Antithrombotic Effects of AbciximabRichard Hayes, MD, James H. Chesebro, MD, Valentin Fuster, MD, George Dangas, MD,

John T. Fallon, MD, Samin K. Sharma, MD, Barry S. Coller, MD, Lina Badimon, PhD,Jonathan D. Marmur, MD, and Juan Jose Badimon, PhD

The observation that platelet-platelet interaction andthrombosis are ultimately regulated by the glycoprotein(GP) IIb/IIIa receptor complex, triggered the develop-ment of agents capable of interfering with this plateletreceptor complex. Several large clinical trials have dem-onstrated the effectiveness of this class of agents. Thefirst of these agents to show beneficial effects after cor-onary interventions was the mouse/human chimeric Fabfragment antibody c7E3 (abciximab; ReoPro). This studyanalyzes whether the addition of heparin to the GPIIb/IIIa antagonist abciximab would enhance the anti-thrombotic effect. Blood drawn directly from patients onaspirin who underwent interventional procedures per-fused an ex vivo perfusion chamber containing a se-verely injured arterial wall at local rheologic conditionsof a mildly stenosed coronary artery. Blood was per-fused directly from patients at baseline and following

administration of heparin, abciximab, or both. The an-tithrombotic effects of the 3 treatments were assessed byreduction of the thrombus formation on the perfusedspecimens. Thrombus formation at baseline was notsignificantly modified by the administration of heparin(13,897 6 1,316 vs 11,917 6 1,519 mm2). Abciximabproduced a 58% reduction in thrombus formation(11,631 6 861 vs 4,925 6 585 mm2; p <0.001). Theaddition of heparin to abciximab did not further reducethrombus area versus abciximab alone (5,651 6 581 vs4,925 6 585 mm2). Thus, our data show that abciximabdramatically decreases mural thrombus formation andthat combining heparin with abciximab did not add anyadditional antithrombotic effect to abciximab alone.Q2000 by Excerpta Medica, Inc.

(Am J Cardiol 2000;85:1167–1172)

Several agents capable of interfering with the gly-coprotein (GP) IIb/IIIa receptor complex have

been developed and clinically tested. The effective-ness of the first of these agents, abciximab, in prevent-ing ischemic complications in unstable angina andafter coronary interventions has been demonstrated inseveral clinical trials.1 The effects of the GP IIb/IIIaantagonists are mediated by interfering with the bind-ing of fibrinogen to the exposed GP IIb/IIIa receptors,blocking platelet-platelet interactions and thrombusformation. In addition, GP IIb/IIIa antagonists mayalso interfere with the exposure of procoagulant phos-pholipids by the platelets and thus inhibit thrombin

generation.2,3 Thus, abciximab may have an anticoag-ulant as well as antiplatelet effect. Based on theseobservations, this study was designed to assesswhether the addition of the anticoagulant heparinwould enhance the antithrombotic effect of abciximabin a well-characterized perfusion system. The studywas performed using an ex vivo perfusion chamber,mimicking the in vivo local rheologic conditions thatdevelop in a mildly stenosed coronary artery withdeep vascular injury. In this perfusion system, throm-bus formation is triggered by exposing medial com-ponents of the arterial wall to flowing blood.4–6 Bloodfrom patients with an acute coronary syndrome whounderwent percutaneous coronary interventions wasallowed to circulate directly from the patient throughthe perfusion system.7 Antithrombotic activity wasassessed by morphometric analysis of the thrombusformed when using blood from patients before andafter receiving abciximab.

METHODSPatient population: Twenty-three patients with un-

stable angina, who were judged eligible for coronaryintervention after diagnostic angiography, were re-cruited for the study. The Institutional Review Boardapproved the study, and all enrolled patients gavevoluntary written informed consent. All procedureswere performed at the Cardiac Catheterization Labo-ratory, Zena and Michael A. Wiener CardiovascularInstitute at Mount Sinai Hospital, New York. Inclu-sion criteria were the presence of an acute coronarysyndrome or an angiographically high-risk lesion (de-fined in the following). Only patients with nativecoronary artery lesions of$70% diameter stenosiswere included. Exclusion criteria included restenotic

From the Zena and Michael A. Wiener Cardiovascular Institute, andthe Departments of Pathology and Medicine, Mount Sinai School ofMedicine, New York, New York; and Cardiovascular Research Cen-ter, CSIC-Hosp Santa Cruz y San Pablo, Barcelona, Spain. This studywas partially supported by grants from the National Institutes of HealthSCOR on Thrombosis # P50 HL54469, Bethesda, Maryland; Na-tional Heart, Lung, and Blood Institute Grant 19278 (BSC) and GrantPNS SAF 712/94, Bethesda, Maryland; and Fundacion Cardiovas-cular-Catalana de Occidente, Barcelona, Spain. Manuscript receivedSeptember 28, 1999; revised manuscript received and acceptedDecember 8, 1999.

