Post on 28-Dec-2015
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Measurement of Clopidogrel Resistance Measurement of Clopidogrel Resistance
by ADP-Inhibition Does Not Reflect the by ADP-Inhibition Does Not Reflect the Benefit of Clopidogrel on Overall Benefit of Clopidogrel on Overall
Thrombotic StatusThrombotic Status
Dr Diana A GorogConsultant Cardiologist & Honorary Clinical
Senior Lecturer
E & N Hertfordshire NHS Trust &Imperial College, London, UK
Presented at
“Clopidogrel resistance”
Definition clinical ongoing thrombotic events despite medication laboratory results of platelet function tests
Does it exist? Clinical resistance infrequent (5-10%) Laboratory resistance frequent (up to 50%)
Relationship between clinical and lab resistance is unclear, if it exists at all
Is “laboratory resistance” clinically relevant? unsure, some evidence that it is only a laboratory
phenomenon
Presented at
Limitations of laboratory assessment of clopidogrel
resistance Most tests use citrated blood Platelet aggregation studies assess response to a specific
agonist or combination of agonists, e.g. PFA 100: Collagen/ADP VerifyNow: ADP/EpinephrineIn addition to physiological doses of ADP used, there is also
ADP release from aggregating plts (only in citrated blood) so overall level can be an order of magnitude higher
Clopidogrel effective at inhibiting low conc ADP but not high conc
Overall effect of clopidogrel on global thrombotic status unclear, as the most important contributor to platelet aggregation, thrombin generation, not assessed
Correlation between tests very poor
Presented at
Effect of ADP in native blood
ADP 5-20 μM aggregation
[Ca2+] 1.0-1.3 mM
Thrombin generation
(only in native blood)
Presented at
activation stabilization
Effect of ADP in citrated bloodADP 5-20 uM
aggregation
[Ca2+]10 – 30 uM
Thrombin generation
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ADPADPADP
ADP
ADP
up to mM
Platelets in native blood are more sensitive to inhibition of ADP-induced aggregation than platelets in citrated blood (Viigimaa M et. al.,1996)
Citrate
release of granule contents
Only in citrated blood
Limitations of platelet function tests
in measuring clopidogrel effect Measuring the effect of clopidogrel on ADP-
induced aggregation in citrated blood does not take into account inhibition of ADP-induced thrombin generation
Because of the individually variable release rxn, actual ADP concentration is much higher (mM?) than that used to induce aggregation (5-20uM).
Clopidogrel is less effective at inhibiting high conc of ADP than low concentration
Presented at
“Ideal” platelet function test for clopidogrel effect
test involves thrombin generation
employs non-citrated blood
assesses response to endogenous ADP concentration
Global Thrombosis Test (GTT)
Native (non-anticoagulated) blood
Mechanism involves high shear, thrombin and ADP
“Global” test of platelet function
Presented at
Normal volunteers before and 12h after 300 mg clopidogrel
0
100
200
300
400
500
Pre[C] Post [C]
OT
(se
c)
P=0.001
Effect of clopidogrel on occlusion time (OT)
0
100
200
300
400
500
Pre[C] Post [C]
GTT – modified to cause ADP release
Wanted to ↑ actual ADP concentration (to assess specific ADP inhibitory effect of clopidogrel) but still using native blood
Small volume water (0.3 ml) added to cartridge prior to testing at the site where thrombus formation occurs
This caused lysis of red cells and thus ADP release, manifesting in more rapid occlusion (aOT)
Presented at
0
100
200
300
400
OT aOT
P=.0007
Normal vs. Accelerated Occlusion Time (aOT)
0
100
200
300
400
500
OT aOT
Pre [C]
Post [C]
Normal vs. Accelerated Occlusion Time (aOT)
Acute coronary syndrome study
ACS patients (n=86)
On aspirin and clopidogrel >48 h
Platelet function and “clopidogrel resistance” tested using
GTT and aOT
VerifyNow P2Y12 cartridge
Accelerated Thrombosis Test • N=60• Criteria OT<150 sec (i.e. <50% of normal OT)• Non-responders 4 (6.7%)
VerifyNow P2Y12 assay• N=86• Criteria <10% inhibition: 19.8% non-responders• Criteria <30% inhibition: 32.6% non-responders• Criteria <50% inhibition: 46.5% non-responders
ACS patients on dual anti-platelet therapy
Conclusion
Measurement of clopidogrel resistance by ADP-inhibition in citrated blood does not reflect the benefit of clopidogrel on overall thrombotic status
Detection of clopidogrel “resistance” using citrated blood is likely to be misleading
When assessing efficacy of clopidogrel, should use a global test of platelet function, using native blood, where thrombin makes a significant contribution to the thrombus formation.
Presented at