GIFT Published: Role of CYP2C19 in Clopidogrel Response Variability Confirmed

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Patients’ CYP2C19 genotype plays a significant role in responsiveness to clopidogrel in both the acute and maintenance phases of antiplatelet therapy, accounting for 10% of response variability at 30 days. The study, published in the May 29, 2012, issue of the Journal of the American College of Cardiology, also found that 2 other gene polymorphisms thought to be involved in clopidogrel response show no such association.

Portions of the data were originally presented at the American College of Cardiology/i2 Scientific Session in New Orleans, LA, in April 2011.

For GIFT (Genotype Information and Functional Testing), a prespecified substudy of GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety), researchers led by Matthew J. Price, MD, of Scripps Clinic (La Jolla, CA), evaluated the influence of genotype on the pharmacodynamic effect of high- or standard-dose clopidogrel treatment using DNA samples from a cohort of 1,028 patients. The samples were genotyped for 41 single-nucleotide polymorphisms (SNPs) in 17 genes related to platelet reactivity or previously implicated in having an effect on clopidogrel response.

In the original randomized GRAVITAS trial, published last year by Dr. Price and colleagues (JAMA. 2011;305:1097-1105), high-dose clopidogrel (600-mg initial dose and 150 mg daily thereafter) did not reduce the incidence of cardiovascular events in patients with high on-treatment platelet reactivity after PCI compared with standard-dose clopidogrel.

CYP2C19 Convicted, Other Suspects Cleared

In GIFT, the presence of 1 CYP2C19*2 reduced-function allele was significantly associated with on-treatment platelet reactivity, the primary endpoint, at 30 days (OR 2.29; 95% CI 1.59-3.30) and at 6 months (OR 2.56; 95% CI 1.75-3.74), while carriage of the CYP2C19*17 gain-of-function allele and candidate SNPs of PON1 and ABCB1 were not.

Clinical factors that contributed to variations in on-treatment platelet reactivity at both time points in the multivariate model incorporating the CYP2C19 genotype included:

• Body mass index
• Diabetes
• Age
• Current smoking

The primary clinical endpoint, the composite of cardiovascular death, nonfatal MI, or stent thrombosis, occurred in 14 patients (1.9%) during follow-up. Patients who carried 2 reduced-function CYP2C19 alleles were at higher risk of this endpoint compared with noncarriers (HR 1.58; 95% CI 1.04-2.41; P = 0.03). However, there was no association with carriage of 1 reduced-function CYP2C19 allele (HR 1.07; 95% CI 0.91-1.25; P = 0.42). In addition, there was no association between PON1 and clinical outcomes, regardless of the number of suspect alleles.

Allele’s Influence on Platelet Response Limited

According to the authors, the data provide “strong evidence” that CYP2C19 is a key genetic determinant of on-treatment platelet reactivity in patients receiving clopidogrel early and late after PCI. However, the study also demonstrates that using platelet function testing to identify the CYP2C19 genotype provides only limited information regarding the risk of persistently high reactivity with a daily clopidogrel maintenance dose of 150 mg.

They further state that after adjustment for clinical and procedural characteristics, the reduced-function CYP2C19 allele explains approximately 10% of clopidogrel response variability at 30 days and 7% at 6 months.

In terms of clinical implications, the study authors say “in patients who are identified to be poor metabolizers by genotyping, the use of alternative P2Y12 antagonists that are not influenced by CYP2C19 should be considered if an adequate pharmacodynamic effect is desired.” Meanwhile, it remains to be seen whether even larger doses of clopidogrel may improve response in patients with reduced-function CYP2C19 alleles. More data on this hypothesis are expected to come from the ELEVATE–TIMI 56 trial, the investigators note.

Personalized Antiplatelet Therapy Still Unproven

In an e-mail communication with TCTMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), affirmed that “the study offers pharmacodynamic data in the setting of a clinical trial. It shows that poor metabolism persists when using 150 mg of clopidogrel.”

However, he pointed out that the study is not powered for clinical outcomes, a point the study authors acknowledge, observing that “the significant association between carriage of 2 reduced-function CYP2C19 alleles and outcomes must be considered exploratory and hypothesis generating, although it is consistent with previous reports.”

In addition, Dr. Bates disagreed with the authors’ conclusions regarding potentially switching patients to alternative P2Y12 antagonists, noting that there are no studies suggesting that switching to prasugrel or ticagrelor improves outcomes in patients with genetic loss-of-function status.

“The vision that oral antiplatelet therapy dosing needs to be personalized by platelet function or genomic testing has yet to be proven,” he added, noting that bioavailability is influenced by many factors other than CYP2C19.

 

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Source:
Price MJ, Murray SS, Angiolillo DJ, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: The GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol. 2012;59:1928-1937.

 

• Dr. Price reports research grant funding from Accumetrics, Bristol-Myers Squibb/Sanofi-Aventis, and Quest Diagnostics; consulting fees from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, Daiichi Sankyo/Eli Lilly, and Medicure; and lecture fees from AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, Daiichi Sankyo/Eli Lilly, Nanosphere, and Quest Diagnostics.
• Dr. Bates reports serving on advisory boards for AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, and Daiichi-Sankyo/Eli Lilly.

 

Related Stories:

• EXOME: New Genetic Sequencing Zeroes in on Clopidogrel Response Variants
• GRAVITAS Published: No Benefit from High-Dose Clopidogrel in Poor Responders
• Meta-analysis: Data Do Not Support Genotyping for Clopidogrel Response

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