Address for reprints: Juan Jose Badimon, PhD, CardiovascularBiology Research Laboratory, Zena and Michael A. Wiener Cardio-vascular Institute, Mount Sinai School of Medicine, New York, NewYork 10029. E-mail: Juanbadimon@mssm.edu.

Conflict of interest statement: Dr. Barry S. Coller is an inventor ofabciximab. In accordance with federal law and the patent policy ofResearch Foundation of the State University of New York, Dr. Collershares in the royalty payments made to the Foundation for the sale ofabciximab. Dr. Coller contributed to the scientific design and review ofthe experiments but did not participate in the collection of any of theclinical data or in their statistical analysis.

1167©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matterThe American Journal of Cardiology Vol. 85 May 15, 2000 PII S0002-9149(00)00722-0

lesions, thrombocytopenia (,130,000 platelets/ml),bleeding disorder, or a history of stroke.

Definitions: The definition of acute coronary syn-dromes included postinfarction, refractory, new, orincreased angina (Braunwald classes II or III, B or C)8

within 2 weeks. Angiographically, high-risk lesionswere defined as complex or types B or C lesionsaccording to the American Heart Association/Ameri-can College of Cardiology classification.9 Lesioncomplexity was assessed according to the Ambrosecriteria and characterized by irregular borders, over-hanging edges, and with or without proximal or distalintracoronary filling defects.10

Study design (Figure 1): All patients enrolled in thestudy received 325 mg of aspirin. An 8Fr introducersheath was placed into the femoral artery and a bolusof 1,000 IU of heparin was given to flush the sheath.This dose did not have any effect on the activatedpartial thromboplastin time (aPTT). Blood was thenobtained for the first perfusion study (PS-1) to assessblood thrombogenicity under baseline conditions inthe ex vivo perfusion chamber. Thereafter, all patientsreceived abciximab (0.25 mg/kg bolus given intrave-nously over 5 minutes followed by an intravenousinfusion of 10mg/min for 12 hours) and heparin (70IU/kg bolus plus 15 IU/kg/h infusion to maintainaPTT of 60 to 80 seconds). Patients were randomizedinto 2 groups (Figure 1): group 1 received abciximabbefore heparin administration, and group 2 receivedheparin before abciximab. A second perfusion study(PS-2) was performed 10 minutes after the initialmedication was given, but before administering thesecond medication. The patients then underwent thescheduled coronary intervention. A third perfusionstudy (PS-3) was performed 6 hours after the coronaryintervention while patients were on abciximab andintravenous heparin infusion.

Revascularization procedures: Percutaneous coro-nary interventions consisted of$1 of the following:transluminal coronary angioplasty (balloon-to-artery

ratio 1.0 to 1.1), rotational coronaryatherectomy, directional coronaryatherectomy, transluminal extractioncatheterization, or intracoronary stentimplantation. All stents were de-ployed with high-pressure balloons(balloon-to-artery ratio 1.0) withoutintravascular ultrasound guidance.Procedural success was defined as#30% residual diameter stenosis andabsence of dissection or major com-plications (death, infarction, need forbypass surgery). The preproceduralheparin infusion was discontinued$1hour before coronary intervention.Heparin was administered during theprocedure as repeated boluses tomaintain the target activated clottingtime of .300 seconds.

Ex vivo perfusion chamber: Theperfusion chamber used in this studyhas been extensively described else-

where.11,12 It consists of a cylindrical flow channel (1mm diameter and 2.5 cm length) that allows the bloodto flow over the thrombogenic substrate. All the per-fusions were performed for a period of 5 minutes at aflow rate of 10 ml/min (calculated shear rate of1,690/s; Reynolds number 60; average blood velocity21.2 cm/s). The selected dynamic conditions modeledthe local rheology to develop on mild to moderatelystenotic coronary arteries. Our previous work demon-strated that these rheologic conditions resulted in con-sistent levels of platelet deposition.4,7 The experimen-tal perfusion system was connected to the arterialsheath to allow the patient’s blood to flow directly intothe perfusion chamber.

