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Antithrombotic Effects of Abciximab

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Antithrombotic Effects of Abciximab Antithrombotic Effects of Abciximab Richard 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 and administration of heparin, abciximab, or both. The an- thrombosis are ultimately regulated by the glycoprotein tithrombotic effects of the 3 treatments were assessed by (GP) IIb/IIIa receptor complex, triggered the develop- reduction of the thrombus formation on the perfused ment of agents capable of interfering with this platelet specimens. Thrombus formation at baseline was not receptor complex. Several large clinical trials have dem- significantly modified by the administration of heparin onstrated the effectiveness of this class of agents. The (13,897 ؎ 1,316 vs 11,917 ؎ 1,519 ␮m2). Abciximab first of these agents to show beneficial effects after cor- produced a 58% reduction in thrombus formation onary interventions was the mouse/human chimeric Fab (11,631 ؎ 861 vs 4,925 ؎ 585 ␮m2;p<0.001). The fragment antibody c7E3 (abciximab; ReoPro). This study addition of heparin to abciximab did not further reduce analyzes whether the addition of heparin to the GP thrombus area versus abciximab alone (5,651 ؎ 581 vs IIb/IIIa antagonist abciximab would enhance the anti- ␮m2). Thus, our data show that abciximab 585 ؎ 4,925 thrombotic effect. Blood drawn directly from patients on dramatically decreases mural thrombus formation and aspirin who underwent interventional procedures per- that combining heparin with abciximab did not add any fused an ex vivo perfusion chamber containing a se- additional antithrombotic effect to abciximab alone. verely injured arterial wall at local rheologic conditions ᮊ of a mildly stenosed coronary artery. Blood was per- 2000 by Excerpta Medica, Inc. fused directly from patients at baseline and following (Am J Cardiol 2000;85:1167–1172) everal agents capable of interfering with the gly- generation.2,3 Thus, abciximab may have an anticoag- Scoprotein (GP) IIb/IIIa receptor complex have ulant as well as antiplatelet effect. Based on these been developed and clinically tested. The effective- observations, this study was designed to assess ness of the first of these agents, abciximab, in prevent- whether the addition of the anticoagulant heparin ing ischemic complications in unstable angina and would enhance the antithrombotic effect of abciximab after coronary interventions has been demonstrated in in a well-characterized perfusion system. The study several clinical trials.1 The effects of the GP IIb/IIIa was performed using an ex vivo perfusion chamber, antagonists are mediated by interfering with the bind- mimicking the in vivo local rheologic conditions that ing of fibrinogen to the exposed GP IIb/IIIa receptors, develop in a mildly stenosed coronary artery with blocking platelet-platelet interactions and thrombus deep vascular injury. In this perfusion system, throm- formation. In addition, GP IIb/IIIa antagonists may bus formation is triggered by exposing medial com- also interfere with the exposure of procoagulant phos- ponents of the arterial wall to flowing blood.4–6 Blood pholipids by the platelets and thus inhibit thrombin from patients with an acute coronary syndrome who underwent percutaneous coronary interventions was allowed to circulate directly from the patient through From the Zena and Michael A. Wiener Cardiovascular Institute, and the perfusion system.7 Antithrombotic activity was the Departments of Pathology and Medicine, Mount Sinai School of Medicine, New York, New York; and Cardiovascular Research Cen- assessed by morphometric analysis of the thrombus ter, CSIC-Hosp Santa Cruz y San Pablo, Barcelona, Spain. This study formed when using blood from patients before and was partially supported by grants from the National Institutes of Health after receiving abciximab. SCOR on Thrombosis # P50 HL54469, Bethesda, Maryland; Na- tional Heart, Lung, and Blood Institute Grant 19278 (BSC) and Grant METHODS PNS SAF 712/94, Bethesda, Maryland; and Fundacion Cardiovas- Patient population: Twenty-three patients with un- cular-Catalana de Occidente, Barcelona, Spain. Manuscript received stable angina, who were judged eligible for coronary September 28, 1999; revised manuscript received and accepted intervention after diagnostic angiography, were re- December 8, 1999. Address for reprints: Juan Jose Badimon, PhD, Cardiovascular cruited for the study. The Institutional Review Board Biology Research Laboratory, Zena and Michael A. Wiener Cardio- approved the study, and all enrolled patients gave vascular Institute, Mount Sinai School of Medicine, New York, New voluntary written informed consent. All procedures York 10029. E-mail: [email protected]. were performed at the Cardiac Catheterization Labo- ratory, Zena and Michael A. Wiener Cardiovascular Conflict of interest statement: Dr. Barry S. Coller is an inventor of Institute at Mount Sinai Hospital, New York. Inclu- abciximab. In accordance with federal law and the patent policy of sion criteria were the