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J Am Coll Cardiol, 2004; 43:966-971, doi:10.1016/j.jacc.2003.09.060
© 2004 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: ACUTE CORONARY SYNDROMES

Administration of eptifibatide to acute coronary syndrome patients receiving enoxaparin or unfractionated heparin

Effect on platelet function and thrombus formation

Eli I. Lev, MD*, David Hasdai, MD*, Erez Scapa, MD{dagger}, Ana Tobar, MD{ddagger}, Abid Assali, MD*, Judith Lahav, PhD§, Alexander Battler, MD*, Juan J. Badimon, PhD|| and Ran Kornowski, MD*,*

* Cardiology Department, Rabin Medical Center, Israel (affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel)
{dagger} Department of Medicine "H," Rabin Medical Center, Israel (affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel)
{ddagger} Pathology Department, Rabin Medical Center, Israel (affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel)
§ Coagulation Laboratory, Rabin Medical Center, Israel (affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel)
|| Cardiovascular Biology Research Laboratory, the Cardiovascular Institute, Mount Sinai Medical Center, New York, New York, USA

Manuscript received August 19, 2003; accepted September 16, 2003.

* Reprint requests and correspondence: Dr. Ran Kornowski, Cardiology Department, Rabin Medical Center, 39 Jabotinski St. Petah-Tikva, 49100, Israel.
rkornowski{at}clalit.org.il


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The goal of this study was to compare the antithrombotic effects of enoxaparin versus unfractionated heparin (UFH) when combined with eptifibatide in acute coronary syndrome (ACS) patients.

BACKGROUND: An increasing number of high-risk ACS patients are treated with low-molecular-weight heparin and a glycoprotein (GP) IIb/IIIa inhibitor. There is a paucity of data regarding the antithrombotic properties of such a combination as compared with UFH and GP IIb/IIIa inhibitors.

METHODS: Twenty-six ACS patients scheduled to undergo coronary angiography were treated with subcutaneous enoxaparin (n = 13) or intravenous UFH (n = 13). All patients received eptifibatide just before coronary angiography. Antithrombotic effects were assessed as changes in platelet-thrombus formation using the Badimon ex vivo perfusion chamber. Perfusions were carried out at a high shear rate (HSR) and a low shear rate (LSR). Patients underwent two perfusion studies: at baseline (under enoxaparin or UFH) and 10 min after the eptifibatide bolus. Platelet function was evaluated by ADP-induced platelet aggregation and the rapid platelet function analyzer.

RESULTS: Both therapeutic combinations achieved a marked reduction in platelet aggregation after eptifibatide (83% to 89.7% reduction in the enoxaparin-eptifibatide group and 77.8% to 85.5% reduction in the UFH-eptifibatide group, inter-group differences not significant). Both groups also demonstrated marked reductions in thrombus formation, but the reductions achieved in the enoxaparin-eptifibatide group were significantly higher than those achieved in the UFH-eptifibatide group (HSR: 75.6% reduction vs. 63.9%, respectively, p = 0.01; LSR: 79.7% reduction vs. 66.1%, respectively, p = 0.0001).

CONCLUSIONS: The combination of eptifibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptifibatide and UFH in the doses tested.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  ACT = activated clotting time
  aPTT = activated partial thromboplastin time
  GP = glycoprotein
  HSR = high shear rate
  LMWH = low-molecular-weight heparin
  LSR = low shear rate
  MI = myocardial infarction
  PCI = percutaneous coronary intervention
  RPFA = rapid platelet function analyzer
  TAT = thrombin antithrombin complex
  UFH = unfractionated heparin

Antithrombotic treatment with aspirin and heparin—either unfracionated (UFH) or low-molecular-weight heparin (LMWH)—represents the current standard of care for patients hospitalized with an acute coronary syndrome (ACS) without ST-elevation (1,2). Low-molecular-weight heparin has several advantages over UFH: it has a more predictable anticoagulant effect with a higher ratio of anti-factor Xa to anti-factor IIa activity (3), requires no monitoring of anticoagulation, is resistant to inhibition by activated platelets (4), and has a lower incidence of heparin-induced thrombocytopenia (5). In addition, the LMWH enoxaparin has been shown to have a significant clinical advantage over UFH in reducing the composite end point of death, myocardial infarction (MI), or need for urgent revascularization in ACS patients (6,7).

