CYP2C19*2 Carriers Do Not Respond to High-Dose Clopidogrel

April 06, 2011

April 6, 2011 (New Orleans, Louisiana) — Results from the genetic substudy of the GRAVITAS trial have shown that genetic information on clopidogrel metabolism status can give some useful information about guiding treatment strategies in patients who have already undergone platelet-function testing, according to lead investigator Dr Matthew Price (Scripps Clinic, La Jolla, CA).

The GRAVITAS trial, reported at the American Heart Association meeting last November, showed no benefit on clinical outcomes of double-dose clopidogrel (150 mg) in patients with high on-treatment platelet reactivity after PCI. The genetic substudy, the Genotype Information and Functional Testing (GIFT), was presented by Price today at the American College of Cardiology 2011 Scientific Sessions.

Lower Achieved Platelet Reactivity Linked to Better Clinical Outcome

Dr Matthew Price

Price noted that a post hoc analysis looking at how platelet function in the GRAVITAS trial related to clinical outcomes suggests that achievement of a platelet reactivity of below 208 platelet reactivity units (PRU) appears to have been associated with a better clinical outcome. He said that the full analysis of these data has been submitted for publication and presentation at an upcoming academic meeting. 

The main genetic results focus on the relationship between genetic markers and platelet reactivity achieved in trial, although some limited clinical-outcome data were also presented. Price noted that this is the first study to look at how genotype information can complement platelet-function testing. But he added that in order for more centers to start using genetic tests, a rapid genotyping assay is needed.

GIFT involved testing 1152 blood samples obtained at platelet-function screening or during follow-up for 40 polymorphisms, including CYP2C19*2, *3, *4, *5, *6, *7, *8, and *17; ABCB1; and the recently discovered PON1.

The main findings show that patients with either one or two CYP2C19 loss-of-function alleles (*2) do not generally respond to double-dose clopidogrel. "We found an 11-fold increased risk of having persistently high platelet reactivity at 30 days in patients homozygous for the CYP2C19*2 gene compared with patients with the wild-type gene and a 62% increase in those with one copy of this loss-of-function gene. So if you want a good pharmacodynamic response in patients not responding to standard-dose clopidogrel, then 150 mg is not likely to work in carriers of the *2 gene," Price told heartwire . "This adds important incremental information."

He pointed out that this argues against the recommendation in the boxed warning on the clopidogrel label about poor metabolizers, which suggests clopidogrel 150 mg as a potential option for these patients. "That recommendation was based on a pharmacokinetic/pharmacodynamic study involving just 10 patients. Our study shows this not a good strategy for carriers of the CYP2C19*2 alleles, and the FDA needs to reconsider its advice on this issue," he said.

 

Odds Ratio (95% CI) for Platelet Reactivity Above 230 PRU at 30 Days According to CYP2C19*2 Carrier Status

Group Clopidogrel 150 mg Clopidogrel 75 mg
No loss-of-function allele 1.0 1.0
1 loss-of-function allele 1.62 (0.93–2.85) 2.67 (1.48–4.82)
2 loss-of-function alleles 11.20 (2.02–62.09) 10.55 (1.19–93.57)

 

Price also reported an analysis of how CYP2C19*2 carrier status related to clinical outcomes, suggesting a worse clinical outcome in patients homozygous for the loss-of-function gene. However, this analysis only included 14 events, and Price stressed it must be interpreted with "extreme caution."

Adjusted Hazard Ratios for CV Death, MI, or Stent Thrombosis According to CYP2C19 Genotype

Group HR (95% CI)
No loss-of-function allele 1.0
1 loss-of-function allele 1.07 (0.91–1.25)
2 loss-of-function alleles 1.67 (1.09–2.56)

No Association of PON1

In contrast to the CYP2C19*2 results, the genetic substudy of GRAVITAS did not find any association of PON1 gene status on platelet reactivity on clopidogrel at screening after PCI or at 30-day follow-up or on the change in platelet reactivity with high-dose clopidogrel in patients with high on-treatment reactivity at baseline.

The study also did not find any association of the CYP2C19*17 gain-of-function gene with significantly lower on treatment reactivity after PCI or an enhanced response to 150-mg clopidogrel.

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