JACC: Plavix adjustment for CYP2C19 gene carriers reduces platelet reactivity

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An increased or adjusted loading dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), depending on platelet reactivity monitoring, can overcome high on-treatment platelet reactivity in patients who carry the CYP2C19 2 polymorphism, and therefore reduce thrombotic risk post-PCI, according to a study published Aug. 11 in the Journal of the American College of Cardiology.

“High on-treatment platelet reactivity (HTPR) after a clopidogrel loading dose has been shown to predict the short- and long-term prognoses in patients undergoing PCI,” the authors wrote. "It has been demonstrated that the level of platelet reactivity inhibition (PRI) after a clopidogrel loading dose strongly correlates with post-PCI outcome, particularly with early stent thrombosis.”

Laurent Bonello, MD, of Hôpital Universitaire Nord in Marseille, France, and colleagues set out to assess a tailored clopidogrel loading dose according to PRI monitoring in carriers of the CYP2C19 2 loss-of-function polymorphism in patients exhibiting high on-treatment platelet reactivity undergoing PCI for acute coronary syndrome.

Bonello et al identified 411 patients undergoing PCI for non-STEMI acute coronary syndrome between January 2009 and January 2010. Patients had a mean age of 62.9 years and 78.1 percent were men.

Patients had a high prevalence of cardiovascular risk factors including 34.8 percent who had diabetes mellitus and 37.5 percent who were smokers.

During the study, all patients were administered an oral loading dose of 600 mg clopidogrel and 250 mg of aspirin at least six hours prior to the first vasodilator-stimulated phosphoprotein (VASP) index, which is used to assess clopidogrel responsiveness.

The researchers drew blood samples and VASP analyses were performed within 24 hours of blood collection using a Platelet VASP kit (Diagnostica Stago). VASP index was measured at least six hours and within 12 hours of the first 600 mg loading dose of clopidogrel.

Researchers considered patients who had a VASP index of less than 50 percent to be good responders and those with VASP indexes greater than or equal to 50 percent to have HTPR.

For patients with HTPR, researchers adjusted dose prior to PCI to obtain VASP index less than 50 percent. For these patients, up to three additional doses of clopidogrel were administered 24 hours after the previous dose and VASP indexes were assessed 12 hours after each dose until an index of 50 percent or less was obtained.

The researchers also collected whole blood genotyping from the arterial sheath of patients.

After a 600 mg loading dose of clopidogrel, VASP index was recorded to be 53.2 ± 23.2 percent. The researchers recorded that 62.5 percent of patients were considered to have HTPR.

Of the 411 patients, 35.3 percent carried at least one loss-of-function CYP2C19 2 allele—2.7 percent were homozygote’s and 32.6 percent were heterozygotes.

VASP indexes in the 134 patients carrying at least one mutant allele was higher than patients who possessed a wild-type allele homozygotes: 61.7 percent versus 49.2 percent, respectively.

Among patients with the CYP2C19 2 allele, 77 percent had a prevalence of HTPR—79 percent for heterozygotes and 54 percent for homozygotes. This number for patients carrying the wild-type genotype was 55.6 percent.

Researchers found that of the 277 patients who carried no loss-of-function alleles, 123 were good responders and 154 had HTPR.

After the additional 600 mg loading doses of clopidogrel were administered to patients who did not have optimal VASP indexes of 50 percent or less, the researchers reported that 90 percent of patients reached a PRI of less than 50 percent and dose adjustment failed in 17 patients.

The 103 patients who carried the CYP2C19 2 allele and who had HTPR underwent a second loading dose of clopidogrel experienced a decrease in VASP indexes after the second bolus injection.

Four patients dropped out of the study. Of the 99 patients remaining who carried at least one mutant allele and exhibiting HTPR, 88 percent reached a platelet reactivity of 50 percent or less after three additional doses of clopidogrel. Twelve patients failed to reach the optimal PRI levels even after 2,400 mg of clopidogrel in four days—one homozygotic and 11 heterozygotic.

The researchers conducted a multivariate analysis during the study and found that BMI was an independent predictor of failed dose adjustment.

The researchers reported two thrombotic events—one incidence of stroke and one subacute stent thrombosis—and four occurrences of minor thrombolysis in MI non-CABG bleeding.

“The present study is the first to demonstrate that, despite having reduced clopidogrel metabolism, most carriers of the loss-of-function CYP2C19 2 polymorphism can reach optimal PRI using a strategy of tailored loading dose according to PRI monitoring,” the authors wrote. “These data reinforce the potential of PRI monitoring to improve the outcome of patients undergoing PCI for an acute coronary syndrome.”

The FDA recently placed a black box warning on clopidogrel after it was reported that some patients may have an inability to metabolize the drug because of the CYP2C19 2 gene. However, researchers said, “Our study demonstrates that higher or tailored loading doses may be used in these selected patients to enable optimal PRI to be achieved in both homozygote’s and heterozygote’s for the loss-of-function polymorphism.

“The results of the present study suggest that the genetic polymorphism is not required to enable optimal PRI to be reached in patients exhibiting HTPR because a dose-adjustment strategy according to platelet reactivity monitoring is efficient regardless of genetic status,” the authors concluded.