg/min), we measured 20 microM ADP- and 1.9 mg/mL collagen-induced platelet aggregation using LTA. Platelet function was also assessed using the bedside Accumetrics Ultegra-Rapid Platelet Function Assay (RPFA) and the Xylum Clot Signature Analyzer (CSA). The degree of platelet inhibition, as assessed by LTA, varied significantly between the clinically recommended doses of these GP IIb-IIIa antagonists. RPFA measurements agreed closely with LTA for abciximab, but tended to overestimate the degree of platelet inhibition for small molecules. CSA demonstrated profoundly inhibited shear-induced platelet function, but lacked sensitivity to discriminate between agents. These findings may have implications for the results of trials comparing the efficacy of these agents in patients undergoing PCI.     

Safety of a high bolus dose of tirofiban in patients undergoing coronary stent placement.

To overcome the suboptimal platelet inhibition induced by tirofiban in the first hour after a percutaneous coronary intervention, a new regimen of 25 microg/kg bolus followed by an 18-hr infusion of 0.15 microg/kg/min has been proposed. The aim of this study was to compare the effects of this high bolus dose of tirofiban with those of abciximab on bleeding risk and 30-day clinical outcome in patients undergoing coronary stenting. We compared two cohorts of patients who underwent coronary stent placement between January 2000 and December 2002. In the first cohort, the only available IIb/IIIa receptor inhibitor was abciximab, which was given to 280 (34.9%) out of 802 stented patients; in the second cohort, tirofiban was administered to 274 (38.3%) out of 716 treated patients. The primary endpoints were the proportion of patients with major bleeding and the rate of site access complications; the 30-day incidence of major adverse cardiac events (MACE) was also assessed. After the procedure, the patients were given ticlopidine for 4 weeks and aspirin indefinitely. Major bleeding episodes were observed in four patients receiving abciximab and in none receiving tirofiban (1.4% vs. 0%; P = 0.12); the rates of site access complications were similar (3.6% vs. 3.3%; P = 0.96). The 30-day incidence of MACE was 7.1% in the abciximab group and 5.8% in the tirofiban group (P = 0.65). In patients undergoing coronary stenting, the high bolus dose of tirofiban is safe and not associated with an increased risk of major bleeding or site access complications in comparison with abciximab.     

Platelet function after a high dose bolus of tirofiban immediately after coronary angioplasty

In the TARGET trial, the lower incidence of cardiac events at one month with abciximab compared with tirofiban was attributed to a lack of efficacy in the first hour because of suboptimal dosage. The object of this study was to confirm that high dose tirofibal is associated with over 90% platelet inhibition during the first hour and to analyse the effect of this new dosage on platelet activation. Thirty-three patients treated with clopidogrel and aspirin for an acute coronary syndrome without ST elevation were given before angioplasty a bolus of 25 microg/Kg of tirofiban injected in 3 minutes, followed by an infusion of 0.15 microg/kg/min. Blood samples were taken before the treatment (TO) and at the 45th minute (T1) to measure platelet aggregation induced by ADP, the expression of P-selection, the quantification of circulating monocyte-platelet aggregates and the phospholyration of VASP protein. The results showed that all patients had over 90% (100%) inhibition of platelet aggregation at T1. The expression of P-selection was significantly reduced (T0: 0.195 +/- 0.057 MFI; T1: 0.186 +/- 0.055 MFI, p = 0.03). There was no significant difference in the number of monocyte-platelet aggregates or in the phosphorylation of VASP. In conclusion, a bolus of 25 microg/Kg/3 min of tirofiban provides over 90% inhibition of platelet aggregation in the first hour. The initial platelet proactivator effect at this dosage was shown to have disappeared with an inhibition of platelet activation.     

Administration of abciximab to patients receiving tirofiban or eptifibatide: effect on platelet function.

