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

[+] Author Affiliations

Author Affiliations: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Drs Mega, Ruff, Scirica, and Sabatine); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (Dr Hochholzer); Center for Platelet Research Studies, Children's Hospital Boston, Boston (Drs Frelinger and Michelson); Center for Advanced Molecular Diagnostics, Department of Pathology, Brigham and Women's Hospital, Boston (Drs Kluk and Longtine); University of Florida College of Medicine, Jacksonville (Dr Angiolillo); Heart and Vascular Center and Lindner Research, The Christ Hospital, Cincinnati, Ohio (Dr Kereiakes); Clinical Trials of America, Hickory, North Carolina (Dr Isserman); University of Alabama at Birmingham Medical Center (Dr Rogers); TIMI Study Group, Boston (Dr Contant); and Harvard Clinical Research Institute and Boston University, Boston (Dr Pencina).

Abstract

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

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