CONTEXT: Variants in the CYP2C19 gene influence the pharmacologic and clinical 
response to the standard 75-mg daily maintenance dose of the antiplatelet drug 
clopidogrel.
OBJECTIVE: To test whether higher doses (up to 300 mg daily) improve the 
response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes.
DESIGN, SETTING, AND PATIENTS: ELEVATE-TIMI 56 was a multicenter, randomized, 
double-blind trial that enrolled and genotyped 333 patients with cardiovascular 
disease across 32 sites from October 2010 until September 2011.
INTERVENTIONS: Maintenance doses of clopidogrel for 4 treatment periods, each 
lasting approximately 14 days, based on genotype. In total, 247 noncarriers of a 
CYP2C19*2 loss-of-function allele were to receive 75 and 150 mg daily of 
clopidogrel (2 periods each), whereas 86 carriers (80 heterozygotes, 6 
homozygotes) were to receive 75, 150, 225, and 300 mg daily.
MAIN OUTCOME MEASURES: Platelet function test results (vasodilator-stimulated 
phosphoprotein [VASP] phosphorylation and VerifyNow P2Y(12) assays) and adverse 
events.
RESULTS: 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% CI, 66.0%-74.0%, vs 57.5%; 95% CI, 55.1%-59.9%, 
and VerifyNow P2Y(12) reaction units [PRU]: mean, 225.6; 95% CI, 207.7-243.4, vs 
163.6; 95% CI, 154.4-173.9; P < .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 < .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 or 300 mg (P < .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 daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) 
and mean PRU, 287.0 (95% CI, 170.2-403.8).
CONCLUSION: 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 the standard 
75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high 
as 300 mg daily did not result in comparable degrees of platelet inhibition.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01235351.