Eric R. Bates, MD

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Variability of Response and Resistance to
Antiplatelet Agents
Eric R. Bates, MD Professor of Internal
Medicine University of Michigan Ann Arbor, MI
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Variation in Response to Antiplatelet Therapy
Resistance
Treatment Failure
Complex Biologic Processes
Inadequate Response on Lab Test
Inadequate Biologic Response
Poor Compliance
Bleeding Time,
LTA, PFA-100,
PlateletWorks, Ultegra,
Flow Cytometry, VASP
LTA light transmission aggregometry PFA
platelet function analyzer VASP
vasodilator-associated stimulated phosphoprotein
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Aspirin Resistance More Than Just a Laboratory
Curiosity

• Clinical factors
• Failure to prescribe
• Noncompliance
• Nonabsorption
• Interaction with ibuprofen

• Cellular factors
• Insufficient suppression of COX-1
• Overexpression of COX-2 mRNA
• Erythrocyte-induced platelet activation
• Increased norepinephrine
• Generation of 8-iso-PGF2a

Aspirin Resistance

• Genetic polymorphisms
• COX-1
• GP IIIa receptor
• Collagen receptor
• vWF receptor

Bhatt D. J Am Coll Cardiol. 2004431127-9.
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Effects of NSAIDs on Platelets and Endothelium
Endothelial cell
Platelet
Nonspecific NSAIDs/ASA
COX-1
COX-1
Coxibs
COX-2
Thromboxane (TxA2)
Prostacyclin (PGI2)
Vasoconstrictor Promotes platelet aggregation
Vasodilator Inhibitor of platelet aggregation
Hemostasis
Thrombosis
McAdam BF et al. Proc Natl Acad Sci USA.
199996272-7.
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ASA Resistance in PCI
ASA/Clopidogrel (n151)
P0.012
Aspirin-resistant
Aspirin-sensitive
P0.006
65.5
70
19 ASA resistant
60
51.7
50
38.5
37.9
40
CK-MB and troponin I elevation ()
30
24.6
23
20
10.3
10
3.4
1.6
0
0
Any
1-3x
3-5x
gt5x
gt2ng/ml
Elevation
Tn I
Magnitude of CK-MB Elevation
Chen W-H. J Am Coll Cardiol. 2004431122-6.
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Platelet Reactivity Responsiveness to Agonist
ADP
P2Y12
P2Y1
PLATELET
Gi
Receptor Reactivity
Monoclonal Antibody
Adenylate cyclase
P-selectin
VASP- P
Flow Cytometry
Activated GP IIb/IIIa
Flow Cytometry
Monoclonal Antibody
Aggregation

• LTA
• TEG
• Point of Service

Receptor Expression
PLATELET
Courtesy of Paul Gurbel, MD, Baltimore, MD.
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Clopidogrel Responsiveness and Recurrent CV
Events in Patients With STEMI
Reduction in Aggregate Size
ADP-Induced Platelet Aggregation
Quartiles
1st n15
4th n15
2nd n15
3rd n15
Clopidogrel Resistance
120
0
100
-5
-10
80
-9
-15
of Baseline
60
-20
of Baseline
-25
-22
40
-30
Plt0.05
-28
-35
20
1st Q
2nd Q
3rd Q
4th Q
-40
0
-45
-45
1
2
3
4
5
6
-50
Days
Six Months Recurrent CVS Events
40
40
35
P-0.007
30
25
of Patients
20
15
6.7
10
0
0
5
0
1st n15
2nd n15
3rd n15
4th n15
Quartiles
Matetzky S et al. Circulation. 20041093171-5.
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Inter-individual Variability Clopidogrel 600 mg
100
y35.28 29.09 e-1.072 x r20.101
80
60
Maximal Aggregation5 µmol/L ADP ()
40
20
0
0
2
4
6
8
10
Time from loading dose to catheterization (hour)
Hochholzer W et al. Circulation. 20051112560-4.
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CYP450 Pathways
Hydrophilic metabolites readily excreted by kidney
CYP450 3A4 2C9 2D6 1A2 Activation Metabolism
Substrate Lipophilic agent requiring
metabolism
Inhibitor Agent that impairs the ability of the
enzyme to activate the substrate or metabolize
the substrate
Decreased therapeutic effect
Plasma levels
Increased potential for adverse drug effects
Plasma levels
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Clopidogrel Resistance Correlates WithLow
CYP3A4 Activity/Conversion to Active Drug
100
80
60
Platelet aggregation ()
40
r-0.6 P.003
20
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
CYP3A4 Activity-14CO2 exhaled/hour ()
Lau W et al. Circulation. 2004109166-71.
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Converting Clopidogrel Non-responders to
Responders by Induction of CYP3A4
P0.004
120
Clopidogrel 450 mg/d
P0.004
P0.03
97
95
100
Clopidogrel St. John's wort 300 mg tid
84
84
79
80
64
Platelet aggregation ()
60
51
46
40
20
0
Baseline
2 h
4 h
6 h
Lau WC et al. J Am Coll Cardiol. 200545382A.
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Resistant Platelets What Can Be Done?

• Uniformity of definition
• Improvement of laboratory assays (POC)
• Correlation of laboratory assays with clinical
  events
• Evaluation of new therapeutic strategies
• In the futurecustomized patient Rx
  (pharmacogenomics)

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