To mimic the in vivo situation of severe arterialinjury associated with coronary interventions, porcineaortic tunica media was used as the substrate to triggerthrombus formation. Segments of porcine tunica me-dia were cut into segments (2.83 0.8 cm) and surgi-cally prepared to expose the deeper components of thearterial wall as described.7,11,13

During each perfusion study, blood was circulateddirectly from the patient arm’s through 3 chambersconnected in series. The input of the perfusion cham-ber system was connected to the intravenous sheath bypolyethylene tubing. The output of the chamber wasconnected to a distal peristaltic pump (Master-Flexmodel 7013, Cole-Palmer Inc., Vernon Hills, Illinois)calibrated to maintain the selected blood flow. All theperfusions were performed at 37°C by placing thechambers in a water bath. Blood samples were takenbefore each perfusion for hematocrit, platelet count,fibrinogen levels, and clotting parameters.

The thrombi that formed on the exposed substrateswere morphologically similar to those that formed onhuman arterial segments that contained lipid-richplaques.2,11,13Previous studies have indicated that mu-rine antibody 7E3 does not react with porcine endo-thelial cell or porcine platelets (BS Coller and LBadimon, unpublished results).

FIGURE 1. Scheme of the study design. All patients enrolled in the study had thefirst perfusion study (Perfusion-1) under basal conditions. Thereafter, group 1 hadthe second perfusion study (Perfusion-2) performed 10 minutes after receiving abcix-imab. Group 2 had the perfusion-2 study performed 10 minutes after receiving hep-arin. The third perfusion study (Perfusion-3) was performed when both groups ofpatients received both therapies.

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Evaluation of platelet-thrombus formation: Afterperfusion, specimens were removed from the chamberand immediately fixed in 4% phosphate buffered para-formaldehyde. Specimens were transversely cut into2- to 4-mm thick pieces and paraffin embedded. His-tologic sections (5mm) from each specimen wereprepared and stained with Combined Mason-Elastin,which stains thrombus red.

Morphometric analysis of thrombus was conductedat 400-fold magnification by 2 independent observersblinded to the treatment assignments. Images weredigitized with a Sony DKC-5000 camera using AdobePhotoshop 4.0 software on a PowerMacIntosh 8500computer. Thrombus area on each section was mea-sured by computerized planimetry using Image 1.6software. The results of$3 sections were averaged todetermine the thrombus area for each chamber, andthen the results of the 3 chambers were averaged tomeasure the overall thrombus formation for each per-fusion study.

Platelet aggregation and receptor occupancy studies:In vitro platelet aggregation in citrated platelet-richplasma was measured as previously described12 usingadenosine diphosphate (ADP) (20mM) as an agonistto initiate aggregation. Platelet aggregation, measuredas the maximal aggregation response, was expressedas a percentage of the baseline.

Platelet membrane GP IIb/IIIa receptor complexoccupancy was evaluated as described.14 In brief, ci-trated platelet-rich plasma prepared from blood ob-tained at the designated time-points was incubatedwith a known amount of iodine-125 abciximab. Un-occupied GP IIb/IIIa receptors can bind radioactiveabciximab, whereas receptors blocked by unlabeledabciximab cannot bind the labeled antibody. The ef-fect of the treatment on receptor occupancy is ex-pressed as percentage occupancy versus the pretreat-ment value. An occupancy of$80% is the therapeutictarget level.

Statistical analysis: The design of the study allowseach patient’s pretreatment value to serve as his/herown control. Data are presented as mean6 SEMunless stated. Thrombus areas are expressed as squaremicrometers. The statistical significance of differ-ences between the normal and treated groups wasdetermined using analysis of variance for repeatedmeasures. Differences were considered significant ifthe p value was,0.05, using Statview 5121 software(Brain Power, Inc.).

RESULTSStudy population: Four of a total of 23 patients who

underwent coronary interventions during the studyperiod were excluded. Two patients were excludedbecause the aPTT at the time of PS-1 was.60 sec-onds. One patient was excluded because the heparinand abciximab treatments were discontinued immedi-ately after the coronary procedure due to local bleed-ing at the femoral artery puncture site; and the fourthpatient was excluded because the intervention wasconsidered unsuccessful due to inability to cross thelesion with the guidewire.

