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

• Published in: JAMA : the journal of the American Medical Association Vol. 306; no. 20; pp. 2221 - 2228
• Main Authors: Mega, Jessica L, Hochholzer, Willibald, Frelinger, Andrew L, Kluk, Michael J, Angiolillo, Dominick J, Kereiakes, Dean J, Isserman, Steven, Rogers, William J, Ruff, Christian T, Contant, Charles, Pencina, Michael J, Scirica, Benjamin M, Longtine, Janina A, Michelson, Alan D, Sabatine, Marc S
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 23.11.2011
• Subjects: Aged; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Blood clots; Cardiovascular disease; Cardiovascular Diseases - drug therapy; Cytochrome P-450 CYP2C19; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Female; General aspects; Genotype; Genotype & phenotype; Heterozygote; Homozygote; Humans; Male; Medical sciences; Middle Aged; Patients; Pharmacogenetics; Platelet Activation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacology; Platelet Function Tests; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Treatment Outcome; Human; Typing; Genotype; Patient; Cardiovascular disease; Posology; Antiplatelet agent; Medicine; Platelet; Reactivity; Antithrombotic agent; Clopidogrel; Thienopyridine derivative
• ISSN: 0098-7484; 1538-3598; 1538-3598
• DOI: 10.1001/jama.2011.1703

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 P2Y12 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 P2Y12 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