OBJECTIVES: The goal of this study was to evaluate platelet function and to preliminarily assess the clinical safety of sequential treatment with tirofiban or eptifibatide followed by abciximab in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: An increasing number of acute coronary syndrome (ACS) patients are treated early with tirofiban or eptifibatide. Some later require PCI and may benefit from switching to abciximab, for which long-term benefits have been reported. METHODS: Fifty ACS patients planned for PCI were enrolled. Twenty-five patients received tirofiban followed by abciximab. Ten patients received eptifibatide followed by abciximab. Fifteen patients received only abciximab. All patients had blood samples drawn six times during the therapeutic course. Platelet function was evaluated by ADP- and TRAP-induced aggregation, flow cytometry analysis of fibrinogen binding and the cone and plate(let) analyzer, which tests shear rate-dependent platelet activation. RESULTS: Administered after tirofiban, abciximab caused a significant further decline in platelet function, as evidenced by all methods. Administered after eptifibatide, abciximab caused a significant further reduction in platelet function, as assessed by the cone and plate(let) analyzer and fibrinogen binding methods. The platelet inhibition achieved by the combination therapy was always greater than or equal to that achieved by abciximab alone. There were no major bleeding or severe thrombocytopenia episodes. Three of the 35 combination therapy patients and one of the 15 who received abciximab alone had minor bleeding. CONCLUSIONS: This is the first in vivo study of combination intravenous platelet glycoprotein IIb/IIIa inhibitor therapy. Administration of abciximab immediately after tirofiban or eptifibatide therapy effectively inhibits platelet function and appears to be safe.     

Pharmacodynamics of two different dosing regimens of tirofiban in citrate or PPACK anticoagulated blood

The primary objective of this study was to compare the inhibitory activity of tirofiban measured with the rapid platelet function assay (RPFA) and with light transmission aggregometry using two different anticoagulants (citrate versus PPACK). Twenty patients treated with tirofiban for percutaneous coronary intervention were studied at six time points during tirofiban treatment. Tirofiban was given with a bolus dose of 10 microg/kg and an infusion of 0.10 microg/kg per min (10 patients) or with a bolus dose of 15 microg/kg and an infusion of 0.15 microg/kg per min (10 patients). Inhibition of platelet function appeared highest using citrated blood and the RPFA-device and lowest when assessed by aggregometry in PPACK-anticoagulated blood. Only the higher dose of tirofiban achieved an inhibition of platelet aggregation of at least 80% in all test systems.     

Abciximab Pharmacodynamics Are Unaffected by Antecedent Therapy with Other GPIIb/IIIa Antagonists in Non-Human Primates

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

Single high-dose bolus tirofiban with high-loading-dose clopidogrel in primary coronary angioplasty

Glycoprotein IIb/IIIa inhibitor therapy during primary percutaneous coronary intervention (PCI) decreases the incidence of major adverse cardiac events. These effects directly result from the level of platelet inhibition. It was shown that standard dosing of tirofiban is insufficient for optimal platelet inhibition. We sought to determine the efficacy and safety of single high-dose bolus (HDB) tirofiban with high-dose clopidogrel loading in primary PCI in acute ST elevation myocardial infarction. A total of 100 patients (mean age 55.2 ± 9.9 years, male/female = 86/14) undergoing primary PCI, pretreated with clopidogrel (450 mg) and aspirin (325 mg), were consecutively randomized into two groups. Group I (n = 50) received a standard dose bolus of tirofiban (10 μg/kg/3 min) with 24-h infusion at a rate of 0.15 μg/kg/min. Group II received single HDB tirofiban (25 μg/kg/3 min). The assessed angiographic, clinical, and echocardiographic endpoints were: initial and final Thrombolysis in Myocardial Infarction (TIMI) grade flow (TGF), corrected TIMI frame count (CTFC), ST-segment resolution (STR) at 90 min, in-hospital bleeding complications, echocardiographic left ventricular ejection fraction (LVEF), death, reinfarction, and repeat target vessel revascularization at 1 month. Platelet function inhibition was measured using PFA-100 (Behring-Dade, Liederbach, Germany) with a test cartridge unit containing a membrane coated with 2 μg of equine Type I collagen and 50 μg adenosine diphosphate before, and 10 min, 2, 4, 6, 12, and 24 h after the bolus of the tirofiban in the first 10 cases of each group. There were no significant differences in baseline characteristics between groups. Initial TGF III was more frequent (24% vs 8%, P = 0.029) and the value of CTFC was lower (75 ± 34 vs 89 ± 25, P = 0.03) in group II. Postprocedural TGF, CTFC, STR, bleeding complications, and LVEF at 1 month were not different between the two groups. There was a higher rate of reinfarction in group II (8%) compared with group I (2%), but this difference was not statistically significant (P > 0.05). The results of platelet function analyses showed that group II patients had significantly prolonged platelet function assay closure times (299 ± 6 s) compared with group patients (236 ± 97 s) at 10 min after the bolus dose (P = 0.04). However, after the first dose between 2 and 24 h, PFA closure times were significantly prolonged in patients with tirofiban infusion. High-dose bolus of tirofiban seems to be safe and more effective than conventional dose at the periprocedural time, whereas continuous infusion of tirofiban may be necessary in the first 24 h before stable and safe antiplatelet status is reached with clopidogrel. However, safety and efficacy of HDB tirofiban and high-loading-dose clopidogrel together with tirofiban infusion requires further studies with a larger population.     