presence of an acute coronary Research Foundation of the State University of New York, Dr. Coller shares in the royalty payments made to the Foundation for the sale of syndrome or an angiographically high-risk lesion (de- abciximab. Dr. Coller contributed to the scientific design and review of fined in the following). Only patients with native the experiments but did not participate in the collection of any of the coronary artery lesions of Ն70% diameter stenosis clinical data or in their statistical analysis. were included. Exclusion criteria included restenotic ©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matter 1167 The American Journal of Cardiology Vol. 85 May 15, 2000 PII S0002-9149(00)00722-0 ratio 1.0 to 1.1), rotational coronary atherectomy, directional coronary atherectomy, transluminal extraction catheterization, or intracoronary stent implantation. All stents were de- ployed with high-pressure balloons (balloon-to-artery ratio 1.0) without intravascular ultrasound guidance. Procedural success was defined as Յ30% residual diameter stenosis and absence of dissection or major com- plications (death, infarction, need for bypass surgery). The preprocedural heparin infusion was discontinued Ն1 hour before coronary intervention. FIGURE 1. Scheme of the study design. All patients enrolled in the study had the Heparin was administered during the first perfusion study (Perfusion-1) under basal conditions. Thereafter, group 1 had procedure as repeated boluses to the second perfusion study (Perfusion-2) performed 10 minutes after receiving abcix- maintain the target activated clotting imab. Group 2 had the perfusion-2 study performed 10 minutes after receiving hep- Ͼ arin. The third perfusion study (Perfusion-3) was performed when both groups of time of 300 seconds. patients received both therapies. Ex vivo perfusion chamber: The perfusion chamber used in this study has been extensively described else- lesions, thrombocytopenia (Ͻ130,000 platelets/␮l), where.11,12 It consists of a cylindrical flow channel (1 bleeding disorder, or a history of stroke. mm diameter and 2.5 cm length) that allows the blood Definitions: The definition of acute coronary syn- to flow over the thrombogenic substrate. All the per- dromes included postinfarction, refractory, new, or fusions were performed for a period of 5 minutes at a increased angina (Braunwald classes II or III, B or C)8 flow rate of 10 ml/min (calculated shear rate of within 2 weeks. Angiographically, high-risk lesions 1,690/s; Reynolds number 60; average blood velocity were defined as complex or types B or C lesions 21.2 cm/s). The selected dynamic conditions modeled according to the American Heart Association/Ameri- the local rheology to develop on mild to moderately can College of Cardiology classification.9 Lesion stenotic coronary arteries. Our previous work demon- complexity was assessed according to the Ambrose strated that these rheologic conditions resulted in con- criteria and characterized by irregular borders, over- sistent levels of platelet deposition.4,7 The experimen- hanging edges, and with or without proximal or distal tal perfusion system was connected to the arterial intracoronary filling defects.10 sheath to allow the patient’s blood to flow directly into Study design (Figure 1): All patients enrolled in the the perfusion chamber. study received 325 mg of aspirin. An 8Fr introducer To mimic the in vivo situation of severe arterial sheath was placed into the femoral artery and a bolus injury associated with coronary interventions, porcine of 1,000 IU of heparin was given to flush the sheath. aortic tunica media was used as the substrate to trigger This dose did not have any effect on the activated thrombus formation. Segments of porcine tunica me- partial thromboplastin time (aPTT). Blood was then dia were cut into segments (2.8 ϫ 0.8 cm) and surgi- obtained for the first perfusion study (PS-1) to assess cally prepared to expose the deeper components of the blood thrombogenicity under baseline conditions in arterial wall as described.7,11,13 the ex vivo perfusion chamber. Thereafter, all patients During each perfusion study, blood was circulated received abciximab (0.25 mg/kg bolus given intrave- directly from the patient arm’s through 3 chambers nously over 5 minutes followed by an intravenous connected in series. The input of the perfusion cham- infusion of 10 ␮g/min for 12 hours) and heparin (70 ber system was connected to the intravenous sheath by IU/kg bolus plus 15 IU/kg/h infusion to maintain polyethylene tubing. The output of the chamber was aPTT of 60 to 80 seconds). Patients were randomized connected to a distal peristaltic pump (Master-Flex into 2 groups (Figure 1): group 1 received abciximab model 7013, Cole-Palmer Inc., Vernon Hills, Illinois) before heparin administration, and group 2 received calibrated to maintain the selected blood flow. All the heparin before abciximab. A second perfusion study perfusions were performed at 37°C by placing the (PS-2) was performed 10 minutes after the initial chambers in a water bath.
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