Journal of the American College of Cardiology 2004 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 43, No. 6, 2004 ISSN 0735-1097/04/$30.00 doi:10.1016/j.jacc.2003.09.060

Administration of Eptibatide 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, Ana Tobar, MD, Abid Assali, MD,* Judith Lahav, PHD, Alexander Battler, MD,* Juan J. Badimon, PHD, Ran Kornowski, MD* Tel Aviv, Israel; and New York, New York
The goal of this study was to compare the antithrombotic effects of enoxaparin versus unfractionated heparin (UFH) when combined with eptibatide 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 eptibatide 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 eptibatide 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 eptibatide (83% to 89.7% reduction in the enoxaparin-eptibatide group and 77.8% to 85.5% reduction in the UFH-eptibatide group, inter-group differences not signicant). Both groups also demonstrated marked reductions in thrombus formation, but the reductions achieved in the enoxaparin-eptibatide group were signicantly higher than those achieved in the UFH-eptibatide 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 eptibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptibatide and UFH in the doses tested. (J Am Coll Cardiol 2004; 43:966 71) 2004 by the American College of Cardiology Foundation OBJECTIVES

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 heparininduced thrombocytopenia (5). In addition, the LMWH enoxaparin has been shown to have a signicant clinical advantage over UFH in reducing the composite end point of
From the *Cardiology Department, Rabin Medical Center, Israel (afliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel); Department of Medicine H, Rabin Medical Center, Israel (afliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel); Pathology Department, Rabin Medical Center, Israel (afliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel); Coagulation Laboratory, Rabin Medical Center, Israel (afliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel); and the Cardiovascular Biology Research Laboratory, the Cardiovascular Institute, Mount Sinai Medical Center, New York, New York. Supported, in part, by Aventis Pharma Ltd. Israel, and by Schering-Plough Israel. Manuscript received August 19, 2003; accepted September 16, 2003.

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 signicantly 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 eptibatide. Recently, the concept of combining LMWH with GP IIb/IIIa inhibitor therapy has gained support (1217). The safety of this combination therapy has been demonstrated when using abciximab or eptibatide and intravenous enoxaparin during PCI (1214) and the combination of tiroban or eptibatide given with subcutaneous enoxaparin to ACS patients (1517). Recent data also suggest that the combination of a GP IIb/IIIa inhibitor with enoxaparin has better clinical efcacy than the combination with UFH. In the Antithrombotic Combination Using Tiroban and Enox-

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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

aparin (ACUTE) II trial, therapy with tiroban and enoxaparin was associated with a reduction in refractory ischemia requiring urgent revascularization, as compared with UFH and tiroban (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 eptibatide 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 eptibatide in ACS patients intended for coronary angiography.

METHODS
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 dened as unstable angina or nonST-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 decit; concurrent administration of oral anticoagulants unless the prothrombin time was 1.2 times control; thrombocytopenia (100,000 cells/l); hemoglobin level 14 g/dl; severe uncontrolled hypertension (180/110); known hypersensitivity to any component of eptibatide, 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 rst, received the combination of enoxaparin and

eptibatide, and group 2 (n 13) received the combination of UFH and eptibatide. 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, eptibatide was administered as an intravenous bolus of 180 g/kg, followed by 2.0 g/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 patients 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, eptibatide 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 rst 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 eptibatide bolus, just before performing the angiography. In group 2, the rst 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 eptibatide 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 ow channel (1- or 2-mm diameter, 2-cm length) that allows the owing 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 ow 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).