Platelet inhibition with tirofiban early during percutaneous coronary intervention: dosing revisited.

Platelet inhibition is central to the efficacy of the intravenous glycoprotein IIb/IIIa receptor inhibitors. Differences in the degree of platelet inhibition achieved with these agents may account for the disparity in clinical efficacy noted in recently completed clinical trials. The purpose of this study was to evaluate ex vivo platelet inhibition with tirofiban in patients admitted with acute coronary syndrome and who were referred for percutaneous coronary interventions. Twenty-five patients were studied. Ten patients received tirofiban 10 microg/kg bolus and 0.15 microg/kg infusion for 16 hr. Platelet inhibition was determined at 5, 15, 30, 45, 60, and 120 min after tirofiban, by light transmission aggregometry (LTA), rapid platelet function assay (RPFA), and platelet works (PW). The average platelet inhibition using RPFA with PPACK, was 87% at 5 min, then decreased to a nadir of 72% at 30 min and recovered back to > 80% at 60 min and onward. Similar trends were noted with RPFA-citrate, PW, and LTA. Ca-chelating anticoagulants (EDTA and citrate) overestimated platelet inhibition at all time points. Dose adjustment was done by increasing the bolus (15 microg/kg) in five patients, increasing the maintenance dose (0.2 microg/kg/min) in five patients, and increasing both the bolus and the maintenance dose in another five patients. Platelet inhibition tested by all the above methods was consistently over 90% when both the bolus and maintenance doses were increased. No increased incidence of major bleeding was noted at this adjusted dose. The current dosing of tirofiban may be inadequate to achieve appropriate platelet inhibition during PCI in patients admitted with acute coronary syndrome and receiving tirofiban immediately before the procedure in the cardiac catheterization laboratory. Dose adjustment may be needed to maximize platelet inhibition early during PCI.     

Downstream administration of a high-dose tirofiban bolus in high-risk patients with unstable angina undergoing early percutaneous coronary intervention

BACKGROUND: The best treatment option for high-risk patients with unstable coronary syndrome is an early invasive strategy accompanied by intensive anti-platelet therapy. We tested the effect on clinical outcome of early coronary angioplasty using a high-dose bolus of tirofiban in patients with non-ST segment elevation acute coronary syndrome. METHODS: One hundred and forty consecutive patients with unstable coronary syndrome who underwent an immediate percutaneous coronary intervention with the administration of a high (25 microg/kg) dose bolus of tirofiban followed by an 18-h infusion of 0.15 microg kg(-1) min(-1) were compared with a matched control group of 162 patients treated with abciximab. The primary endpoint of the study was the 30-day incidence of major adverse cardiac events; the secondary endpoints were the incidence of major and minor bleeding. RESULTS: The time from admission to PCI was slightly shorter in the tirofiban group (3.9+/-4.8 vs. 4.5+/-4.4 h; P=0.26). The 30-day rate of major adverse cardiac events was similar in the two groups (6% with tirofiban and 8.6% with abciximab: OR=1.37, 95% CI=0.58-3.29, P=0.52). No major bleeding episodes were observed; the incidence of minor bleeding was 3.6% in the tirofiban group and 2.5% in the abciximab group (OR=0.68, 95% CI=0.18-2.59, P=0.74). CONCLUSIONS: In this preliminary study, the beneficial effect of the administration of a high-dose tirofiban bolus on 30-day clinical outcomes was similar to that of abciximab in high-risk patients with unstable angina undergoing immediate percutaneous coronary intervention. The results of this therapeutic strategy should be tested in a larger randomised study.     

