MANAGEMENT OF CARDIAC SURGICAL PATIENTS RECEIVING PLATELET INHIBITORS Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia

Events Leading to Thrombus Formation Adhesion Activation Aggregation

Platelet-fibrin clot

Gp IIb/IIIa ANTAGONISTS Platelet Gp IIb/IIIa receptors play a pivotal role in platelet-mediated thrombus formation, binding to binds to fibrinogen and vWF IIb/IIIa antagonists differ in receptor affinity, reversibility, and specificity

PLATELET INHIBITORS ASA Clopidogrel (Plavix), Ticlid Aggrastat (tirofiban) ReoPro (abciximab) Integrilin (eptifibatide)

Platelet Activation Pathways Collagen Thrombin Epinephrine ADP Arachidonic acid TxA2 GP IIb/IIIa

Aggregating platelets GP IIb/IIIa antagonist Inhibition of platelet aggregation GP IIb/IIIa receptors occupied by antagonists Agonist ADP, thrombin, collagen Resting platelet GP IIb/IIIa receptors in unreceptive state Fibrinogen Aggregating platelets

Tirofiban (Aggrastat) Nonpeptide KD 15 nmol/L Indication: acute coronary syndrome

Eptifbatide (Integrelin) Cyclic peptide KD 120 nmol/L Acute coronary syndrome

Abciximab (ReoPro) Human/murine chimeric monoclonal antibody Fab KD 5 nmol/L Indication: PCI

PLATELET DYSFUNCTION DURING CPB Hemodilution Contact activation Shear stresses Hypothermia Intrinsic/extrinsic defects Anticoagulation/reversal

PLATELET FUNCTION AGGREGATION IIb/IIIa - fibrinogen interaction Key step for hemostasis, part of final common pathway Therapeutic target of inhibitors

PLATELET FUNCTION EVALUATION Platelet count Bleeding time Aggregation TEG/SonoClot Platelet function assays Accumetrics

Accumetrics’ Ultegra System Step 1 Step 2 Step 3 Insert Cartridge Insert whole blood sample Read result in 60 seconds

Correlation of Platelet Aggregation and Accumetrics RPFA Mean and S.D. of 6 Donors 100 90 80 70 Aggregometry (%) 60 50 40 y = 0.9874x - 0.4028 = 0.988 r2 30 20 10 10 20 30 40 50 60 70 80 90 100 Accumetrics RPFA (%)

Postop drainage (1,300 vs 400 mL) Tx pRBC (6 versus 0 U; p = 0.02), Gammie: Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thor Surg 65:465-9, 1998 11 pts req emerg CABG, operated on <12 hr after abciximab (n = 6), or late >12 hr after abciximab (n = 5) Postop drainage (1,300 vs 400 mL) Tx pRBC (6 versus 0 U; p = 0.02), Platelets transfused (20 versus 0 packs) Max ACT (800 vs 528 sec; p = 0.01)

Methods (EPILOG and EPISTENT Trials) Patients undergoing CABG during index hospitalization Data from both CRF andretrospective data collection at sites Pooling of all abciximab tx groups and of all placebo groups in 39 sites Most patients were unblinded undergoing CABG

Patients requiring CABG following Abciximab EPILOG EPISTENT 1 2 3 4 5 3.8 1.5 1.1 Placebo % Abciximab

Pre-Operative Anticoagulation Placebo Abciximab (n = 37) (n = 41) Total heparin (U) 12,000 6500 (8600 - 12,000) (5900 - 6500) Total heparin (U/kg) 146 77 (100 - 195) (70 - 106)

Anticoagulation and Surgery Placebo Abciximab (n = 34) (n = 40) OR heparin load 26,500 27,000 (18,000 - 30,000) (10,000 - 30,000) OR heparin on pump 10,000 7000 (5000 - 15,000) (5000 - 10,000) OR heparin total 35,000 31,000 (26,000 - 51,000) (13,800 - 40,000)

Operative ACTs and Abciximab Placebo Abciximab (n = 32) (n = 36) Pre-op ACT 207 166 (152 - 266) (154 - 223) First ACT on pump 597 646 (478 - 751) (530 - 864) Highest ACT 600 711 (568 - 786) (580 - 999)