Three patients underwent balloon angioplastyalone (2 in group 1, 1 in group 2); 2 underwentrotational coronary atherectomy plus stent placement(both in group 2); 6 patients underwent rotationalatherectomy (5 in group 1 and 1 in group 2); 5 under-went stent placement alone (3 in group 1, 2 in group2); 1 underwent directional atherectomy alone (group2); 1 underwent directional atherectomy plus stentplacement (group 2); and 1 underwent transluminalextraction catheterization combined with balloon an-gioplasty (group 2). All patients who underwent stentplacement (5 in group 1 and 3 in group 2) received250 mg of ticlopidine after PS-2 was completed, butbefore coronary interventions.

There were no significant differences between the2 groups of patients with respect to their clinical andangiographic characteristics. Hematocrit, plateletcount, activated clotting time (ACT), and aPTT duringthe baseline studies were also similar in both groups.

Evaluation of thrombus formation: Results of theperfusion studies for groups 1 and 2 are shown inFigure 2. At baseline there was no significant differ-ence in thrombus area between groups 1 and 2(11,6316 861 vs 13,9876 1,316mm2, respectively).

Data obtained from group 1 indicated that thetreatment with abciximab alone reduced thrombus for-mation by 58% (4,9246 585; p,0.01 vs baseline).Furthermore, the addition of heparin to abciximab didnot produce a further reduction in thrombus area ver-sus abciximab alone (5,6516 581 vs 4,9246 585mm2, respectively). The data in group 2 showed thatthrombus formation was not inhibited by the admin-istration of heparin alone (13,8976 1,316 vs11,9176 1,519mm2). The addition of abciximab toheparin significantly reduced thrombus formation(6,0386 1,519 vs 11,9176 1,519mm2; p ,0.001).

Results on platelet aggregation, receptor occupancy,and anticoagulation: The effects of the treatments onplatelet aggregation in response to 20mM ADP arepresented in Figure 3. Heparin did not inhibit plateletaggregation (986 2% of the baseline), whereas ab-ciximab, either alone or in combination with heparin,significantly inhibited platelet aggregation (126 6%and 256 5%, respectively; p,0.001 vs baseline forboth values). Comparison of platelet aggregation withabciximab treatment alone versus combined therapywith heparin and abciximab demonstrated that abcix-imab alone produced a greater reduction of plateletaggregation than the combined therapy (p,0.05).

The results of the GP IIb/IIIa receptor occupancystudies are presented in Figure 4. The average receptoroccupancy in group 1 after abciximab treatment alonewas 84 6 6%. When abciximab and heparin wereadministered, the average receptor occupancy was75 6 4%, which was not significantly less than thatobtained with abciximab alone. Receptor occupancyvalues after abciximab administration, either alone orin combination with heparin, were significantly highercompared with either baseline or heparin treatment (p,0.001). The administration of heparin alone did nothave any effect on receptor occupancy compared withbaseline (46 3% vs 0%, respectively).

CORONARY ARTERY DISEASE/ABCIXIMAB AND HEPARIN 1169

The effects of the different therapies on aPTTvalues are presented in Figure 5. As expected, heparinadministration significantly prolonged the aPTT(1446 22 seconds heparin vs 256 1 second baselinegroup, respectively; p,0.001), but abciximab did not(24 6 1 second vs 256 1 second, respectively).Combining abciximab and heparin did not result in a

greater prolongation of aPTT than that produced byheparin alone (1126 13 vs 1446 22 seconds; p5 NS).

GP IIb/IIIa receptor occupancy correlated in-versely with both the platelet aggregation (r5 0.94; p,0.0001) and thrombus formation (r5 0.57; p,0.0001). No correlation was observed between re-ceptor occupancy and aPTT (r5 0.01; p5 0.5524).

FIGURE 2. Effect of the different treatments on thrombus formation. (A) The composite data of all the patients involved in the study.(B) and (C) The results corresponding to groups 1 and 2, respectively. The results are expressed as square micrometers (X 6 SEM; *p<0.001).

FIGURE 3. Results of in vitro platelet-rich plasma–platelet aggre-gation in response to 20-mM ADP. Results are expressed as per-centage of the baseline values (X 6 SEM; *p <0.001).