The Effect of Glycoprotein IIb/IIIa Receptor Inhibitor on the Microcirculation in Patients Undergoing High-Risk Coronary Stenting; A Prospective, Randomized Study

OBJECTIVES: We evaluated the effect of the glycoprotein IIb/IIIa inhibitor, tirofiban, on the microcirculation measured by Doppler coronary flow reserve (CFR) in patients undergoing high-risk coronary stenting. BACKGROUND: The mechanisms by which glycoprotein IIb/IIIa inhibitors benefit patients undergoing high-risk angioplasty are not fully understood. This may be due to prevention of distal embolization of the coronary clot at the site of angioplasty. METHODS: Thirty two consecutive patients with acute coronary syndrome within 72 hours or with high-risk angiographic features were randomized into 2 groups. Group A (n = 17) received tirofiban (10 microg/kg bolus followed 0.15 microg/kg/min). Group B (n = 15) received placebo bolus and infusion. Coronary flow reserve was measured by Doppler wire technique at baseline, post balloon angioplasty and post-stenting. Platelet aggregation was measured at baseline, 10 minutes, 6 hours and 12 hours post bolus. RESULTS: There was no significant difference in CFR between the groups at baseline and after balloon angioplasty. Post-stenting CFR, however, was significantly higher in the group pretreated with tirofiban (2.94 vs. 2.25, p = 0.014). The inhibition of platelet aggregation was 94% at 10 minutes, 97% at 6 hours and 94% at 12 hours in the tirofiban group. CONCLUSION: In patients undergoing high-risk coronary stenting, tirofiban protects and improves the microcirculation measured by Doppler wire technique. This may be due to prevention of distal embolization of clot by tirofiban and explain the clinical benefit.     

Comparison of abciximab with "high-dose" tirofiban in patients undergoing percutaneous coronary intervention

BACKGROUND: The TARGET study has been criticised for sub-optimal platelet inhibition with tirofiban. We aimed to compare a high-dose bolus regimen of tirofiban (hd-tirofiban) to standard dose of abciximab for patients undergoing percutaneous coronary intervention (PCI). METHODS: We assessed consecutive patients who received either hd-tirofiban (25 mcg/kg bolus followed by 0.15 mcg/kg/min infusion for 18 h) or standard dose abciximab. In-hospital and 6-month outcomes were obtained in all cases. RESULTS: Over an 18-month period, 109 patients who received hd-tirofiban were compared with 110 patients who received abciximab. Both hd-tirofiban and abciximab groups had acute coronary syndromes in 86% and 80% and diabetes in 10% and 13% respectively. Most patients had coronary stent implantation (96% vs. 98%). Thrombocytopenia (platelet count< 100,000) developed in 0.9% of patients receiving hd-tirofiban and 2% of patients receiving abciximab (p = 0.566). Bleeding requiring transfusion occurred in 7.3% and 3% of patients respectively (p = 0.118). Peri-procedural troponin rise was 0.9% in patients receiving hd-tirofiban and 5.5% in patients receiving abciximab (p = 0.07). MACE (Myocardial infarction, Stroke, Revascularisation and Death) at 6 months was 23% in the hd-tirofiban group and 20% in the abciximab group (p = 0.711). The pharmaceutical costs were AUD 322 for hd-tirofiban (one ampoule) and AUD 1,350 for abciximab (3 ampoules). CONCLUSION: There was a small increase in bleeding requiring transfusion and a lower rate of peri-procedural troponin rise in the hd-tirofiban group however, the overall 6-month MACE rates were similar in both groups. There was a considerable cost-saving with the use of hd-tirofiban. A prospective randomised trial of hd-tirofiban vs. abciximab is warranted.     

Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention

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

Rapid assessment of glycoprotein IIb/IIIa blockade with the platelet function analyzer (PFA-100) during percutaneous coronary intervention

BACKGROUND: The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole blood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time (CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-microg/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established. METHODS AND RESULTS: We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin; patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery from platelet inhibition and in 72% of patients CT returned to normal (< or =130 seconds). CONCLUSIONS: Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.     

