Aprotinin for reduction of bleeding and transfusions in patients on clopidogrel undergoing urgent coronary surgery

Abstract: Background: An increased proportion of patients with acute coronary syndrome undergo coronary surgery while treated with clopidogrel, an irreversible platelet ADP-receptor inhibitor. Clopidogrel in combination with aspirin is known to augment bleeding, transfusion requirements, and reoperation rates after coronary surgery. Aprotinin, a protease inhibitor, has been approved for use in cardiac surgery to reduce bleeding. Studies on the safety of aprotinin in coronary surgery have given conflicting results. The aim was to investigate whether or not intraoperative use of aprotinin decreases bleeding and number of transfusions after coronary surgery in patients treated with clopidogrel <5 days before surgery. The possible link between perioperative aprotinin treatment and renal dysfunction in patients undergoing first time coronary surgery with a high risk of bleeding was also studied. Finally, we studied the adenosinediphosphate mediated platelet aggregation before and after administration of aprotinin in patients on clopidogrel. Methods: I. We retrospectively reviewed the medical records of all consecutive patients, with preoperative clopidogrel exposure <5 days before surgery, who underwent urgent coronary surgery at our institution during 1 year (n=33). 18 patients received a full-dose aprotinin, 15 patients served as a control group. II. 75 consecutive patients with unstable angina, administered clopidogrel <5 days before coronary surgery, were randomized to full-dose aprotinin (n=37) or saline (n =38). III. In a matched cohort study, 200 patients receiving high-dose aprotinin were compared with 200 patients receiving tranexamic acid during primary isolated coronary surgery. IV. 15 clopidogrel-treated patients with acute coronary syndrome undergoing coronary surgery were studied. ADP-mediated platelet aggregation and platelet count ratio (%) were measured before and after a bolus dose of aprotinin. Results: I. Mean postoperative bleeding was 710 mL (95%CI:560-860) in the aprotinin group vs. 1210 mL (95%CI:860-1550) in the control group (p=0.004). The aprotinin group received fewer transfusions of packed red blood cells (0.9 U, 95%CI:0.1-1.7, vs. 2.7 U, 95% CI:1.4-4.1; p=0.01), platelets (0.1 U, 95%CI:0-0.3, vs. 0.6 U, 0.2- 0.9; p=0.02), and fewer blood product units (1.1 U, 95%CI:0.1-2.0, vs. 3.7 U, 95%CI:2.1-5.4; p=0.002). There were 3 reoperations for bleeding, all in the control group (p = 0.05). II. Postoperative bleeding was 760±350 mL in aprotinin-treated patients versus 1200±570 mL (P<0.001) in control. During the hospital stay, patients in the aprotinin group received 1.2±1.5 and 0.1±0.4 U of erythrocytes and platelets, respectively, versus 2.8±3.2 (P=0.02) and 0.9±1.4 (P=0.002) units in the control. In the aprotinin group, 53% of patients received transfusions, whereas 79% of controls were exposed to blood products (p=0.02). III. No significant differences were found in fractional change in creatinine clearance (-11% vs. -12%, medians, p=0.75) or any other assessments of postoperative renal function between the tranexamic acid and the aprotinin group. Patients in the aprotinin group received fewer transfusions (48% vs. 60.5%, p=0.02), fewer units of packed red blood cells (2.0 U vs. 1.4 U, p=0.02) and plasma (1.3 U vs. 0.5 U, p<0.001), but more platelets (0.1 U vs. 0.2 U, p=0.02). IV. Aprotinin induced an increased aggregation in eleven of fifteen patients (73%), and a decrease was registered in two patients (13%). The median (25th/75th percentile) adenosinediphosphate mediated platelet aggregation before and after aprotinin, was 84% (76/91) and 94% (86/97, p<0.01). Clopidogrel non-responders with >90% aggregation (n=4) had a median aggregation of 94.5% (91.5/97.5) versus 82% (73/87, p<0.01) in the responders (n=11). The median increase in platelet aggregation after aprotinin was 8% (5/20) in the responders versus 0% (-5.25/3, p<0.01) in the non-responders. Conclusions: Full-dose aprotinin reduces bleeding, transfusion requirements of packed red blood cells, platelets, and total number of blood units in patients on clopidogrel undergoing urgent CABG. Perioperative aprotinin treatment during primary coronary surgery in patient on clopidogrel treatment is not associated with impaired renal function postoperatively in comparison with patients receiving tranexamic acid. The use of aprotinin reduces the overall transfusions rate to a greater extent than tranexamic acid. Aprotinin reduces the antiplatelet effect of clopidogrel. This effect is restricted to patients with a platelet inhibition of ≥ 10%.