Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. A number of different alleles of CYP2C19 have been identified; depending on the allele present the enzymatic activity of CYP2C19 can be normal, or reduced.<\/p>\n
The *1 allele is the normal copy that has full enzymatic activity. The *2 and *3 alleles are the most common variants and result in complete loss of enzymatic activity. Consequently, carriers of the *2 and *3 alleles have reduced formation of clopidogrel’s active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition.<\/p>\n
In the Lancet, Roberts et al. publish the first evidence of successful validation and clinical application of a point-of-care genetic test in medicine. They use a rapid, bedside test to identify carriers of the CYP2C19*2 allele and assessed a pharmacogenetic approach to dual antiplatelet treatment after PCI.<\/p>\n
The RAPID GENE study randomised patients undergoing PCI to either standard therapy or rapid point-of-care genotyping to identify carriers of the CYP2C19*2 and treat them with prasugrel (10mg) instead of\u00a0clopidogrel (75mg)\u00a0post-PCI.<\/p>\n
The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, which is a surrogate marker that has consistently tracked closely with adverse cardiovascular events following PCI.<\/p>\n
With regards to the gene testing, the point-of-care test had a sensitivity of 100% (95% CI 92\u00b73\u2013100) and a specificity of 99\u00b73% (96\u00b73\u2013100). Clinically, 187 patients completed follow-up (91 genotyping group, 96 standard treatment) and there were 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a high PRU value at day 7, compared with seven given standard treatment (p=0\u00b70092).<\/p>\n
Conclusion:<\/strong><\/p>\n This proof-of-concept study shows that a rapid pharmacogenetic approach is feasible to guide antiplatelet therapy in the setting for PCI. However, large randomised trials using clinical end-points are required to fully assess the success of this strategy.<\/p>\n Reference:<\/strong><\/p>\n