Determination of platelet aggregation inhibition during percutaneous coronary intervention with the platelet function analyzer PFA-100

Background A simple device to rapidly evaluate platelet function may aid in optimizing glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention (PCI). We prospectively studied platelet function in 250 patients receiving abciximab or eptifibatide during PCI. Methods and Results The platelet function analyzer PFA-100 (Dade-Behring, Deerfield, Ill) measures platelet function by determining the time to occlusion of an aperture in a biochemically active membrane as whole blood flows under high shear conditions. Platelet aggregation causes aperture occlusion, and results are reported as a closure time (CT). All patients received either abciximab or eptifibatide, along with aspirin and heparin; patients undergoing stent implantation received aspirin and a thienopyridine postprocedure. The CT was measured at baseline and 10 minutes, 4 hours, 12 hours (abciximab-only), and 24 hours after the bolus. Profound inhibition was exhibited in most patients shortly after the platelet inhibitor bolus and during the course of therapy. We observed recovery of platelet function 12 hours after discontinuation of abciximab, with a high degree of interpatient variability, and ongoing profound platelet inhibition 4 to 6 hours after the discontinuation of eptifibatide. Among patients treated with abciximab, patients who were obese recovered from platelet inhibition sooner than patients who were not obese, whereas patients who were elderly had delayed recovery compared with patients who were not elderly. Failure to achieve maximal platelet inhibition (nonclosure) at 10 minutes indicated a possible association with adverse clinical events at the 6-month follow-up examination (60% vs 20%). Conclusions PFA-100 is a rapid simple assay used as a means of assessing inhibition of platelet aggregation during PCI performed with glycoprotein IIb/IIIa inhibition. Failure to achieve nonclosure early after the initiation of abciximab therapy warrants further investigation because there may be an association with adverse cardiac events at 6-month follow-up. (Am Heart J 2002;144:151-8.)     

Platelet inhibition by increased tirofiban dosing during primary coronary angioplasty for ST elevation myocardial infarction

BACKGROUND: Platelet receptor IIb/IIIa inhibition during percutaneous coronary interventions (PCI) decreases incidence of major adverse cardiac events (MACE). These effects directly result from the level of platelet inhibition. Due to existing data indicating that standard dosing of tirofiban is insufficient for optimal platelet inhibition, we proposed a novel, experimental dosing. AIM: In this study we assessed, with the use of Ultegra Rapid Platelet Function Assay (RFPA), the level of platelet inhibition with increased tirofiban dosing during primary PCI for ST elevation myocardial infarction (STEMI). METHODS: Twenty eight patients (22 males, 6 females, mean age 63 years, range 32-78 years) with STEMI were included into the study. All patients received 300 mg of aspirin, iv. heparin in a dose of 10 000 IU, which was followed by platelet receptor GP IIb/IIIa inhibitor tirofiban - 10 micro g/kg iv bolus, 0.4 micro g/kg/min for 30 min and infusion 0.1 micro g/kg/min continued for 12-24 h. Platelet function was assessed with RFPA before tirofiban administration and after 10, 30, 90 minutes as well as 8 hours from the initial dose of tirofiban. Baseline fibrinogen binding to platelet receptor IIb/IIIa was defined as PAU (platelet aggregation unit) and the effects of tirofiban on platelets were expressed as a percentage of platelet inhibition. RESULTS: During in-hospital stay, no deaths, re-infarction nor recurrences of ischaemia requiring intervention were noted. The mean total duration of tirofiban administration was 21 hours. Thrombocytopenia was not observed in any patient. Bleeding complications occurred in 5 (17.9%) patients. Blood transfusion was required in three patients. The percentages of platelet inhibition measured at the pre-specified time-points were 95%, 94%, 91% and 87%, respectively. In 32% of patients an inhibition of platelet exceeding 95%, measured 10 minutes from the onset of tirofiban infusion, was not achieved. At the same time, platelet inhibition <90% was found in only 3 (11%) patients. Eight hours from the initiation of tirofiban, platelet inhibition <70% was found in 3 (11%) patients; of them, two had platelet inhibition <95% when measured 10 minutes from the onset of therapy with tirofiban. CONCLUSIONS: 1. Increased dosing of tirofiban resulted in an enhanced platelet inhibition. 2. Optimal platelet inhibition, especially during first minutes of drug administration, was not achieved in a substantial number of patients. 3. Increased IIb/IIIa inhibitor dosing resulted in a high partial and normal baseline coronary flow in an infarct-related artery. 4. Increased tirofiban dosing resulted in a relatively high bleeding complications rate.