The development of platelet glycoprotein (GP) IIb/IIIa inhibitors has extended the therapeutic options for antithrombotic and anti-platelet treatment in the ACS and percutaneous coronary intervention (PCI) setting. Glycoprotein IIb/IIIa inhibitors given to ACS patients and/or patients undergoing PCI have been shown to significantly reduce the rate of ischemic complications (8–11). Therefore, an increasing number of high-risk ACS patients are treated with enoxaparin and a GP IIb/IIIa inhibitor, such as eptifibatide.

Recently, the concept of combining LMWH with GP IIb/IIIa inhibitor therapy has gained support (12–17). The safety of this combination therapy has been demonstrated when using abciximab or eptifibatide and intravenous enoxaparin during PCI (12–14) and the combination of tirofiban or eptifibatide given with subcutaneous enoxaparin to ACS patients (15–17). Recent data also suggest that the combination of a GP IIb/IIIa inhibitor with enoxaparin has better clinical efficacy than the combination with UFH. In the Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE) II trial, therapy with tirofiban and enoxaparin was associated with a reduction in refractory ischemia requiring urgent revascularization, as compared with UFH and tirofiban (16). Similar results were obtained in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial, in which treatment of ACS patients with eptifibatide and enoxaparin was associated with decreased ischemia as detected by continuous electrocardiographic monitoring (17). Despite the emerging clinical evidence, there is a paucity of data comparing the antithrombotic properties of the two combination treatments, apart from a trend toward reduced inhibition of platelet aggregation when GP IIb/IIIa inhibitors are administered with UFH (15,18,19). The aim of the current study, therefore, was to compare the antithrombotic effects of enoxaparin versus UFH when combined with eptifibatide in ACS patients intended for coronary angiography.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   Twenty-six ACS patients scheduled to undergo coronary angiography within 24 to 48 h of enrollment were included in the study. Acute coronary syndrome was defined as unstable angina or non–ST-segment elevation MI, with symptoms presenting in the 24 h before admission. Exclusion criteria were ST-segment elevation acute MI; history of hemorrhagic diathesis; any major surgery; gastrointestinal or genitourinary bleeding within six weeks; history of stroke within two years or a residual neurological deficit; concurrent administration of oral anticoagulants unless the prothrombin time was ≤1.2 times control; thrombocytopenia (<100,000 cells/µl); hemoglobin level <14 g/dl; severe uncontrolled hypertension (≥180/110); known hypersensitivity to any component of eptifibatide, enoxaparin, or UFH; renal failure (creatinine level ≥2.5 mg/dl); or prior use of a GP IIb/IIIa inhibitor within the previous month. The study was approved by the Institutional Review Board of the Rabin Medical Center, and informed consent was obtained from each patient.

Study medications.   The study was comprised of two groups of consecutively enrolled patients. Group 1 (n = 13), which was enrolled first, received the combination of enoxaparin and eptifibatide, and group 2 (n = 13) received the combination of UFH and eptifibatide. In group 1, the patients received enoxaparin at a 1 mg/kg dose, administered subcutaneously every 12 h. After at least two enoxaparin injections, and 3 to 5 h after the last injection, the patients were taken to the catheterization laboratory. Just before the angiography, after obtaining arterial access, eptifibatide was administered as an intravenous bolus of 180 µg/kg, followed by 2.0 µg/kg/min infusion over 18 to 24 h. In group 2, the patients received UFH as a bolus of 70 U/kg intravenously and an infusion of 15 U/kg, adjusted every 8 h to achieve 1.5 to 2.5 times the control activated partial thromboplastin time (aPTT) value (1), which is 30 s at the Rabin Medical Center laboratory. Unfractionated heparin was continued during the patient's arrival at the catheterization laboratory, arterial access gain, and performance of the second perfusion chamber, as detailed below. It was discontinued after the perfusion chamber. Before the angiography, after obtaining the arterial access, eptifibatide was administered in an identical manner to group 1. In the patients who underwent PCI in group 2, additional UFH boluses were given as necessary during PCI (after the perfusion chamber) to maintain an activated clotting time (ACT) of 225 to 275 s.

Concomitant medical therapy included oral aspirin 200 mg daily from admission time, given to all patients. In addition, patients who underwent intracoronary stent deployment received clopidogrel at a dose of 75 mg daily for four weeks after PCI.

Ex vivo perfusion chamber.   All patients underwent two perfusion chamber studies. This design allows each patient to serve as his own control. Immediately before each perfusion study, blood was also collected for coagulation and platelet function tests. In group 1, the first perfusion chamber was performed 3 to 5 h after an enoxaparin injection, when maximum anti-Factor Xa and anti-Factor IIa activities occur (4). The second chamber was also performed 3 to 5 h after an enoxaparin injection, and 10 min after the eptifibatide bolus, just before performing the angiography. In group 2, the first perfusion chamber was performed at least 1 h after the UFH bolus and beginning of infusion. The second chamber was performed, similar to group 1, 10 min after the eptifibatide bolus, when the patient was still receiving UFH and just before performing the angiography.