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Thrombogenic substrates and perfusion studies. To trigger thrombus formation, porcine aortic tunica media was used as substrate. The substrates (25 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 ow 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 patients intravenous access and distally to a peristaltic pump (Masterex model 7013, ColePalmer Inc., Vernon Hills, Illinois) calibrated to maintain the selected blood ow. Perfusion time was 5 min in both studies. All the perfusion studies were performed at 37C by placing the chambers in a water bath. Evaluation of thrombus formation. After perfusion, specimens were removed from the chamber and immediately xed in 4% phosphate-buffered para-formaldehyde. Specimens were then transversely cut into 2- to 4-mm thick pieces and parafn embedded. Histologic sections (5 m) from each specimen were prepared and stained with two types of stain: combined Massons trichrome-elastin, which stains total thrombus, and a murine monoclonal anti-human B15 42 antibody, which reacts with brin polymer. Morphometric analyses were conducted at 10-fold magnication. 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 brin 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 prole (aPTT), complete blood count, anti-factor Xa activity, thrombin antithrombin complex (TAT), and prothrombin fragment 1 2 (F1.2). Anti-factor Xa activity was quantied 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 M adenosine 5-diphosphate (ADP), as previously described (24). The extent of aggregation was dened 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 brinogen-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

Group 1 (n 13) Age (yrs) Males, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Hypertension, n (%) Current smoking, n (%) Unstable angina, n (%) NonST-elevation MI, n (%) Previous MI, n (%)
MI myocardial infarction.

Group 2 (n 13) 59.4 13.1 12 (92.3%) 4 (30.8%) 8 (61.5%) 7 (53.8%) 3 (23.1%) 2 (15.4%) 11 (84.6%) 4 (30.8%)

60.2 11.2 11 (84.6%) 5 (38.5%) 9 (69.2%) 9 (69.2%) 4 (30.8%) 4 (30.8%) 9 (69.2%) 3 (23.1%)

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 signicance was considered as p 0.05.

RESULTS
The characteristics of the patient populations are outlined in Table 1. There were no signicant 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 posteptibatide 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 signicantly 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-eptibatide), 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). The results of platelet function tests are outlined in Table 3. In both groups, marked reductions in platelet function were achieved after eptibatide (p 0.0001 for baseline vs. post-eptibatide in all tests). Differences between the groups in the extent of platelet function reduction were not signicant. Total thrombus formation is presented in Figure 1. The administration of eptibatide signicantly 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 reduc-

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Table 2. Results of Complete Blood Count and Coagulation Tests

Group 1 (n 13) Baseline Hg (gm/dl) Plt (1,000/l) Fibr (mg/dl) INR aPTT (s) Anti-Xa (IU/ml) TAT (g/l) F1.2 (nmol/l) 14.5 2.1* 240.1 57.5 499.3 133.3 1.0 0.1 28.2 4.4 0.85 0.2 10.0 10.7 1.4 0.4 Post-Eptibatide 13.9 2.0* 235.9 43.7 510.6 123.9 1.0 0.1 29.8 4.6 0.84 0.2 11.5 11.6 1.6 0.6 Group 2 (n 13) Baseline 13.8 1.5 223.5 43.6 538.9 136.0 1.1 0.1 58.9 20.9 0.57 0.1 9.0 9.6 1.8 1.0 Post-Eptibatide 13.7 1.5 233.2.1 50.6 583.2 183.3 1.0 0.1 52.4 10.4 0.55 0.1 8.2 6.5 1.8 0.8

Data presented as mean SD. *p 0.01, for baseline vs. post-eptibatide in the specic group; p 0.001, for differences between the two groups in both baseline and post-eptibatide values. Anti-Xa anti-factor Xa activity; aPTT activated partial thromboplastin time; Fibr brinogen; F1.2 prothrombin fragment 1 2; Hg hemoglobin; INR international normalized ratio; Plt platelets; TAT thrombin-antithrombin complex.

tions achieved in group 1 were signicantly higher than those achieved in group 2 (HSR: 75.6% reduction from 10,845 1,279 m2 to 2,647 507 m2 in group 1 vs. 63.9% reduction from 12,878 1,258 m2 to 4,648 340 m2 in group 2, p 0.01; LSR: 79.7% reduction from 7,753 542 m2 to 1,576 240 m2 in group 1 vs. 66.1% reduction from 8,098 1,281 m2 to 2,747 273 m2 in group 2, p 0.0001). There were no signicant 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. To investigate the contribution of brin deposition to thrombus formation, we quantied brin area in both groups. Fibrin deposition at HSR in group 1 decreased from 7,276 1,033 m2 at baseline to 3,064 767 m2 post-eptibatide (57.9% decline, p 0.0001). In group 2, brin deposition decreased from 8,081 2,039 m2 at baseline to 4,093 1,009 m2 after the eptibatide bolus (49.4% decline, p 0.0001). Although the reduction in brin deposition achieved in group 1 was higher, the difference between the groups did not reach statistical signicance.