FIGURE 4. Effect of the treatments of GP IIb/IIIa receptor occu-pancy. Results are expressed as percentage of the baseline val-ues (X 6 SEM; *p <0.001).

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DISCUSSIONOur study demonstrates that blockade of the plate-

let membrane GP IIb/IIIa receptor complex at the dosecurrently used in clinical practice significantly reducesmural thrombus formation on severely damaged arte-rial walls when exposed to human arterial blood. Theconditions used in our study, severe arterial injury andhigh shear rate, were selected to mimic the clinicalscenario occurring in mildly stenosed coronary arter-ies after plaque disruption. Our data indicate thatabciximab dramatically decreases thrombus formationand that adding heparin, at the doses currently used forcoronary interventions, with the GP IIb/IIIa receptorantagonist did not further reduce mural thrombuscompared with abciximab alone. Moreover, the ad-ministration of heparin alone did not have any effecton mural thrombus formation despite its marked anti-coagulant effect.

This study again shows that drugs that decrease theincidence of total occlusion can differ in their abilityto decrease mural thrombus formation. Heparin, aspi-rin, or both, decrease clinical acute occlusion.15,16

Heparin or aspirin mildly decrease in vivo muralthrombus formation over 2 hours on deeply injuredcarotid arteries, and both prevent short-term in vivoacute occlusion.17 Abciximab is another example ofan antithrombotic therapy that decreases clinical acuteocclusion more than heparin plus aspirin,9,10,12and inthis study it also markedly decreased mural thrombusformation, whereas heparin plus aspirin did not (com-pared with aspirin alone). Thus, prevention of totalocclusion is a less sensitive measure of antithromboticpotency and does not predict the extent of muralthrombus formation. However, superiority of reducingmural thrombus formation appears to predict superiorclinical outcome of reducing clinical acute occlusion.

Our data are of particular interest in view of theresults from the Evaluation of c7E3 Fab in the Pre-vention of Ischemic Complications (EPIC), Evaluationin PTCA to Improve Long-term Outcome with abcix-imab GPIIb/IIIa Blockade (EPILOG), and Evaluationof Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)

studies. In EPIC, abciximab was given in conjunctionwith a 10,000 to 12,000 U recommended bolus dose ofheparin that resulted in prolongation of the ACT to300 to 350 seconds. The clinical benefit of abciximabtreatment in reducing ischemic complications in EPICwas offset by a significant increase in major bleeding.A careful analysis of the results of EPIC indicated anassociation between the risk of bleeding and theweight-adjusted heparin dose. This suggested that areduction of the heparin dose might decrease the hem-orragic risk without decreasing the efficacy of thetherapy. As a result, in EPILOG and EPISTENT, alower bolus of heparin was recommended (70 IU/kg/min) and lower target ACTs were considered accept-able (.200 seconds). The results of these trials sup-ported the hypothesis developed from the analysis ofEPIC because the efficacy of abciximab treatment wasas great or greater than in EPIC, whereas the risk ofmajor hemorrhage was dramatically decreased and, infact, did not differ from the control group.

At present, it is unclear what dose, if any, ofheparin should be combined with abciximab to opti-mize the safety and efficacy of the treatment. Becausethe current heparin dose does not increase majorbleeding, decreasing the dose further is unlikely tosignificantly decrease the risk of major bleeding, butmay decrease the risk of minor bleeding associatedwith percutaneous coronary interventions. It is doubt-ful that reducing the heparin dose to that used in thecoronary care unit (55 to 75 seconds) would eitherdecrease or increase the efficacy of abciximab in pre-venting ischemic complications, because heparincould be beneficial, by virtue of its anticoagulanteffects, or detrimental by virtue of its platelet proag-gregatory effects.

Although our data raise the possibility that it mightbe possible to perform coronary interventions withabciximab and achieve maximal antithrombotic poten-tial without the concomitant use of heparin, we wouldurge caution because of the demonstrated value ofheparin in avoiding clot formation on interventioncatheters and in regions of stasis, and because ofuncertainty in extrapolating the data obtained with ourex vivo model to patients undergoing percutaneousinterventions. However, these observations could havesignificant clinical implication for those patients withheparin-induced thrombocytopenia.

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FIGURE 5. Results of the different treatments on aPTT values. Theresults are expressed in seconds (X 6 SEM; *p <0.001).

CORONARY ARTERY DISEASE/ABCIXIMAB AND HEPARIN 1171

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