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

Arachidonicacid

TxA2

GP IIb/IIIa

Epinephrine

Collagen Thrombin

ADP

Resting platelet

GP IIb/IIIa receptors in unreceptive

state

Inhibition of platelet aggregation

GP IIb/IIIa receptors occupied by antagonists

Agonist

ADP, thrombin, collagen

GP IIb/IIIa antagonist

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

Step 1 Step 2 Step 3

Accumetrics’ Ultegra System

Insert Cartridge Insert whole blood sample Read result in 60 seconds

Correlation of Platelet Aggregation and Accumetrics RPFA

Agg

rego

met

ry (

%)

r2

y = 0.9874x - 0.4028

= 0.988

Mean and S.D. of 6 Donors

0

Accumetrics RPFA (%)

10

20

30

40

50

60

70

80

90

100

10 20 30 40 50 60 70 80 90 100

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

EPILOGEPILOG EPISTENTEPISTENT00

11

22

33

44

55

3.83.8

1.51.5 1.51.51.11.1

Placebo Abciximab%

Pre-Operative Anticoagulation

PlaceboPlacebo AbciximabAbciximab(n = 37)(n = 37) (n = 41)(n = 41)

Total heparin (U)Total heparin (U) 12,00012,000 65006500(8600 - 12,000)(8600 - 12,000) (5900 - 6500)(5900 - 6500)

Total heparin (U/kg)Total heparin (U/kg) 146146 7777(100 - 195)(100 - 195) (70 - (70 - 106))

Anticoagulation and Surgery

PlaceboPlacebo AbciximabAbciximab(n = 34)(n = 34) (n = 40)(n = 40)

OR heparin loadOR heparin load 26,50026,500 27,00027,000(18,000 - 30,000)(18,000 - 30,000) (10,000 - 30,000)(10,000 - 30,000)

OR heparin on pumpOR heparin on pump 10,00010,000 70007000(5000 - 15,000)(5000 - 15,000) (5000 - 10,000)(5000 - 10,000)

OR heparin totalOR heparin total 35,00035,000 31,00031,000(26,000 - 51,000)(26,000 - 51,000) (13,800 - 40,000)(13,800 - 40,000)

Operative ACTs and Abciximab

PlaceboPlacebo AbciximabAbciximab(n = 32)(n = 32) (n = 36)(n = 36)

Pre-op ACTPre-op ACT 207207 166166(152 - 266)(152 - 266) (154 - 223)(154 - 223)

First ACT on pumpFirst ACT on pump 597597 646646(478 - 751)(478 - 751) (530 - 864)(530 - 864)

Highest ACTHighest ACT 600600 711711(568 - 786)(568 - 786) (580 - 999)(580 - 999)

Operative Data and Abciximab

PlaceboPlacebo AbciximabAbciximab(n = 36)(n = 36) (n = 42)(n = 42)

Total pump time (hr)Total pump time (hr) 1.31.3 1.41.4(0.8 - 1.7)(0.8 - 1.7) (0.8 - 1.8)(0.8 - 1.8)

Total OR time (hr)Total OR time (hr) 3.43.4 4.54.5(3.0 - 5.1)(3.0 - 5.1) (3.5 - 5.3)(3.5 - 5.3)

Off pump to close (hr)Off pump to close (hr) 0.90.9 0.90.9(0.5 - 1.1)(0.5 - 1.1) (0.6 - 1.4)(0.6 - 1.4)

Hemostatic Agents and Abciximab

PlaceboPlacebo AbciximabAbciximab(n = 37)(n = 37) (n = 43)(n = 43)

CryoprecipitateCryoprecipitate 22%22% 12%12%

AutotransfusionAutotransfusion 57%57% 61%61%Auto-tx volumeAuto-tx volume 1090 ml1090 ml 1038 ml1038 ml

Aminocaproic acidAminocaproic acid 32%32% 44%44%

AprotininAprotinin 8%8% 2%2%

DesmopressinDesmopressin 3%3% 5%5%

Re-explorationRe-exploration 11 55Diffuse oozingDiffuse oozing 11 22Other bleedingOther bleeding 00 33

Chest tube drainage and Abciximab

PlaceboPlacebo AbciximabAbciximab00

10001000

20002000

30003000

40004000Drains (ml)

Abciximab and BleedingTime to Surgery

PlaceboPlacebo AbciximabAbciximab PlaceboPlacebo AbciximabAbciximab

RBC TxRBC Tx 78%78% 87%87% 69%69% 64%64%

Plt TxPlt Tx 44%44% 67%67% 13%13% 42%42%

Major bleedMajor bleed 89%89% 96%96% 63%63% 75%75%

Drain Blood Loss (ml)Drain Blood Loss (ml) 730730 870870 10571057 700700

Hgb decrease (mg/dl)Hgb decrease (mg/dl) 7.87.8 9.49.4 7.37.3 7.17.1

Death or MIDeath or MI 72%72% 46%46% 17%17% 8%8%

Time Time 12 hr 12 hr Time > 12 hrTime > 12 hr

Additional MedicationsPlacebo (n=38) Abciximab

(n=44)ASA 97.4% 93.2%

Ticlid 13.2% 22.7%

Warfarin 2.6% 2.3%

Thrombolytics 13.2% 11.4%

Abciximab and CABGIncreased bleeding risk with urgent Increased bleeding risk with urgent CABG CABG

Abciximab therapy associated with Abciximab therapy associated with minimal increase in blood loss with minimal increase in blood loss with urgent CABG with conventional urgent CABG with conventional heparin dosing and platelet Tx heparin dosing and platelet Tx transfusionstransfusions

Patients requiring surgery in first 12 Patients requiring surgery in first 12 hours are at highest riskhours 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:

SAFETYBased 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.

BLEEDINGAlthough 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 DOSINGThere 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