By Turna Ray

CHICAGO Data from a prospectively designed, randomized study involving patients who have undergone a percutaneous coronary intervention suggests that individuals who are carriers of the CYP2C19*2 allele experience lower platelet aggregation, and therefore greater response, to standard-dose Effient than they do to high-dose Plavix.

In the study, called RESET, University of Rome's Gennaro Sardella and colleagues also identified a possible platelet aggregation cutoff above which patients may be more likely to harbor genotypic variations in CYP2C19 that compromise their ability to respond to Plavix.

Although the US Food and Drug Administration has placed a "black box" warning on Plavix to note that patients with certain CYP2C19 genotypes may not respond to the drug, physicians have been reluctant to adopt testing without more specific guidance on how genotypic information can guide dosing. Preliminary data from the RESET trial, presented here this week at the American College of Cardiology's annual meeting by Sardella, may further inform such a genotype-driven dosing strategy.

The data confirms results from other trials suggesting that patients who have undergone PCI and harbor certain CYP2C19 alleles respond better to Daiichi Sankyo/Eli Lilly's Effient (prasugrel) than they do to Plavix (clopidogrel), marketed by Bristol-Myers Squibb and Sanofi-Aventis. Specifically, the findings in RESET corroborate results from a retrospective gene substudy of the GRAVITAS trial, in which Matthew Price and colleagues from the Scripps Clinic found that CYP2C19*2 carriers compared to those with the normal allele experienced increased platelet reactivity despite a double dose of Plavix (150 mg/day).

Meanwhile, a prospective study published by researchers at Brigham and Women's Hospital last November in the Journal of the American Medical Association genotyped more than 300 patients with cardiovascular disease and reported the most detailed genotype-guided dosing data for Plavix to date. In that study, called ELEVATE-TIMI 56, the researchers found that patients with CYP2C19*2 genotypes given triple the maintenance dose of clopidogrel (225 mg/day) experienced the same level of platelet reactivity as patients without the CYP2C19*2 allele who received a 75 mg/day dose of the drug. However, the researchers, led by Jessica Mega, found that in patients who carried two copies of the *2 allele, "doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition."

While the Mega study investigated the influence of genotype on response to increasing doses of Plavix, the Sardella study compared the influence of genotype on response to high-dose Plavix and standard-dose Effient. Also, the Meta study broke down Plavix response by whether patients had one or two copies of the *2 allele, whereas Sardella's study only considered *2 carriers versus non-carriers. The retrospective GRAVITAS genetic substudy, meanwhile, also found that *2 homozygous patients fared worse on Plavix than did heterozygous *2 patients.

It is currently controversial in medical practice to use genetic testing to determine whether patients should be treated with Plavix, since a number of studies have come to divergent conclusions about the association between CYP2C19 genotypes and Plavix response, depending on whether researchers focused on surrogate markers of response, such as platelet reactivity, or patient outcomes in terms of cardiovascular events. Many of these studies have been retrospective in design, involved heterogenous disease populations, or been too small to provide definitive answers. Most doctors are waiting for the FDA to provide more definitive dosing recommendations by genotype before deciding whether to adopt genetic testing in this setting.

RESET

In RESET, the study investigators used a crossover, randomized design to compare the antiplatelet effect of standard-dose Effient (10 mg/day) versus high-dose Plavix (150 mg/day) in patients who were stable after a PCI, but had high on-treatment antiplatelet activity upon receiving moderate- to low-dose Plavix. Researchers looked at the relationship between platelet reactivity and CYP2C19*2 genotype when patients were on Effient and then switched to Plavix, or were first on Plavix and then given Effient.

Original post:
Study: Higher Plavix Dose Doesn't Improve Response for CYP2C19*2 Carriers; Effient May Be Best Option