1. 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

2. Events Leading to Thrombus Formation
Adhesion
Activation
Aggregation

3. Platelet-fibrin clot

4. 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

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

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

7. 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

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

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

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

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

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

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

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

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

16. 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)

17. 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

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

19. Pre-Operative Anticoagulation
Placebo Abciximab
(n = 37) (n = 41)
Total heparin (U) 12,
( ,000) ( )
Total heparin (U/kg)
( ) ( )

20. Anticoagulation and Surgery
Placebo Abciximab
(n = 34) (n = 40)
OR heparin load 26,500 27,000
(18, ,000) (10, ,000)
OR heparin on pump 10,
( ,000) ( ,000)
OR heparin total 35,000 31,000
(26, ,000) (13, ,000)

21. Operative ACTs and Abciximab
Placebo Abciximab
(n = 32) (n = 36)
Pre-op ACT
( ) ( )
First ACT on pump
( ) ( )
Highest ACT
( ) ( )

22. Operative Data and Abciximab
Placebo Abciximab
(n = 36) (n = 42)
Total pump time (hr)
( ) ( )
Total OR time (hr)
( ) ( )
Off pump to close (hr)
( ) ( )

23. 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

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

25. 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)
Hgb decrease (mg/dl)
Death or MI 72% 46% 17% 8%

26. Additional Medications

27. 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

28. 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.

29. 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

30. 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 .

31. 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

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

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

34. 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.

35. 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.

36. 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.

37. 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.

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