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J Am Coll Cardiol, 2001; 37:1323-1328
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY: INTERVENTIONAL CARDIOLOGY

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

Franz-Josef Neumann, MDa, Willibald Hochholzera, Gisela Pogatsa-Murray, MDa, Albert Schömig, MDa and Meinrad Gawaz, MDa

a Medizinische Klinik and Deutsches Herzzentrum, Technische Universität München, Munich, Germany. This study was supported in part by grants from MSD Sharp & Dohme, Haar, Germany, and from Accumetrics, San Diego, California

Manuscript received June 26, 2000; revised manuscript received December 13, 2000, accepted January 4, 2001.

Reprint requests and correspondence: Dr. Franz-Josef Neumann, Medizinische Klinik der Technischen Universität, Ismaningerstrasse 22, 81674 Munich, Germany
neumann{at}dhm.mhn.de


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
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 µg per min for 12 h), tirofiban (bolus 10 µg/kg, infusion 0.15 µg/kg per min for 72 h) or eptifibatide (bolus 180 µg/kg, infusion 2 µg/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.

Abbreviations and Acronyms
  ADP = adenosine diphosphate
  FITC = fluorescein isothiocyanate
  GP = glycoprotein
  mAB = monoclonal antibody
  PE = phycoerythrin
  RPFA = rapid platelet-function assay
  TRAP = thrombin receptor activating peptide

Glycoprotein (GP) IIb/IIIa blockade reduces the risk of percutaneous coronary interventions substantially (1,2). In many countries, the GP IIb/IIIa antagonists—abciximab, tirofiban and eptifibatide—have been approved for clinical use on the basis of several phase III trials. Among these trials, however, the risk reduction by GP IIb/IIIa blockade varies (1).

Abciximab, tirofiban and eptifibatide differ in chemical structure, binding site and pharmacokinetics (3). Abciximab is the humanized chimeric Fab fragment of a monoclonal mouse antibody (3–5). Abciximab cross reacts with the {alpha}vß3 integrin on endothelial cells and smooth muscle cells and with the {alpha}Mß2 integrin (Mac-1) on myeloid leukocytes (6,7). Platelet-bound abciximab persists for many days (5). Tirofiban is a nonpeptide tyrosine derivative that blocks arginine-glycine-aspartic binding sites of GP IIb/IIIa (8). The cyclic heptapeptide eptifibatide blocks the lysine-glycine-aspartic binding site (9). Tirofiban and eptifibatide are competitive inhibitors with short half-lives. Continuous infusion is needed for sustained platelet inhibition (3,8,9).

The clinical relevance of the pharmacologic differences between abciximab, tirofiban and eptifibatide is currently unclear. Thus far, there are only limited data on the differential efficacy of the three agents in the peri-interventional inhibition of platelet aggregation (10). Moreover, other platelet effects of abciximab, such as inhibition of the platelet-monocyte aggregation (11) or induction of alpha-degranulation, are not very well characterized for tirofiban and eptifibatide (12,13). Therefore, we performed a prospective, randomized study comparing the platelet effects of abciximab, tirofiban and eptifibatide in patients undergoing stent implantation.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patient selection and study protocol.   The study group consisted of patients undergoing intracoronary stent placement for symptomatic coronary artery disease. Exclusion criteria included contraindications for aspirin, ticlopidine or GP IIb/IIIa blockade, absolute indication for anticoagulation, acute myocardial infarction, serum creatinine concentration ≥2.0 mg/dl and >24 h of antecedent treatment with ticlopidine. All patients gave written, informed consent. The study was approved by our institutional Ethics Committee.

Immediately before the balloon angioplasty that preceded stenting, the patients were assigned to one of three open-label treatment regimens by means of a computer-generated randomization scheme: 1) abciximab bolus of 0.25 mg/kg body weight, followed by a continuous infusion at 10 µg/min for 12 h (14); 2) tirofiban bolus of 10 µg/kg, followed by a continuous infusion at 0.15 µg/kg per min for 72 h (15); and 3) eptifibatide bolus of 180 µg/kg, followed by a continuous infusion at 2 µg/kg per min for 72 h (16).

