MANAGEMENT OF CARDIAC SURGICAL PATIENTS RECEIVING PLATELET INHIBITORS

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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

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Events Leading to Thrombus Formation
Adhesion
Activation
Aggregation
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Platelet-fibrin clot
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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

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PLATELET INHIBITORS

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

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Platelet Activation Pathways
Collagen
Thrombin
Epinephrine
ADP
Arachidonic acid
TxA2
GP IIb/IIIa
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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
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Tirofiban (Aggrastat)

• Nonpeptide
• KD 15 nmol/L
• Indication acute coronary syndrome

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Eptifbatide (Integrelin)

• Cyclic peptide
• KD 120 nmol/L
• Acute coronary syndrome

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Abciximab (ReoPro)

• Human/murine chimeric monoclonal antibody Fab
• KD 5 nmol/L
• Indication PCI

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PLATELET DYSFUNCTION DURING CPB

• Hemodilution
• Contact activation
• Shear stresses
• Hypothermia
• Intrinsic/extrinsic defects
• Anticoagulation/reversal

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PLATELET FUNCTION AGGREGATION

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

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PLATELET FUNCTION EVALUATION

• Platelet count
• Bleeding time
• Aggregation
• TEG/SonoClot
• Platelet function assays
• Accumetrics

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Accumetrics Ultegra System
Step 1
Step 2
Step 3
Insert Cartridge
Insert whole blood sample
Read result in 60 seconds
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Correlation of Platelet Aggregation and
Accumetrics RPFA
Mean and S.D. of 6 Donors
100
90
80
70
Aggregometry ()
60
50
40
r2
30
20
10
0
Accumetrics RPFA ()
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Gammie Abciximab and excessive bleeding in
patients undergoing emergency cardiac operations.
Ann Thor Surg 65465-9, 1998

• 11 pts req emerg CABG, operated on lt12 hr after
  abciximab (n 6), or late gt12 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)

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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

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Patients requiring CABG following Abciximab

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

1000
1000
0
0
Placebo
Abciximab
Placebo
Abciximab
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Abciximab and Bleeding
Time to Surgery
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
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Additional Medications
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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

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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.

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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

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TICOLPIDINE and CABG Anesth Analg 199988SCA
105

• 96/1166 CABG pts receiving ticlopidine
• 83 of ticlop pt also on ASA, 28 ticlop pt were
  urgent vs 9
• Blood loss gt1500 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 gt30 in ticlop
• .

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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

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FACTORS AFFECTING ACT

• Factor deficiency fibrinogen, XII, VIII
• Contact activation inhibitors aprotinin
• Warfarin therapy
• Heparin therapy
• Hypothermia
• Thrombocytopenia/cytosis
• Platelet inhibitors

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

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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.

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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.

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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.

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SUMMARY PLATELET INHIBITORS AND CARDIAC SURGERY

• Do not transfuse with platelets before CPB
• Normal heparin doses
• Platelet transfusions when needed after CPB