Clopidogrel

Impact of genetic variation on response to therapy

Clopidogrel is a pro-drug, requiring bioactivation by CYP enzymes including CYP2C19. In patients with loss of function variants in the CYP2C19 gene resulting in poor or intermediate metaboliser phenotypes, clopidogrel forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function.

The SmPC for clopidogrel states that in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5μM ADP) was decreased with differences in inhibition of platelet aggregation of 5.9% and 21.4%, respectively, when compared to normal metabolisers.

The SmPC for clopidogrel provides a special warning and precaution for use that in patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function and advises that tests are available to identify a patient’s CYP2C19 genotype.  

Testing recommendations

The UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx) recommends that any patient who is about to be prescribed clopidogrel, regardless of indication, should have pharmacogenetic testing to identify clinically relevant CYP2C19 variants, where testing is available, to optimise their antiplatelet therapy. Consideration should also be given to testing in patients already on clopidogrel who either have another atherothrombotic event or are at high risk of recurrent events, if the information is not already available in the medical record.

NICE recommends CYP2C19 genotype testing to assess if clopidogrel is a suitable antiplatelet drug for people who have just had an ischaemic stroke or a transient ischaemic attack (TIA).

Therapeutic recommendations

CYP2C19 metaboliser status unknown

Use at standard dose.

CYP2C19 Ultra-rapid metabolisers

Some examples of CYP2C19 genotypes include: *17/*17

• Predictive of increased levels of active metabolites compared to normal metabolisers which theoretically may potentiate bleeding risk however this has no impact on the recommended dose.
• Use at standard dose.

CYP2C19 Rapid metabolisers

Some examples of CYP2C19 genotypes include: *1/*17

• Predictive of normal or increased levels of active metabolites compared to normal metabolisers which theoretically may potentiate bleeding risk however this has no impact on the recommended dose.
• Use at standard dose.

CYP2C19 Normal metabolisers

Some examples of CYP2C19 genotypes include: *1/*1

• Use at standard dose.

CYP2C19 Intermediate metabolisers

Some examples of CYP2C19 genotypes include: *1/*2, *1/*3, *2/*17, *3/*17

• Predictive of reduced levels of active metabolite compared to normal metabolisers.
• Reduced platelet inhibition.
• Increased likelihood of therapeutic failure.
• Consider alternative antiplatelet agents according to disease specific guidelines.

CYP2C19 Poor metabolisers

Some examples of CYP2C19 genotypes include: *2/*2, *3/*3, *2/*3

• Predictive of significantly reduced levels of active metabolite compared to normal metabolisers.
• Reduced platelet inhibition.
• Greatly increased likelihood of therapeutic failure.
• Avoid clopidogrel. Consider alternative antiplatelet agents according to disease specific guidelines.

Further information

CYP2C19 rapid and ultrarapid metabolisers may experience lower on-treatment platelet reactivity which may potentiate bleeding risk. However, due to lack of evidence demonstrating significant differences in bleeding risk compared with normal metabolisers in cardiovascular and neurovascular indications, the use of clopidogrel at standard doses is recommended in individuals with these phenotypes.

Clopidogrel is metabolised to its active metabolite mostly by CYP2C19, with contributions from other CYP enzymes including CYP1A2, CYP2B6 and CYP3A4.  The SmPC recommends that the use of strong or moderate CYP2C19 inhibitors, or strong CYP2C19 inducers, should be discouraged.  Clopidogrel also inhibits the activity of CYP2C8, and caution should be taken with concomitant administration of drugs primarily cleared via CYP2C8 metabolism.  Consult the SmPC for a full list of interactions.

Alternative antiplatelet agents without significant CYP2C19 metabolism include aspirin, dipyridamole, prasugrel and ticagrelor. Further information can be found in disease-specific and specialist guidance where available. 

Guidance on therapeutic options for CYP2C19 intermediate metabolisers differs between sources.  International guidance from the Dutch Pharmacogenetics Working Group (DPWG) recommends choosing an alternative or doubling the clopidogrel dose to 150 mg daily (600 mg loading dose) for intermediate metabolisers undergoing percutaneous coronary intervention, or in those who have a stroke or TIA. However, the UK CERSI-PGx and CPIC guidelines advise the use of alternative antiplatelets in preference to clopidogrel dose escalation. The UK CERSI-PGx guidelines advise that clopidogrel 150 mg daily may be reserved for use in specific CYP2C19 intermediate metaboliser populations, such as those where the bleeding risk with ticagrelor, or other alternative agents, is considered too high. Authors note that the extent to which this reduces bleeding risk compared to alternatives is uncertain.

References

Sanofi (2024) Plavix® 300mg film-coated tablets SmPC. Available at:  https://www.medicines.org.uk/emc/product/5934/smpc (Accessed online 16^th April 2025).

Dello Russo C, Frater I, Kuruvilla R, et al. CYP2C19 genotype testing for clopidogrel: A guideline developed by the UK Centre of Excellence for regulatory science and innovation in pharmacogenomics (CERSI-PGx). Br J Clin Pharmacol. 2025;1‐19. doi:10.1002/bcp.70370 (Accessed online 6^th January 2026).

National Institute for Health and Care Excellence (2024) CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack. HTG724. Available at: https://www.nice.org.uk/guidance/htg724 (Accessed online 19^th March 2025). 

Clinical Pharmacogenetics Implementation Consortium (2022) Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 update. Available at: https://cpicpgx.org/guidelines/guideline-for-clopidogrel-and-cyp2c19/ (Accessed online 16^th April 2025).

Dutch Pharmacogenetics Working Group Pharmacogenetic Recommendation Text (20230801 update). Available at: https://www.knmp.nl/dossiers/farmacogenetica Information in English available at: https://www.knmp.nl/dossiers/farmacogenetica/pharmacogenetics (Accessed online 18th December 2025).