The concomitant preinterventional heparin dosage was 70 U/kg in the abciximab group and 100 U/kg in the other groups. In addition, all patients received ticlopidine and aspirin (100 mg twice daily), starting 1 to 8 h before the intervention. Ticlopidine was administered twice daily at 500 mg for the first three doses, and subsequently at 250 mg for four weeks. We performed stent placement, as described previously (17).

Peripheral venous blood samples were taken before the start of drug administration, as well as 2, 24, 48, 72 and 96 h after the start of infusion. In patients randomized to tirofiban or eptifibatide, we obtained an additional sample at 2 h after discontinuation of the infusion. We collected 2.5 ml of blood in tubes with disodium ethylene diamine tetra-acetic acid for determination of platelet count by use of a Coulter Counter (Beckman Coulter, Krefeld, Germany). For flow cytometry, 1 ml of blood was collected into tubes with a fixative solution (1:3 vol/vol) containing metacroleine (Cyfix II, gift of Dr. Andreas Ruf, Karlsruhe, Germany), as described previously (11,13). For analysis of platelet aggregation, 15 ml of blood was collected in citrate tubes (3.8%) for studies on abciximab or tirofiban, or in hirudin tubes (500 mg/liter) for studies on eptifibatide (18). In preliminary studies, we compared hirudin with citrate as an anticoagulant for platelet function tests. These studies did not show appreciable differences in any of the platelet function tests after administration of abciximab or tirofiban.

Platelet aggregometry.   For analysis of thrombin receptor-induced platelet aggregation in whole blood, we used the rapid platelet-function assay (RPFA, Accumetrics, San Diego, California). The details of this rapid, automated, point-of-care platelet-function test have been described previously (19,20). Briefly, the RPFA, assesses the interaction between platelet GP IIb/IIIa receptors and fibrinogen-coated beads after stimulation with the thrombin receptor-activating peptide (TRAP) ([iso-TRAP]) ([iso-S]FLLRN) at 4 µmol/liter, which corresponds to a 5-µmol/liter dose of TRAP (SFLLRNPNDKYEPF). The rate of aggregation is calculated automatically and expressed as platelet aggregation units. We report RPFA data as percentages of the baseline value before administration of the study drug.

In addition, we analyzed platelet aggregation in platelet-rich plasma by turbidimetric aggregometry by using a two-channel Chronolog aggregometer (Nobis, Germany) (13). Platelet-rich plasma was prepared by centrifugation at 200g for 20 min. After adjustment from baseline, 20 µmol/liter of adenosine diphosphate (ADP; Sigma, Steinheim, Germany) or 50 µmol/liter of TRAP (Sigma) was added, and aggregation was recorded for 5 min. We assessed the maximal initial slope of the increase in photovoltage as a measure of the rate of aggregation. The results are expressed as percentages of the baseline value before administration of the study drug.

Flow cytometry.   Immunostaining and flow cytometry were performed without ex vivo addition of platelet agonists, as described previously (11,13). We stained leukocytes in whole blood by triple-color immunofluorescence with the use of fluorescein isothiocyanate (FITC)-labeled monoclonal antibodies (mAbs) for the {alpha}M chain of Mac-1 (CD11b); phycoerythrin (PE)-labeled mAbs for GP Ib{alpha} of the von Willebrand factor receptor complex (CD42b); and PE-Cy5-labeled mAbs for the monocyte marker CD14 (endotoxin receptor; all mAbs from Immunotech, Hamburg, Germany). As shown earlier, binding of the anti-CD11b mAbs used in our study was not affected by administration of abciximab (11). Platelets were stained with PE-labeled CD42b mAbs and FITC-conjugated mAbs for P-selectin (CD62P, Dianova, Hamburg, Germany). Nonspecific membrane immunofluorescence is determined by use of an irrelevant isotype-matched fluorescein-conjugated immunoglobulin G (Dianova). We used a fluorescence activated cell sorter scan (Becton-Dickinson, Heidelberg, Germany) equipped with a 488-nm argon laser at 500 mW, and we analyzed 5,000 events. We identified monocytes as anti-CD14-positive events on the histogram generated by PE-Cy5 fluorescence, and platelets by size and CD42b immunofluorescence. The mean channel of fluorescence intensity was taken as a measure for antibody binding, and thus antigen surface exposure.

