3. Lee C.R., Luzum J.A., Sangkuhl K., Gammal R.S., et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022.
4. Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Clopidogrel – CYP2C19 [Cited 1 Feb 2022]. Available from:
https://www.knmp.nl/dossiers/farmacogeneticaThis section contains excerpted
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information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2022 Statement from the US Food and Drug Administration (FDA)
WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE
The effectiveness of clopidogrel bisulfate results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 … Clopidogrel bisulfate at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed "CYP2C19 poor metabolizers"). Tests are available to identify patients who are CYP2C19 poor metabolizers … Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
[…]
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 … The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel bisulfate.
[…]
Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers. […]
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition… Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole.
[…]
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxoclopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed "CYP2C19 poor metabolizers." Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers.
Please review the complete therapeutic recommendations that are located here: (
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2022 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
In patients with ACS and/or undergoing PCI…avoid clopidogrel in CYP2C19 Ims and PMs and use an alternative antiplatelet agent, such as prasugrel or ticagrelor, if no contraindications.
[…]
If considering clopidogrel and the patient is a CYP2C19 NM, the standard dose (75 mg/day) is recommended. Although clopidogrel-treated CYP2C19 RMs and Ums may experience lower on-treatment platelet reactivity compared with NMs, clinical data also support the use of clopidogrel at standard doses in CYP2C19 RMs and Ums due to the lack of evidence demonstrating significant differences in risk of bleeding or ischemic events compared with NMs in patients undergoing PCI.
[…]
There remain limited data regarding the potential benefit of CYP2C19-guided antiplatelet therapy on outcomes exclusively in patients undergoing PCI for a non-ACS indication. Patients undergoing elective PCI have a lower risk of cardiovascular events compared with patients with ACS, but were included in multiple studies evaluating outcomes of genotype-guided antiplatelet therapy, including the IGNITE and TAILOR-PCI studies (Table S2). Therefore, the therapeutic recommendations for patients with ACS and/or undergoing PCI may also be considered for patients undergoing elective PCI.
[…]
In patients with a cardiovascular indication for clopidogrel outside the setting of an ACS or PCI, including the treatment of patients with peripheral arterial disease or stable coronary artery disease following a recent MI, the standard dose (75 mg/day) is recommended if the patient is a CYP2C19 NM. However, there are insufficient data to make a clinical recommendation for CYP2C19 Ums, RMs, and Ims. If the patient is a CYP2C19 PM, it is recommended to avoid clopidogrel and use prasugrel or ticagrelor at standard doses if no contraindication.
[…]
If considering clopidogrel for patients with neurovascular disease, including the treatment of acute ischemic stroke or TIA, the secondary prevention of stroke, or the prevention of thromboembolic events following neurointerventional procedures, such as carotid artery stenting and endarterectomy and stent-assisted coiling of intracranial aneurysms, the standard dose (75 mg/day) is recommended in CYP2C19 NMs (Table 3). In CYP2C19 Ims and PMs, there is a “moderate” recommendation to avoid clopidogrel if possible and consider an alternative P2Y12 inhibitor at standard doses if clinically indicated and no contraindication. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants with indications for patients with stroke include ticagrelor and ticlopidine. However, ticlopidine has serious hematological adverse effects that also need to be considered. Prasugrel is contraindicated in patients with a history of stroke or TIA.
Please review the complete therapeutic recommendations that are located here:
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2019 Summary of Recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2C19 PM: CLOPIDOGREL
The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, because the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been proved in other patients.
- PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA:
- avoid clopidogrel
- Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).
- OTHER INDICATIONS:
- determine the level of inhibition of platelet aggregation by clopidogrel
- consider an alternative in poor responders
- Prasugrel and ticagrelor are not metabolised by CYP2C19 (or to a lesser extent).
CYP2C19 IM: clopidogrel
The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, as the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been observed in other patients.
- PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA:
- choose an alternative or double the dose to 150 mg/day (600 mg loading dose); Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolised by CYP2C19 (or to a lesser extent).
- OTHER INDICATIONS:
CYP2C19 UM: clopidogrel
NO action is required for this gene-drug interaction.
The genetic variation results in increased conversion of clopidogrel to the active metabolite. However, this can result in both positive effects (reduction in the risk of serious cardiovascular and cerebrovascular events) and negative effects (increase in the risk of bleeding).
Please review the complete therapeutic recommendations that are located here: (
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Table 3. The CPIC (2022) Antiplatelet Therapy Recommendations Based on CYP2C19 Phenotype when Considering Clopidogrel for Neurovasculara
Indications| a
. Neurovascular disease includes acute ischemic stroke or transient ischemic attack (TIA), secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures, such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. |
| b
. The strength of the recommendation for “likely” phenotypes are the same as their respective confirmed phenotypes; “likely” indicates the uncertainty in phenotype assignment due to limited data for reduced function alleles. |
| c
. Alternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in individuals with a history of stroke or TIA. Given limited outcomes data for genotype-guided antiplatelet therapy for neurovascular indications, selection of therapy should depend on the individual’s treatment goals and risks for adverse events. |
| Please see Therapeutic Recommendations based on Genotype for more information from CPIC. This table is adapted from (3). CPIC - Clinical Pharmacogenetics Implementation Consortium |
| CYP2C19 phenotype | Implications for clopidogrel | Therapeutic recommendation | Classification of recommendationb
|
|---|
| Ultrarapid metabolizer (UM) | Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding risk | No recommendation | No recommendation |
| Rapid metabolizer (RM) | Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding risk |
| Normal metabolizer (NM) | Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivity | If considering clopidogrel, use at standard dose (75 mg/day) | Strong |
| Likely and confirmed intermediate metabolizer (IM) | Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events | Consider an alternativec
P2Y12 inhibitor at standard dose if clinically indicated and no contraindication | Moderate |
| Likely and confirmed poor metabolizer (PM) | Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular events | Avoid clopidogrel if possible.
Consider an alternativec
P2Y12 inhibitor at standard dose if clinically indicated and no contraindication | Moderate |
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The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.