Bedside genetic test identifies non-responders to Clopidogrel

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.

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.

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.

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 clopidogrel (75mg) post-PCI.

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.

With regards to the gene testing, the point-of-care test had a sensitivity of 100% (95% CI 92·3–100) and a specificity of 99·3% (96·3–100). 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=0·0092).

Conclusion:

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.

Reference:

  • Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O’Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY.  Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.  Lancet. 2012 Mar 29. doi:10.1016/S0140-6736(12)60161-5.