Aprotinin Shows Both Hemostatic and Antithrombotic Effects During Off-Pump Coronary Artery Bypass Grafting Robert S. Poston, MD, Charles White, MD, Junyan.

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Aprotinin Shows Both Hemostatic and Antithrombotic Effects During Off-Pump Coronary Artery Bypass Grafting Robert S. Poston, MD, Charles White, MD, Junyan Gu, MD, PhD, James Brown, MD, James Gammie, MD, Richard N. Pierson, MD, Andrew Lee, Ingrid Connerney, RN, DrPH, Thrity Avari, MS, Robert Christenson, PhD, Udaya Tandry, PhD, Bartley P. Griffith, MD The Annals of Thoracic Surgery Volume 81, Issue 1, Pages 104-111 (January 2006) DOI: 10.1016/j.athoracsur.2005.05.085 Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Intraoperative blood loss. Bleeding was reduced twofold during the course of off-pump coronary artery bypass graft surgery (A) and threefold over the first 24 hours postoperatively (B) by aprotinin versus placebo. The middle line in each box is the median value; the box itself represents the 25th to 75th percentile, and the error bars are the range. (Hct = hematocrit; hr = hours.) The Annals of Thoracic Surgery 2006 81, 104-111DOI: (10.1016/j.athoracsur.2005.05.085) Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 In vivo thrombin generation was determined by measuring the prothrombin fragment (F1.2 [enzyme-linked immunosorbent assay]). At the completion of off-pump coronary artery bypass graft surgery, aprotinin (open bars [n = 29]) therapy was associated with reduced perioperative (preoperative versus postoperative) and transmyocardial (coronary sinus versus a simultaneously drawn sample from the aorta) changes in F1.2 levels. Reduced transmyocardial F1.2 levels suggest aprotinin blocks thrombin formation within the saphenous vein graft. (Solid bars = placebo [n = 31].) The Annals of Thoracic Surgery 2006 81, 104-111DOI: (10.1016/j.athoracsur.2005.05.085) Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Postoperative acetylsalicylic acid (aspirin) resistance (ASA-R). The correlation of the peak platelet response obtained at any of the four time points using thrombelastography (TEG) and whole blood aggregometry (WBA) was strong (R = 0.72, p < 0.001). Therefore, the diagnosis of ASA-R was considered when a response was found to be greater than 50% of control (dashed double-headed arrows) by both assays. Of 20 patients (33%) who met this criteria (upper right quadrant of the graph), 6 (20%) received aprotinin (open squares) intraoperatively and 14 (47%) received placebo (solid squares; p < 0.04). ASA-R was determined using TEG by comparing the response to arachidonic acid versus thrombin released during standard clot formation and using WBA by comparing the response to low- versus high-dose collagen. The Annals of Thoracic Surgery 2006 81, 104-111DOI: (10.1016/j.athoracsur.2005.05.085) Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 The diagnosis of acetylsalicylic acid (aspirin) resistance (ASA-R) made by thrombelastography (TEG) and whole blood aggregometry (WBA) was confirmed by comparing in vivo thromboxane production with serum 11-dehydro-thromboxane B2 (TXB2) levels before and after off-pump coronary artery bypass graft surgery. In addition, a subset of patients were analyzed for a change in mean fluorescence intensity for P-selectin mAb after stimulation with AA. Aprotinin (open bars) suppressed the response across all four assays relative to placebo (solid bars). (FACS = fluorescence-activated cell sorter.) The Annals of Thoracic Surgery 2006 81, 104-111DOI: (10.1016/j.athoracsur.2005.05.085) Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Graft patency, aprotinin (solid line) versus placebo (dashed line). Saphenous vein graft (SVG) patency was determined noninvasively by computed tomography angiography on postoperative day 5 and again at midterm follow-up (10 to 20 months). Patients treated with aprotinin showed no evidence of SVG failure compared with 3 in the placebo group at the initial assessment. A strong trend toward a significant improvement in the freedom from graft thrombosis was seen in the aprotinin group at midterm analysis (p = 0.08, log-rank test). The Annals of Thoracic Surgery 2006 81, 104-111DOI: (10.1016/j.athoracsur.2005.05.085) Copyright © 2006 The Society of Thoracic Surgeons Terms and Conditions