Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease

Study Questions:

What is the effect of higher doses (up to 300 mg daily) of clopidogrel on response in the setting of loss of function CYP2C19 genotype?


ELEVATE-TIMI 56 was a multicenter, randomized, double-blind trial that enrolled and genotyped 333 patients with cardiovascular disease across 32 sites. Maintenance doses of clopidogrel for four treatment periods, each lasting approximately 14 days, were based on genotype. In total, 247 noncarriers of CYP2C19*2 loss of function allele were to receive 75 mg and 150 mg of clopidogrel daily (two periods each), whereas 86 carriers (80 heterozygotes, 6 homozygotes) were to receive 75, 150, 225, and 300 mg daily. The main outcome measures were platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y12 assays) and adverse events.


With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% confidence interval [CI], 66.0%-74.0%, vs. 57.5%; 95% CI, 55.1%-59.9%, and VerifyNow P2Y12 reaction unit [PRU]: mean 225.6; 95% CI, 207.7-243.4, vs. 163.6; 95% CI, 154.4-173.9; p < 0.001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity with VASP PRI decreasing to 48.9% (95% CI, 44.6%-53.2%) and PRU to 127.5 (95% CI, 109.9-145.2) (p < 0.001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (≥230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 mg or 300 mg (p < 0.001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04). In CYP2C19*2 homozygotes, even with 300 mg of daily clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) and mean PRU, 287.0 (95% CI, 170.2-403.8).


The authors concluded that among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with 75 mg in noncarriers, but doses up to 300 mg in CYP2C19*2 homozygotes did not result in a comparable degree of platelet inhibition.


This study suggests that daily maintenance of 225 mg of clopidogrel or greater in CYP2C19*2 heterozygotes can achieve platelet reactivity comparable to that achieved with 75 mg in noncarriers with cardiovascular disease. However, even 300 mg of daily clopidogrel did not result in a comparable degree of platelet inhibition in CYP2C19*2 homozygotes. Further studies are indicated to ascertain whether these higher doses of clopidogrel do in fact translate into better clinical outcomes in CYP2C19*2 heterozygotes.

Keywords: Platelet Aggregation Inhibitors, Platelet Function Tests, Homozygote, Heterozygote, Genotype

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