Antithrombotic effects were assessed as changes in the surface of the platelet thrombus formed on the Badimon perfusion chamber. The perfusion chamber used in this study has been extensively described elsewhere (20–22). In brief, it consists of a cylindrical flow channel (1- or 2-mm diameter, 2-cm length) that allows the flowing of blood, pumped directly from the patient, over an exposed thrombogenic surface. Perfusions were performed at rheologic conditions of low (212/s) and high (1,690/s) shear rate. These local flow conditions mimic mild to moderately stenotic coronary arteries, respectively. Our previous work demonstrated that these rheologic conditions resulted in consistent levels of platelet deposition and thrombus formation (22,23).

Thrombogenic substrates and perfusion studies.   To trigger thrombus formation, porcine aortic tunica media was used as substrate. The substrates (25 x 10-mm sections) were surgically prepared to simulate the degree of severe arterial injury induced by PCI, as previously described (20,21). During each perfusion study, venous blood was circulated from the patient directly through three flow chambers connected in series—one at low shear rate (LSR) and two at high shear rate (HSR). The perfusion chamber system was connected with polyethylene tubing to the patient's intravenous access and distally to a peristaltic pump (Masterflex model 7013, Cole-Palmer Inc., Vernon Hills, Illinois) calibrated to maintain the selected blood flow. Perfusion time was 5 min in both studies. All the perfusion studies were performed at 37°C by placing the chambers in a water bath.

Evaluation of thrombus formation.   After perfusion, specimens were removed from the chamber and immediately fixed in 4% phosphate-buffered para-formaldehyde. Specimens were then transversely cut into 2- to 4-mm thick pieces and paraffin embedded. Histologic sections (5 µm) from each specimen were prepared and stained with two types of stain: combined Masson's trichrome-elastin, which stains total thrombus, and a murine monoclonal anti-human Bß15–42 antibody, which reacts with fibrin polymer.

Morphometric analyses were conducted at 10-fold magnification. Thrombus area was measured on each section by computerized planimetry using Image-Pro Plus software (Media Cybernetics, Silver Spring, Maryland). The results of six sections were averaged to determine the total thrombus and fibrin area for each chamber.

Platelet function assessment and coagulation tests.   Before each of the perfusion studies, blood was collected in vacutainers containing D-Phe-Pro-Arg chloromethyl ketone dihydrochloride (PPACK). The samples were evaluated for platelet function, as well as coagulation profile (aPTT), complete blood count, anti-factor Xa activity, thrombin antithrombin complex (TAT), and prothrombin fragment 1 + 2 (F1.2). Anti-factor Xa activity was quantified by the Coamatic Heparin kit (Chromogenix Instrumentation, Milano, Italy). Thrombin antithrombin complex and F1.2 levels were measured by enzyme immunoassay kits (Enzygnost-Dade Behring, Liederbach, Germany). Platelet function was assessed by in vitro platelet aggregation and the rapid platelet function analyzer (RPFA) (Accumetrics Inc., San Diego, California). Platelet aggregation was performed in platelet-rich plasma in response to 10 and 20 µM adenosine 5-diphosphate (ADP), as previously described (24). The extent of aggregation was defined as the maximal amount of light transmission reached within 6 min after the agonist addition. The RPFA is a point-of-care system that quantitatively measures the ability of platelets to agglutinate fibrinogen-coated beads (25). Results were expressed as platelet activation units and percentage of baseline.

