Raising Clopidogrel Dosage For Patients With Genetic Variation Improves Drug Response

Editor's Choice
Academic Journal
Main Category: Genetics
Article Date: 16 Nov 2011 - 5:00 PST

 

According to an investigation in JAMA, tripling the standard daily dosage of the antiplatelet drug clopidogrel among individuals with stable cardiovascular disease who have a genetic variation that reduces the response to the drug, resulted in improved platelet reactivity. The study is being released online early in order to accompany its presentation at the American Heart Association Scientific Sessions.

Background data in the study reveals that:

"Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel.

Variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with higher platelet reactivity while receiving clopidogrel are at increased risk of adverse cardiovascular events ... data are needed to offer guidance as to what might constitute optimal treatment strategies in patients with loss-of-function CYP2C19 alleles [an alternative form of a gene]."

Jessica L. Mega, M.D., M.P.H., and Marc S. Sabatine, M.D., M.P.H., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues carried out a multicenter, randomized trial (ELEVATE-TIMI 56) in order to assess if clopidogrel maintenance doses of up to 300 mg daily can enhance platelet reactivity in the setting of loss-of-function CYP2C19 genotypes, especially among individuals who carry one copy of a variant gene (heterozygotes), who depending on racial background make up for around 25 to 45% of the population. 333 individuals with cardiovascular disease were enrolled and genotyped across 32 sites from Oct. 2010 to Sept. 2011.

Based on genotype, participants received maintenance doses of the drug for four treatment periods (each lasting about 14 days). 247 individuals who did not carry CYP2C19*2 loss-of-function allele were randomly assigned to receive either 75 mg or 150 mg daily of clopidogrel (2 periods each), while 86 carriers (80 heterozygotes, 6 homozygotes [having two copies of the variant gene]) were randomly assigned to receive either 75 mg, 150 mg, 225 mg, and 300 mg daily. The researchers used two different techniques to measure platelet function. In the trial:

• 75% of participants were male
• 60 years was the average age of participants
• 97% of patients had a history of percutaneous coronary intervention (procedures such as stent placement of balloon angioplasty used to open narrow coronary arteries)
• 57% of participants had a history of heart attack.

The researchers discovered that higher maintenance doses of clopidogrel in participants carrying a CYP2C19*2 allele considerably reduced platelet reactivity. In addition, they found that daily doses of 225 mg or greater of clopidogrel in CYP2C19*2 heterozygotes enhanced platelet reactivity levels that were at least the same to what is achieved in noncarrier individuals with cardiovascular disease with 75 mg daily of clopidogrel. When the researchers assessed CYP2C19*2 homozygotes, they saw a trend toward less platelet reactivity with higher doses of the drug, although these individuals were not likely to achieve optimal degrees of platelet inhibition even with 300 mg daily of clopidogrel.

The researchers conclude:

"These data help define how patients with different CYP2C19 genotypes respond to clopidogrel maintenance dosing strategies and provides useful information to guide further clinical studies."

Written by Grace Rattue
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Raising Clopidogrel Dosage For Patients With Genetic Variation Improves Drug Response