Implementing genotype-guided Antithrombotic Therapy

Abstract

Genotyping has the potential to improve the efficacy and safety of major antithrombotic drugs. For warfarin, the stable maintenance dose varies from 1–10 mg/day. The VKORC1 -1639G>A allele and the CYP2C9*2 and *3 alleles (cumulative frequency: 90% in Asians, 65% in Europeans and 20% in Africans), explain 45% of response variability in European and 30% in African populations. The large clinical trials COAG and EU-PACT will define the extent to which pharmacogenetic dosing affects the safety and efficacy of warfarin and coumarin derivatives. The platelet inhibitor clopidogrel requires activation by the CYP2C19 enzyme. CYP2C19*2 and *3 alleles (cumulative frequency: 20–50%) produce null enzyme activity, and their presence attenuates platelet inhibition and increases cardiovascular events. The US FDA-mandated drug labeling recognizes the relevance of genotyping in the selection and dosing of both warfarin and clopidogrel.

Keywords:

• clopidogrel
• CYP2C19
• CYP2C9
• pharmacogenetics
• platelet
• VKORC1
• warfarin

Financial & competing interests disclosure

Research by the authors has been supported in part by the following grants: NIH NCRR RCMI Grant # G12RR-03051 (Jorge Duconge); NIH NICHD EARDA Grant # 5G11HDO46326 (Jorge Duconge); and NIH NIGMS Grant # 5 R44 GM085201 (Gualberto Ruaño). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.