Operative Data and Abciximab Placebo Abciximab (n = 36) (n = 42) Total pump time (hr) 1.3 1.4 (0.8 - 1.7) (0.8 - 1.8) Total OR time (hr) 3.4 4.5 (3.0 - 5.1) (3.5 - 5.3) Off pump to close (hr) 0.9 0.9 (0.5 - 1.1) (0.6 - 1.4)

Hemostatic Agents and Abciximab Placebo Abciximab (n = 37) (n = 43) Cryoprecipitate 22% 12% Autotransfusion 57% 61% Auto-tx volume 1090 ml 1038 ml Aminocaproic acid 32% 44% Aprotinin 8% 2% Desmopressin 3% 5% Re-exploration 1 5 Diffuse oozing 1 2 Other bleeding 0 3

Chest tube drainage and Abciximab ¨ 4000 4000 Drains (ml) 3000 3000 2000 2000 ¨ 1000 1000 Placebo Placebo Abciximab Abciximab

Abciximab and Bleeding Time to Surgery Time £ 12 hr Time > 12 hr Placebo Abciximab Placebo Abciximab RBC Tx 78% 87% 69% 64% Plt Tx 44% 67% 13% 42% Major bleed 89% 96% 63% 75% Drain Blood Loss (ml) 730 870 1057 700 Hgb decrease (mg/dl) 7.8 9.4 7.3 7.1 Death or MI 72% 46% 17% 8%

Additional Medications

Abciximab and CABG Increased bleeding risk with urgent CABG Abciximab therapy associated with minimal increase in blood loss with urgent CABG with conventional heparin dosing and platelet Tx transfusions Patients requiring surgery in first 12 hours are at highest risk

TICLOPIDINE AND CLOPIDOGREL Antiplatelet agents are used to treat, prevent arterial thrombosis. Thienopyridine derivatives,inactive in vitro, requiring metabolism to achieve in vivo activity. Inhibit binding of ADP to platelet receptor, inhibiting fibrinogen binding to the IIb/IIIa complex.

TICOLPIDINE/CLOPIDOGREL In CAD stenting, ticlopidine reduces risk for subacute stent thrombosis Clopidogrel reduces ischemic events with recent MI, stroke, or PVD Clopidogrel + aspirin in stenting, is rapidly growing, given before stenting procedure Bleeding variability for cardiac surgery relates to the duration of therapy

TICOLPIDINE and CABG Anesth Analg 1999;88:SCA 105 96/1166 CABG pts receiving ticlopidine 83% of ticlop pt also on ASA, 28% ticlop pt were urgent vs 9% Blood loss >1500 ml/24 hr more frequent in ticlop (14% vs 5%) 62% ticlop pts received allogneic blood vs 45% pRBC Tx 2 units vs 0 Post op CT drain >30% in ticlop .

HEMOSTATIC GOALS FOR CARDIAC SURGERY Prevent clotting for cannulation and initiation of extracorporeal circulation Reverse anticoagulation in a safe and complete manner. Prevent the inflammatory effects of CPB and contact activation

FACTORS AFFECTING ACT Factor deficiency: fibrinogen, XII, VIII Contact activation inhibitors: aprotinin Warfarin therapy Heparin therapy Hypothermia Thrombocytopenia/cytosis Platelet inhibitors

RECOMMENDATIONS FOR MANAGING PATIENTS RECEIVING ANTIPLATELET AGENTS AND REQUIRING CARDIAC SURGERY:

SAFETY Based on the data in press and published, urgent cardiac surgery can be safely performed on patients who have received abciximab or one of the other GpIIb/IIIa receptor inhibitors.

BLEEDING Although the relative risk of abciximab-related bleeding may be increased within 12 hrs, this should not preclude urgent CABG. Platelets may be needed, and should be available when operating on abciximab-tx pts.

HEPARIN DOSING There are no data to support reductions in heparin dosing during CPB and for cardiac surgery. Therefore, standard-loading doses should be considered and additional heparin doses, based on time and duration of bypass or on actual heparin levels, should be maintained.

PLATELETS Platelets can be transfused to correct the bleeding defects associated with abciximab use. However, patients should not receive routine platelet transfusion prior to surgery and CPB. Rather, platelets should be administered after heparin reversal by protamine and after CPB.

SUMMARY: PLATELET INHIBITORS AND CARDIAC SURGERY Do not transfuse with platelets before CPB Normal heparin doses Platelet transfusions when needed after CPB