Clopidogrel Resistance Testing
Clopidogrel resistance is assessed primarily through platelet function assays that measure ADP-induced platelet aggregation, with the most commonly used tests being optical aggregometry (light transmission aggregometry), VASP phosphorylation assay, and point-of-care devices like VerifyNow P2Y12. 1
Primary Testing Methods
Gold Standard Laboratory Tests
Light transmission aggregometry (LTA) using ADP as the agonist is considered the reference standard for assessing clopidogrel's antiplatelet effect 1, 2. This test can be performed in platelet-rich plasma using optical transmittance aggregometry or in whole blood using impedance aggregometry 1.
VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay directly measures the effect of clopidogrel on the platelet P2Y12 receptor, the drug's pharmacological target 1, 2. This flow cytometric analysis provides a specific assessment of P2Y12 receptor inhibition 1.
Point-of-Care Testing Options
VerifyNow P2Y12 assay is the most widely used point-of-care device and can be accepted as the ideal bedside test 1, 2, 3. This rapid assay:
- Measures platelet activity in 3 minutes 4
- Uses ADP combined with prostaglandin E1 (PGE1) to specifically assess P2Y12 receptor function 4
- Reports results in P2Y12 reaction units (PRU) 4
- Has been validated in multiple clinical studies for predicting thrombotic events 1
Multiplate analyzer uses impedance aggregometry in whole blood and provides another point-of-care option 1, 5, though it shows only modest correlation with other methods 5.
Thromboelastography with Platelet Mapping software and INNOVANCE PFA P2Y are additional whole blood testing options 1, 6.
Defining Resistance: Cut-off Values
The European Society of Cardiology guidelines note significant variability in cut-off values across studies 1:
For optical aggregometry with ADP:
60% aggregation with 20 mM ADP 1
50% aggregation with 5 mM ADP 1
70% aggregation with 10 mM ADP (associated with stent thrombosis) 1
62% aggregation with 20 mM ADP in diabetic patients 1
For VASP phosphorylation:
- Platelet reactivity index (PRI) >50% indicates inadequate response 1
For VerifyNow P2Y12:
- Device-specific cut-off values have been established through ROC analysis in post-PCI patients 1
Critical Limitations and Caveats
Important: The correlation between different testing methods is only modest, ranging from 66-78% agreement 5. A patient may be classified as resistant by one method but responsive by another 1, 5.
The clinical utility of routine testing remains controversial because:
- Cut-off values are not standardized and vary widely between studies 1
- We lack definitive evidence that these cut-offs reliably identify populations with different cardiovascular outcomes 1
- Test results can be affected by blood preservative choice (citrate vs. antithrombins) 1
- Pre-analytical and analytical errors can significantly impact results 1
Genetic Testing Alternative
CYP2C19 genetic testing identifies poor metabolizers who cannot adequately convert clopidogrel to its active form 7. The FDA label specifically warns about diminished antiplatelet effect in patients with two loss-of-function alleles of CYP2C19 and states that "tests are available to identify patients who are CYP2C19 poor metabolizers" 7. Consider alternative P2Y12 inhibitors in identified poor metabolizers 7.
Prevalence of Resistance
Clopidogrel resistance frequency ranges from 5-44% depending on the test used, with approximately 21% of patients undergoing PCI showing incomplete platelet inhibition 1. This wide variability reflects differences in definitions, laboratory methods, patient populations, and dosing regimens 1.
Clinical Context
Resistance rates are dose-dependent: Lower prevalence occurs with 600 mg loading doses versus 300 mg, and with 150 mg/day maintenance versus 75 mg/day 1. This suggests true pharmacodynamic resistance is relatively rare, with most cases representing pharmacokinetic issues 1.