The American Heart Association has a statement of CYP2C19 and clopidogrel and testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention.
The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy for CYP2C19 poor or intermediate metabolizers (cardiovascular indications: prasugrel or ticagrelor if no contraindication; neurovascular indications: alternative P2Y12 inhibitor if clinically indicated and no contraindication.)
Avoid clopidogrel use in patients who are CYP2C19 poor metabolizers and are undergoing percutaneous coronary intervention, stroke or TIA. For CYP2C19 intermediate metabolizers who are undergoing percutaneous coronary intervention, stroke, or TIA, choose an alternative drug or double the dose to 150 mg/day (600 mg loading dose). No action is required for patients who are CYP2C19 ultra-rapid metabolizers.
Testing for the main CYP2C19 deficiency alleles before instituting clopidogrel treatment is recommended (a test is essential for coronary angioplasty with stenting and based on the current state of knowledge this test is potentially useful in the other indications). For patients carrying at least one deficiency allele, the RNPGx recommends using an alternative treatment that is not a CYP2C19 substrate (eg. prasugrel, ticagrelor).
The FDA-approved drug label for clopidogrel (Plavix) states that in patients who are CYP2C19 poor metabolizers, clopidogrel at recommended doses has a reduced effect on platelet activity, and that use of another platelet P2Y12 inhibitor should be considered.
Drug labels from sources other than the FDA are available.
| Level of Evidence | Level 1A |
|---|---|
| Type | Efficacy |
| Genes | CYP2C19 |
| Phenotypes | Cardiovascular Disease |
| Variant | CYP2C19*1, CYP2C19*17, CYP2C19*2, CYP2C19*3 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C19*1 allele is assigned as a normal function allele by CPIC. Patients carrying the CYP2C19*1 allele in combination with a normal function allele who are treated with clopidogrel may have increased platelet inhibition and decreased residual platelet aggregation as compared to patients with a no or decreased function allele in combination with a normal or increased function allele or with two no or decreased function alleles. Patients carrying the CYP2C19*1 allele in combination with a normal function allele who are treated with clopidogrel may have decreased platelet inhibition and increased residual platelet aggregation compared to patients with two increased function alleles or a combination of a normal function allele with an increased function allele. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence platelet inhibition. |
| *2 | The CYP2C19*2 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*2 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have decreased platelet inhibition and increased residual platelet aggregation as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence platelet inhibition. |
| *3 | The CYP2C19*3 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*3 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have decreased platelet inhibition and increased residual platelet aggregation as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence platelet inhibition. |
| *17 | The CYP2C19*17 allele is assigned as an increased function allele by CPIC. Patients carrying the CYP2C19*17 allele in combination with a no or decreased function allele who are treated with clopidogrel may have decreased platelet inhibition and increased residual platelet aggregation as compared to patients with two normal function alleles. Patients carrying the CYP2C19*17 allele in combination with a normal or increased function allele who are treated with clopidogrel may have increased platelet inhibition and decreased residual platelet aggregation as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence platelet inhibition. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Metabolism/PK |
| Genes | CYP2C19 |
| Variant | CYP2C19*1, CYP2C19*10, CYP2C19*17, CYP2C19*19, CYP2C19*2, CYP2C19*25, CYP2C19*26, CYP2C19*3, CYP2C19*8 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C19*1 allele is assigned as a normal function allele by CPIC. Patients carrying the CYP2C19*1 allele in combination with a normal function allele may have increased metabolism of clopidogrel as compared to patients with no or decreased function allele in combination with a normal or increased function allele or with two no or decreased function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *2 | The CYP2C19*2 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*2 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *3 | The CYP2C19*3 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*3 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *8 | The CYP2C19*8 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*8 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *10 | The CYP2C19*10 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C19*10 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *17 | The CYP2C19*17 allele is assigned as an increased function allele by CPIC. Patients carrying the CYP2C19*17 allele with another increased function allele may have increased metabolism of clopidogrel compared to two normal function alleles. Patients carrying the CYP2C19*17 allele in combination with a no or decreased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *19 | The CYP2C19*19 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C19*19 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *25 | The CYP2C19*25 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C19*25 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| *26 | The CYP2C19*26 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C19*26 allele in combination with a no, decreased, normal, or increased function allele may have decreased metabolism of clopidogrel as compared to patients with two normal function alleles. This annotation only covers the pharmacokinetic relationship between CYP2C19 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence the metabolism of clopidogrel. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Efficacy, Toxicity |
| Genes | CYP2C19 |
| Phenotypes | Acute coronary syndrome, Cardiovascular Disease, Stroke, Transient Ischemic Attack |
| Variant | CYP2C19*1, CYP2C19*17, CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*8 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C19*1 allele is assigned as a normal function allele by CPIC. Patients carrying the CYP2C19*1 allele in combination with a normal function allele who are treated with clopidogrel may have a decreased, but not absent, risk for adverse cardiac and cerebrovascular events as compared to patients with a no or decreased function allele in combination with a normal or increased function allele or with two no or decreased function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *2 | The CYP2C19*2 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*2 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *3 | The CYP2C19*3 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*3 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *4 | The CYP2C19*4 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*4 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *5 | The CYP2C19*5 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*5 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *6 | The CYP2C19*6 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*6 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *8 | The CYP2C19*8 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C19*8 allele in combination with a no, decreased, normal, or increased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| *17 | The CYP2C19*17 allele is assigned as an increased function allele by CPIC. Patients carrying the CYP2C19*17 allele in combination with a no or decreased function allele who are treated with clopidogrel may have an increased risk for adverse cardiac and cerebrovascular events as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk for adverse cardiovascular events. |
| Level of Evidence | Level 2B |
|---|---|
| Type | Efficacy |
| Genes | CES1 |
| Variant | rs71647871 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs71647871 CC genotype who are treated with clopidogrel may have increased platelet aggregation as compared to patients with the CT or TT genotypes. Other genetic and clinical factors may also influence response to clopidogrel. |
| CT | Patients with the rs71647871 CT genotype who are treated with clopidogrel may have decreased platelet aggregation as compared to patients with the CC genotype. Other genetic and clinical factors may also influence response to clopidogrel. |
| TT | Patients with the rs71647871 TT genotype who are treated with clopidogrel may have decreased platelet aggregation as compared to patients with the CC genotype. Other genetic and clinical factors may also influence response to clopidogrel. |
| Level of Evidence | Level 2B |
|---|---|
| Type | Metabolism/PK |
| Genes | CES1 |
| Variant | rs71647871 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs71647871 CC genotype who are treated with clopidogrel may have decreased exposure to clopidogrel as compared to patients with the CT or TT genotype. This annotation only covers the pharmacokinetic relationship between rs71647871 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence clopidogrel pharmacokinetics. |
| CT | Patients with the rs71647871 CT genotype who are treated with clopidogrel may have increased exposure to clopidogrel as compared to patients with the CC genotype. This annotation only covers the pharmacokinetic relationship between rs71647871 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence clopidogrel pharmacokinetics. |
| TT | Patients with the rs71647871 TT genotype who are treated with clopidogrel may have increased exposure to clopidogrel as compared to patients with the CC genotype. This annotation only covers the pharmacokinetic relationship between rs71647871 and clopidogrel and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence clopidogrel pharmacokinetics. |
Clinical annotations with lower levels of evidence are available.