Statistical analysis.   The primary end point was the inhibition of platelet aggregation, as assessed by RPFA after 2 h of infusion. We considered abciximab as the reference drug, because abciximab was the only drug with documented clinical efficacy in the setting of stenting (14). We intended an 80% power to detect a 10% difference in inhibition of platelet aggregation between abciximab and one of the two other agents, with a level of significance (p value) <0.05. On the basis of earlier studies, we assumed a standard deviation of 10% for variables of platelet aggregation (13). Thus, we obtained a sample size of 20 patients in each group.

Discrete variables, expressed as counts, were tested by using the Fisher exact test. The results of continuous variables were reported as the mean value ± SD, and were tested by analysis of variance, followed by the Scheffé test, where appropriate. To account for potential deviations from normal distribution, we corroborated these analyses by nonparametric testing using the Kruskal-Wallis test, followed by the Mann-Whitney U test, where appropriate. Unless stated otherwise, the results of the nonparametric tests confirmed those of the parametric tests. A p value <0.05 (two-tailed test) was regarded as significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Study cohort, platelet counts and clinical events.   The study groups were not significantly different with respect to major demographic, angiographic and procedural variables (Table 1). In all patients, stenting achieved residual stenosis <15%, with Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. Platelet counts at baseline (Table 1) and during follow-up were not significantly different between the three groups, and we did not find a significant decrease in the average platelet count after the intervention in any of the groups. Nevertheless, in one patient assigned to abciximab, the platelet count dropped to 16 103/µl at 24 h after infusion (confirmed with a citrated sample); otherwise, thrombocytopenia ≤50 103/µl was not encountered in any of the patients. Access site complications requiring surgical intervention, or serious bleeding complications, such as hemorrhagic stroke, gastrointestinal or other bleeding necessitating transfusion, did not occur in either group. During 30-day follow-up, none of the patients incurred a serious adverse cardiac event, including death, large myocardial infarction (Q-wave or creatinine kinase >5 times the upper limit) or target vessel repeat intervention.


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  		Table 1 Baseline Demographic, Clinical and Angiographic Characteristics of the Study Group

 
Inhibition of platelet aggregation.   As assessed by RPFA (Fig. 1), all agents achieved a mean inhibition of platelet aggregation >80% during infusion. This mean level of inhibition was maintained during infusion of tirofiban and eptifibatide. After discontinuation of infusion, recovery of platelet aggregation was delayed with abciximab and more rapid with tirofiban and eptifibatide (Fig. 1). With abciximab and tirofiban or eptifibatide, there were no significant differences in either mean platelet inhibition or the percentage of patients achieving >80% inhibition at 2 h (Fig. 2).



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  		Figure 1 Time course of the rate of platelet aggregation after stimulation with 4 µmol/liter of iso-TRAP, as assessed by RPFA during and after infusion of abciximab for 12 h (solid circles), tirofiban for 72 h (solid diamonds) or eptifibatide for 72 h (solid triangles). The plot shows the mean value ± SD. From 24 h onwards, the differences between the three agents were statistically significant (p < 0.001).

 


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  		Figure 2 Scatter plot of the rate of platelet aggregation after a 2-h infusion of abciximab (solid circles), tirofiban (solid diamonds) or eptifibatide (solid triangles), as assessed by rapid platelet-function assay (RPFA) with 4 µmol/liter of iso-thrombin receptor activating peptide or by turbidimetric aggregometry with 20 µmol/liter of adenosine diphosphate. The p values were calculated by one-way analysis of variance.

