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

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This article was originally posted March 29.

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 and experience high platelet reactivity, have a 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 Mega 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.

The study investigators used the Multiplate P2Y12 Assay to test platelet reactivity in 180 patients who had undergone PCI and received Plavix. Of these patients, 77 percent had high on-treatment platelet aggregation (defined as an area under the aggregation curve of greater than 450) and were placed in the Plavix non-responder arm. Patients who had low platelet aggregation at the start of the study were considered responders and given standard-dose Plavix (75 mg/day).

After assessing clinical factors for patients in the non-responder arm, 32 patients were genotyped to gauge whether they were CYPC19*2 carriers, given a platelet reactivity test, and randomized to receive high-dose Plavix or standard-dose Effient. After 15 days of treatment, their platelet aggregation was tested again and patients on each arm were crossed over to the other drug. Patients were given the new drug for 15 days and then followed for three months.

Generally, the data showed that when patients in the non-responder arm were given Effient for the first 15 days, their platelet aggregation decreased and then began increasing again when they were crossed over to the Plavix arm. Plavix non-responders who started off with Plavix treatment experienced smaller decreases in platelet aggregation, which continued to decrease when switched to Effient. "No patients remained non-responsive after treatment with [Effient]," Sardella said during his presentation.

Investigators observed a similar trend in carriers of CYP2C19*2, most of whom were observed to have platelet aggregation of above 600 AUC at baseline. CYP2C19*2 carriers who received Plavix first experienced a drop in platelet reactivity from approximately 600 AUC to 520 AUC when given Plavix for the first 15 days. Reactivity continued to fall to 252 AUC when they were switched to Effient. In contrast, when CYP2C19*2 carriers started off on Effient treatment, platelet aggregation dropped to 205 AUC and then increased to 313 AUC when switched to Plavix.

In non-carriers of the genotype, however, researchers did not observe a similar trend. Patients in this arm experienced similar platelet aggregation irrespective of treatment.

Given that CYP2C19*2 carriers in the study tended to have platelet aggregation above 600 AUC, Sardella proposed that this phenotype might be used to hone in on patients most likely to harbor genomic variations that may compromise their ability to metabolize Plavix. The phenotype was predictive for genotype in RESET with 75 percent sensitivity and 72 percent specificity.

This finding was exploratory, but if such a phenotype-genotype relationship is validated then it might help doctors hone in on which patients they should genetically test to better inform treatment.

In RESET, investigators also considered patient outcomes on Plavix and Effient, focusing on bleeding and cardiac-cerebrovascular events in genotyped, non-responder patients, but the study wasn't powered to gauge statistically significant differences in these events based on patients' carrier status and the treatment they received. Ultimately, many physicians have balked at adopting CYP2C19 genotyping to administer Plavix because there is inconsistent data on whether pharmacogenetic testing lowers the risk of cardiovascular events and bleeding in patients receiving the drug.

RESET participants "didn't experience major events, only minor events" on the two therapies, Sardella said during his presentation. He added, however, that some patients experienced chest pain "every time" they were switched from Effient to high-dose Plavix, but did not break out the carrier status of these patients.

Based on the results of the study, Sardella concluded that standard-dose Effient significantly reduced platelet aggregation in patients with high on-treatment platelet reactivity following PCI, compared to when they were given high-dose Plavix. "High [Plavix] dose, in contrast to [Effient], is frequently ineffective in the presence of the CYP2C19*2 allele, while in non-carriers … both drugs have similar effects," he highlighted.

Any Closer to a Dosing Strategy?

In reviewing the data, Scripps' Price told PGx Reporter that results from the RESET study corroborate findings from the GRAVITAS genetic substudy, as well as "several other studies that have shown a more potent pharmacodynamics effect of Effient compared with Plavix patients who are CYP2C19 carriers."

Past studies suggest that response to Effient, a newer drug than Plavix, is not dependent on CYP2C19 genotype. As such, personalized medicine proponents have suggested that the drug is a suitable alternative for individuals deemed to be poor Plavix responders either through platelet reactivity testing or by genotyping.

Another proposed strategy, based on data from previous trials, has been to increase the Plavix dose in poor responders.

In the updated label for Plavix, the FDA notes that "CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to [Plavix]. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established."

However, data from the GRAVITAS substudy, the prospective analysis by Mega et al. In JAMA, and now the RESET trial may help to build the kind of evidence FDA needs to provide more definitive guidance regarding Plavix dosing in CYP2C19*2 carriers. Lawrence Lesko, former FDA official and head of University of Florida's Center for Pharmacometrics and Systems Pharmacology, previously told PGx Reporter that the findings and the design of the Mega study may be strong enough to warrant another PGx update to Plavix's label (PGx Reporter 3/28/2012).

Furthermore, regarding the preliminary finding in RESET that patients with platelet aggregation above 600 AUC tended to be CYP2C19*2 carriers, Price reflected that it was a "provocative" suggestion "that you can predict genotype based on phenotype," but noted that the observation needed to be further investigated.

"I think it is an academically interesting finding, [but] I am not sure about its clinical utility," Price told PGx Reporter. "In the GRAVITAS genetic substudy, we found that the attributable risk of the CYP2C19 genotype for persistently high reactivity on high-dose Plavix was pretty low. So I don't think it would change your decision about what antiplatelet therapy to give."

RESET had several limitations, according to Sardella, including a small patient cohort despite being powered for the sample size collected. In addition, platelet reactivity was not gauged at one month, which could mislead the assessment of variation in plate aggregation over time.

Furthermore, there was no wash-out period and since patients had received PCI, this could have affected platelet aggregation when patients were crossed over in the second half of the study. Finally, investigators didn't test for the gain-of-function CYP2C19*17 allele, which could have impacted response to Plavix.


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