Statistical analysis.   Patient demographics, platelet function data, and coagulation tests are described using mean ± SD. Thrombus area is described using mean ± standard error of mean (SEM). Intra-group comparisons were performed using paired two-tailed Student t tests. Inter-group comparisons were performed using unpaired t tests and the Mann-Whitney non-parametric tests. Categorical variables were compared with the chi-square test. Analyses were performed using SPSS version 10 statistical software (SPSS Inc., Chicago, Illinois), and statistical significance was considered as p < 0.05.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The characteristics of the patient populations are outlined in Table 1. There were no significant differences in any of the clinical parameters between the two groups. Table 2 presents the complete blood count parameters and coagulation tests. Intra-group differences between the baseline and post-eptifibatide samples were observed only in the hemoglobin level of group 1 (a decrease from 14.5 ± 2.1 to 13.9 ± 2.0 gm/dl, p < 0.01, both within normal range). Inter-group differences were observed in the aPTT and anti-Xa levels. As expected, group 2 (treated by UFH) had significantly higher aPTT levels (28.2 ± 4.4 s and 29.8 ± 4.6 s in group 1 vs. 58.9 ± 21.5 s and 52.4 ± 10.4 s in group 2, p < 0.001), whereas group 1 (treated by enoxaparin) exhibited higher levels of anti-Xa activity (0.85 ± 0.2 and 0.84 ± 0.2 IU/ml in group 1 vs. 0.57 ± 0.1 and 0.55 ± 0.1 IU/ml in group 2, p < 0.001). In group 2, at the second time point (on arrival at the catheterization laboratory and post-eptifibatide), all patients were within the recommended aPTT range (at least 45 s), except for one patient who had an aPTT level of 42.2 s. Activated clotting time values at the second time point were 128.2 ± 6.2 s in group 1 and 179.7 ± 21.8 s in group 2 (p < 0.001).


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  		Table 1 Clinical Characteristics

 

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  		Table 2 Results of Complete Blood Count and Coagulation Tests

 
The results of platelet function tests are outlined in Table 3. In both groups, marked reductions in platelet function were achieved after eptifibatide (p < 0.0001 for baseline vs. post-eptifibatide in all tests). Differences between the groups in the extent of platelet function reduction were not significant.


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  		Table 3 Results of Platelet Function Tests*

 
Total thrombus formation is presented in Figure 1. The administration of eptifibatide significantly reduced thrombus formation in both groups. The antithrombotic effect was observed at both high and low shear rates (p < 0.0001 for both groups at both shear rates). However, the reductions achieved in group 1 were significantly higher than those achieved in group 2 (HSR: 75.6% reduction from 10,845 ± 1,279 µm2 to 2,647 ± 507 µm2 in group 1 vs. 63.9% reduction from 12,878 ± 1,258 µm2 to 4,648 ± 340 µm2 in group 2, p = 0.01; LSR: 79.7% reduction from 7,753 ± 542 µm2 to 1,576 ± 240 µm2 in group 1 vs. 66.1% reduction from 8,098 ± 1,281 µm2 to 2,747 ± 273 µm2 in group 2, p = 0.0001). There were no significant differences in the absolute baseline values of thrombus area at HSR or LSR between the two groups. Photomicrographs of total thrombus formation in a representative patient from group 1 are shown Figure 2.



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  		Figure 1 (A) Total thrombus area (µm2) at high shear rate (HSR) and low shear rate (LSR) in the enoxaparin-eptifibatide group, and (B) the UFH-eptifibatide group. Data presented as mean ± SEM. In both groups and at both shear rates, highly significant differences were observed between the baseline value and the post-eptifibatide value (p < 0.0001). However, the reductions achieved in group 1 were significantly higher than those achieved in group 2 (p = 0.01 for inter-group differences at HSR, p = 0.0001 for LSR). Solid bars = baseline; open bars = post-eptifibatide.

 


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  		Figure 2 Photomicgrographs of total thrombus formation in a representative patient from group 1. (Upper panel) At baseline under enoxaparin treatment. (Lower panel) Combined treatment by enoxaparin and eptifibatide (post-eptifibatide bolus). Staining with combined Masson's trichrome-elastin, 10-fold magnification.

 
To investigate the contribution of fibrin deposition to thrombus formation, we quantified fibrin area in both groups. Fibrin deposition at HSR in group 1 decreased from 7,276 ± 1,033 µm2 at baseline to 3,064 ± 767 µm2 post-eptifibatide (57.9% decline, p < 0.0001). In group 2, fibrin deposition decreased from 8,081 ± 2,039 µm2 at baseline to 4,093 ± 1,009 µm2 after the eptifibatide bolus (49.4% decline, p < 0.0001). Although the reduction in fibrin deposition achieved in group 1 was higher, the difference between the groups did not reach statistical significance.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The current study compared the antithrombotic efficacy of eptifibatide administered to ACS patients receiving either enoxaparin or UFH. Both therapeutic combinations induced marked reductions in platelet aggregation and platelet-thrombus formation. However, eptifibatide administered with enoxaparin was associated with a significantly higher reduction in thrombus formation. This combination therapy, therefore, appears to exert a more potent antithrombotic effect than eptifibatide administered with UFH in the doses tested.