 
The time courses of the mean rate of ADP-induced platelet aggregation (Fig. 3) , as assessed by turbidimetric aggregometry, were largely similar to those of RPFA. When comparing the effects of abciximab at 2 h with those of tirofiban or eptifibatide (Fig. 2), we did not find significant differences in the mean inhibition or the percentage of patients achieving >80% inhibition of the ADP-induced aggregation rate. With all three agents, inhibition of TRAP-induced platelet aggregation was substantially less than inhibition of ADP-induced platelet aggregation (Fig. 4). At 2 h, the rate of TRAP-induced platelet aggregation was inhibited by only ~50% on average, but there were no significant differences between the three agents (p = 0.37).



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  		Figure 3 Time course of the rate of platelet aggregation after stimulation with 20 µmol/liter of adenosine diphosphate, as assessed by turbidimetric aggregometry during and after infusion of abciximab for 12 h (solid circles), tirofiban for 72 h (solid diamonds) or eptifibatide for 72 h (solid triangles). The plot shows the mean value ± SD. From 24 h onwards, the differences between the three agents were statistically significant (p < 0.034).

 


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  		Figure 4 Time course of the rate of platelet aggregation after stimulation with 50 µmol/liter of thrombin receptor activating peptide, as assessed by turbidimetric aggregometry during and after infusion of abciximab for 12 h (solid circles), tirofiban for 72 h (solid diamonds) or eptifibatide for 72 h (solid triangles). The plot shows the mean value ± SD. At 24, 48 and 72 h, the differences between the three agents were statistically significant (p < 0.002).

 
Inhibition of the platelet-monocyte interaction and P-selectin exposure.   With all three agents, GP Ib{alpha} fluorescence of the monocyte population decreased significantly (p < 0.005) after 2 h and 24 h of infusion (Fig. 5, left panel). This decrease was caused by a reduction in GP Ib{alpha} fluorescence intensity of the GP Ib{alpha}-positive monocytes, whereas the percentage of GP Ib{alpha}-positive monocytes remained essentially constant (data not shown). Among the three agents, there were no significant differences in the reduction of GP Ib{alpha} fluorescence on monocytes (Table 2). The reduction in the platelet-monocyte interaction by GP IIb/IIIa antagonists was associated with a reduction in surface expression of Mac-1 on GP Ib{alpha}-positive monocytes (Fig. 5, right panel). Again, this effect was not significantly different between the three agents (Table 2).



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  		Figure 5 Time course of glycoprotein (GP) Ib{alpha} immunofluorescence of monocytes as a measure of platelet-monocyte binding (left panel), and Mac-1 immunofluorescence of GP Ib{alpha}-positive monocytes as a measure of Mac-1 expression on monocytes with adherent platelets (right panel) before and during infusion of abciximab (solid circles), tirofiban (solid diamonds) or eptifibatide (solid triangles). The plot shows the mean value ± SD.

 

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  		Table 2 Relative Changes in Platelet-Monocyte Interaction, Mac-1 Expression on Monocytes With Adherent Platelets and P-Selectin Surface Expression on Platelets

 
With all three agents, we found a significant (p < 0.041) increase in the percentage of P-selectin-positive platelets, maximal at 2 h. This increase in P-selectin-positive platelets did not show any significant differences between the three agents (Table 2).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our prospective, randomized trial investigated the platelet effects of three approved GP IIb/IIIa antagonists at currently recommended dosages in the setting of coronary stenting. Our major findings are: among abciximab, tirofiban and eptifibatide, there are no significant differences in: 1) the mean inhibition of the rate of platelet aggregation induced by ADP or thrombin-receptor stimulation at 2 h of infusion; 2) the mean inhibition of platelet-monocyte interactions; and 3) mean alpha-degranulation, as a measure of antagonist-induced platelet activation.

Platelet aggregation.   As in previous studies, analysis of whole blood after low dose thrombin receptor stimulation by the automated RPFA yielded results similar to those of analysis of platelet-rich plasma after stimulation with high dose ADP by turbidimetric aggregometry (20,21). Both methods consistently showed a mean inhibition of platelet aggregation >90% at 2 h, with no significant differences between the three agents. With stimulation by high dose TRAP, the mean inhibition of platelet aggregation by the three agents was substantially weaker, albeit not significantly different among them. In an earlier study (22), abciximab inhibited thrombin-induced platelet aggregation only by ~50%, despite ~80% inhibition of ADP-induced platelet aggregation. This discrepancy can be explained by mobilization of nonblocked GP IIb/IIIa receptors by the most potent platelet stimulus thrombin (22,23). Our study demonstrates that this mechanism affects the antiplatelet efficacy of tirofiban and eptifibatide to a similar extent.