DISCUSSION
The current study compared the antithrombotic efcacy of eptibatide administered to ACS patients receiving either enoxaparin or UFH. Both therapeutic combinations induced marked reductions in platelet aggregation and platelet-thrombus formation. However, eptibatide administered with enoxaparin was associated with a signicantly higher reduction in thrombus formation. This combination therapy, therefore, appears to exert a more potent antithrombotic effect than eptibatide 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 addi-

tion 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 brinogen binding to the integrin and, therefore, enhanced brinogen 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 eptibatide 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 tiroban 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 tiroban or abciximab with UFH attenuated the inhibition of brinogen-GP IIb/IIIa receptor binding achieved without UFH (18). This attenuation was not demonstrated when combining these GP IIb/IIIa inhibitors with LMWH (18).
Table 3. Results of Platelet Function Tests*
Group 1 (n 13) 10 M ADP aggregation 20 M ADP aggregation RPFA 89.7% 83.0% 94.7% Group 2 (n 13) 85.5% 77.9% 92.9%

Differences between the two groups were not signicant. *Expressed as percent inhibition from baseline. ADP adenosine 5-diphosphate; RPFA rapid platelet function analyzer.

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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 eptibatide (post-eptibatide bolus). Staining with combined Massons trichrome-elastin, 10-fold magnication.

Figure 1. (A) Total thrombus area (m2) at high shear rate (HSR) and low shear rate (LSR) in the enoxaparin-eptibatide group, and (B) the UFHeptibatide group. Data presented as mean SEM. In both groups and at both shear rates, highly signicant differences were observed between the baseline value and the post-eptibatide value (p 0.0001). However, the reductions achieved in group 1 were signicantly 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-eptibatide.

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 signicant differences in platelet aggregation between our two treatment groups. Eptibatide at a dose of 180 g/kg bolus, followed by 2.0 g/kg/min infusion, has been consistently shown to induce platelet aggregation inhibition 80% (3133). 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 brin deposition. Treatment with abciximab has been shown to reduce both platelet aggregates and the brin layer of the thrombus when using a perfusion ow chamber model (34). We have also observed, apart from a marked reduction in total thrombus formation, a decline in brin deposition after eptibatide administration in both groups (57.9% reduction when eptibatide 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 efciently (35). The reduction in brin deposition after eptibatide 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 eptibatide on thrombin seems unlikely because, as previously observed (36), no reduction in thrombin formation (F1.2) or TAT occurred after eptibatide administration, and furthermore, eptibatide 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 patients baseline value served as his own control, highly signicant intra-group differences could be obtained. The signicant 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 ndings of clinical trials evaluating combination therapy with small molecule GP IIb/IIIa inhibitors and enoxaparin in ACS patients (16,17). Both tiroban and eptibatide 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 (1217). Given the results of the recent clinical efcacy trials and our ndings regarding antithrombotic activity, the combination of eptibatide with enoxaparin appears to exert a more potent antithrombotic effect than eptibatide and UFH in the doses tested. Further studies are needed in order to determine whether our ndings 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.

JACC Vol. 43, No. 6, 2004 March 17, 2004:966 71 Reprint requests and correspondence: Dr. Ran Kornowski, Cardiology Department, Rabin Medical Center, 39 Jabotinski St. Petah-Tikva, 49100, Israel. E-mail: rkornowski@clalit.org.il.

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19.

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