In vitro and ex vivo effects of UFH and LMWH.   In vitro and ex vivo studies have demonstrated that UFH causes enhanced platelet activation (19,26,27). Unfractionated heparin administrated to coronary patients or ex vivo addition of UFH to blood from normal volunteers resulted in activation of GP IIb/IIIa receptors, increased expression of P-selectin, and enhanced platelet aggregation with low concentrations of agonists (19,26–28). The mechanism responsible for the UFH-induced platelet activation may be its binding to the platelet integrin alphaIIb-beta3 resulting in increased fibrinogen binding to the integrin and, therefore, enhanced fibrinogen binding to the activated platelet (29). In contrast with UFH, LMWH has been shown to have a more predictive anticoagulant effect with only minor effects on platelet activation (26,27). Furthermore, administration of LMWH, but not UFH, prevented repetitive platelet-dependent thrombus formation in a stenosed canine coronary artery model (30).

Platelet effects of other GP IIb/IIIa inhibitors with UFH or LMWH.   The reported increased platelet reactivity associated with UFH could be the responsible mechanism for the relatively reduced antithrombotic activity of eptifibatide administered with UFH when compared with the combination with enoxaparin in the current study. Other groups have reported similar observations on the variability and platelet inhibitory effects of other GP IIb/IIIa inhibitors when combined with UFH or LMWH. Administration of tirofiban or abciximab with LMWH resulted in lesser variability and a trend towards greater inhibition of platelet aggregation, as compared with the combination with UFH (15,18). Furthermore, coadministration of tirofiban or abciximab with UFH attenuated the inhibition of fibrinogen-GP IIb/IIIa receptor binding achieved without UFH (18). This attenuation was not demonstrated when combining these GP IIb/IIIa inhibitors with LMWH (18). Similarly, UFH induced a reduction in the extent of platelet inhibition produced by abciximab (19). However, this reduction was only present at abciximab doses that induced partial platelet inhibition, and not when abciximab induced >80% platelet aggregation inhibition (19). This observation may explain the lack of significant differences in platelet aggregation between our two treatment groups. Eptifibatide at a dose of 180 µg/kg bolus, followed by 2.0 µg/kg/min infusion, has been consistently shown to induce platelet aggregation inhibition >80% (31–33). This marked platelet inhibitory effect may have overshadowed subtle differences in platelet aggregation between the two combination groups in our study. Microscopic evaluation of platelet-thrombus formation under severe arterial injury conditions and at various shear rates may represent a more physiologic and sensitive method for assessment of therapeutic antithrombotic effects.

Effect on fibrin deposition.   Treatment with abciximab has been shown to reduce both platelet aggregates and the fibrin layer of the thrombus when using a perfusion flow chamber model (34). We have also observed, apart from a marked reduction in total thrombus formation, a decline in fibrin deposition after eptifibatide administration in both groups (57.9% reduction when eptifibatide was combined with enoxaparin and 49.4% reduction when combined with UFH). Platelet aggregates facilitate thrombin generation by providing a phospholipid surface on which coagulation reactions occur efficiently (35). The reduction in fibrin deposition after eptifibatide administration is explained by a decrease in the platelet mass available for thrombin formation as a result of inhibition of platelet aggregation. A direct effect of eptifibatide on thrombin seems unlikely because, as previously observed (36), no reduction in thrombin formation (F1.2) or TAT occurred after eptifibatide administration, and furthermore, eptifibatide therapy has been shown not to prolong ACT (37).

Study limitations.   Our study is limited by the small number of patients in each group. However, because each patient's baseline value served as his own control, highly significant intra-group differences could be obtained. The significant differences observed between the two groups in total thrombus formation are further emphasized given the relatively small patient number. The study was not randomized, although we enrolled consecutive patients, and the demographic and clinical characteristics of the two groups were similar.

The results of the current study support the recent findings of clinical trials evaluating combination therapy with small molecule GP IIb/IIIa inhibitors and enoxaparin in ACS patients (16,17). Both tirofiban and eptifibatide in combination with enoxaparin have been shown to reduce parameters of ischemia as compared with their combination with UFH (16,17). The combination of GP IIb/IIIa inhibitors with enoxaparin has also been shown to be safe (12–17). Given the results of the recent clinical efficacy trials and our findings regarding antithrombotic activity, the combination of eptifibatide with enoxaparin appears to exert a more potent antithrombotic effect than eptifibatide and UFH in the doses tested. Further studies are needed in order to determine whether our findings can be extrapolated to other GP IIb/IIIa inhibitors and other LMWHs.


   Acknowledgments
 
The authors gratefully acknowledge the critical comments by Dr. David Varon and Dr. Yochai Birnbaum, which were essential to the design and analysis of the study.


   Footnotes
 
Supported, in part, by Aventis Pharma Ltd. Israel, and by Schering-Plough Israel.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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