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At a Glance
The definition of clopidogrel “resistance” or residual platelet reactivity (RPR) is suboptimal inhibition of platelet function, despite therapy with clopidogrel.
Loss of function alleles for CYP2C19 (*2, *3, others) are associated with a decreased metabolism of clopidogrel to its active form. Conversely, the gain of function allele (*17) is associated with increased levels of active clopidogrel. Additionally, a polymorphism of ABCB1 (coding for a transporter protein) is associated with decreased clopidogrel gastrointestinal (GI) absorption.
Clinical features suggesting clopidogrel resistance are thrombotic complications or adverse cardiovascular events during therapy with clopidogrel. Physicians may use clinical judgment to increase dose of clopidogrel from 75 mg to 150 mg daily. Alternative therapy with other anti-platelet drugs, such as prasugrel, may be considered.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Clopidogrel resistance can be detected by either functional platelet assays or genomic tests.
Platelet function assays include ADP-induced platelet aggregation, Verify Now P2Y12, and VASP-phosphorylation. There are varying definitions of clopidogrel resistance for each of these tests. For ADP-induced aggregation, a difference of less than 10% from pre-drug baseline or a maximal aggregation greater than 40% are used. For Verify Now P2Y12 a PRU (platelet response unit) greater than 240 is indicative of residual platelet reactivity (RPR), and, for VASP phosphorylation, a platelet reactivity index (PRI) greater than 50% is indicative of RPR.
Genotyping of CYP2C19 is used to detect poor metabolizers (*2, *3), intermediate metabolizers (*4,*10), and ultrametabolizers (*17). Patients with *2 and *3 alleles have been shown to have increased cardiovascular events while on clopidogrel therapy. Ultrametabolizers have been shown to be at increased bleeding risk while on clopidogrel therapy.
Point of Care (i.e., bedside) testing for CYP2C19 polymorphisms are not available at this time (Table 1).
Table 1.
| ADP-induced platelet aggregation | VerifyNow P2Y12 | VASP-Phosphorylation | CYP2C19 *2, *3 | CYP2C19 *17 |
| >40% | PRU >240 | PRI >50% | Poor metabolizer | Ultrametabolizer |
The platelet function analyzer (PFA-100) is relatively insensitive to Clopidogrel and is not recommended for assessment of clopidogrel effect.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Clopidogrel metabolism may be affected by other drugs also metabolized through the cytochrome P450 system, especially those metabolized by CYP2C19. These include proton pump inhibitors (also metabolized by CYP2C19) and atorvastatin (Lipitor, metabolized through CYP3A4).
Concomitant therapy with other antiplatelet drugs (e.g., aspirin) can increase platelet inhibition.
Other anticoagulants (e.g., heparin, warfarin, and DTIs) can increase bleeding risk.
What Lab Results Are Absolutely Confirmatory?
Genotyping CYP2C19 can confirm a genetic predisposition to clopidogrel RPR. Identification of a *2 or *3 allele can indicate poor metabolism to the active form. This has been associated with high RPR and adverse cardiovascular outcomes.
The American Heart Association has not recommended either platelet function testing or genetic testing at the present time. However, genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism may be considered before starting clopidogrel in patients thought to be at moderate or high risk for poor outcomes.
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