Although the optimal level of platelet inhibition at various time points has not been definitely established (24–27), it is commonly accepted that >80% inhibition of ADP-induced platelet aggregation is needed for effective prevention of thrombotic events after coronary interventions. We therefore analyzed those patients achieving this level of inhibition, and again, we found no significant differences between the three agents. It has to be noted, however, that while most patients achieved >80% inhibition, 8.3% did not by RPFA and 10% did not by turbidimetric aggregometry. Hence, there is still room for improved dosing approaches, such as the double bolus regimen recently pursued in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (28).

Platelet-monocyte interaction.   We addressed heterotypic adhesion of platelets to leukocytes, which appears to play a role in the regulation of inflammatory responses in ischemic heart disease (11,29,30). Recently, we showed that abciximab reduced the mass of platelets attached to circulating myeloid leukocytes in patients with acute myocardial infarction (11). The reduction in the platelet-monocyte interaction by abciximab was associated with downregulation of surface expression of Mac-1, one of the major leukocyte adhesion molecules (11). Xiao et al. (31) described a reduction of the platelet-neutrophil interaction by tirofiban, but they did not address the consequential changes in Mac-1 expression. In this study, we show that inhibition of the platelet-monocyte interaction by abciximab, tirofiban and eptifibatide is similar and leads to a comparable downregulation of Mac-1 in circulating platelet-leukocyte aggregates.

Agonist-induced platelet activation.   We found a comparable increase in P-selectin surface expression after abciximab, tirofiban and eptifibatide. Engagement of the GP IIb/IIIa receptor by natural ligands or antagonists induces platelet activation (12,32,33). Recently, we were able to demonstrate antagonist-induced platelet activation in patients treated with abciximab, by showing an abciximab-induced increased P-selectin surface expression (13). By demonstrating a similar increase in P-selectin surface expression with all three agents, our current study does not suggest that there are major differences in antagonist-induced platelet activation in the clinical setting.

Study limitations.   Our study was not powered to specifically address the proportions of patients reaching a certain level of platelet inhibition. Nevertheless, the distribution of data points (Fig. 2) does not suggest major differences.

We intended to analyze the three GP IIb/IIIa inhibitors at currently recommended dosages, as well as concomitant medications. Therefore, heparin dosing differed between the three treatment arms. We cannot fully exclude that this might have had an effect on our platelet function studies. Heparin can directly activate platelets, and yet may limit thrombin-induced platelet activation.

Our study focused on platelet effects. Contrary to tirofiban and eptifibatide, abciximab has nonplatelet effects, such as inhibition of the vitronectin receptor and Mac-1. In this respect, it is noteworthy that with abciximab, but not with the other agents, downregulation of the number of surface-expressed Mac-1 complexes in platelet-leukocytes aggregates is complemented by direct Mac-1 blockade (6). Such nonplatelet effects were not addressed in our study (6,7).

Implications.   By demonstrating comparable platelet effects of various GP IIb/IIIa inhibitors, the data reported here yielded a rationale for trials that directly compare the clinical efficacy of various GP IIb/IIIa inhibitors, such as TARGET (do Tirofiban And ReoPro Give similar Efficacy outcomes Trial) (34). In the meantime, the 30-day primary end point analysis of TARGET was reported. It showed a significantly better outcome with abciximab than with tirofiban. Among potential explanations for the superiority of abciximab in TARGET, our study points toward the Mac-1 and vitronectin receptor-dependent nonplatelet effects, and it refutes failure of platelet inhibition during the steady state of infusion at 2 h and beyond.


   Acknowledgments
 
We thank Dr. Andreas Ruf for the gift of Cyfix II.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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