Clopidogrel Dosing Based on Genotype: What Difference Does It Make?

In patients heterozygous for the CYP2C19*2 allele, higher doses significantly reduced platelet reactivity, but whether genotype-guided dosing improves outcomes remains unknown.


Genetic variation in liver cytochrome PY450 enzymes affects individuals' pharmacologic and clinical response to clopidogrel. However, no effective treatment strategy for poor metabolizers of clopidogrel has yet been validated in clinical trials. To assess the effects of escalating doses of clopidogrel on platelet reactivity according to CYP2C19 genotype, investigators conducted an industry-funded trial in 333 patients (mean age, 60; 75% men) with stable coronary artery disease. Fifty-seven percent of patients had a history of myocardial infarction, and 97% had undergone percutaneous coronary intervention.

After genotyping and platelet function testing, participants were allocated to a sequence of maintenance clopidogrel doses for four 2-week treatment periods. Carriers of a loss-of-function CPY2C19 allele (CYP2C19*2) received doses of 75, 100, 225, and 300 mg daily; noncarriers received two cycles each of 75 and 150 mg daily. Platelet reactivity and clinical events were ascertained at the end of each treatment period.

A total of 86 patients were CYP2C19*2 carriers (80 heterozygotes, 6 homozygotes). Platelet reactivity at 75 mg of clopidogrel was significantly higher in CYP2C19*2 heterozygotes and homozygotes than in noncarriers. In heterozygotes, each 75-mg dose increase resulted in a significant absolute reduction in platelet reactivity of approximately 8% to 9%. A platelet reactivity level similar to that of noncarriers at 75 mg was achieved in heterozygotes at a dose of 225 mg. In CYP2C19*2 homozygotes, platelet reactivity trended lower with higher maintenance doses but remained higher than baseline reactivity in noncarriers at all doses. Rates of ischemic and bleeding events were low and similar between the two groups, and no other serious clinical adverse events occurred.


Citation(s):

Mega JL et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011 Nov 23/30; 306:2221.