Cytochrome P-450 Polymorphisms and Response to Clopidogrel

• Published in: The New England journal of medicine Vol. 360; no. 4; pp. 354 - 362
• Main Authors: Mega, Jessica L, Close, Sandra L, Wiviott, Stephen D, Shen, Lei, Hockett, Richard D, Brandt, John T, Walker, Joseph R, Antman, Elliott M, Macias, William, Braunwald, Eugene, Sabatine, Marc S
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 22.01.2009
• Subjects: Acute Coronary Syndrome - therapy; Adult; Angioplasty, Balloon, Coronary; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Cardiovascular disease; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Combined Modality Therapy; Cytochrome P-450 CYP2C19; Drug therapy; Female; General aspects; Genotype; Heart attacks; Heterozygote; Humans; Male; Medical sciences; Mutation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - metabolism; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Stents; Studies; Thrombosis - epidemiology; Thrombosis - genetics; Ticlopidine - adverse effects; Ticlopidine - analogs & derivatives; Ticlopidine - metabolism; Ticlopidine - pharmacology; Ticlopidine - therapeutic use; Medicine; Genetic variability; Enzyme; Cytochrome P450; Antithrombotic agent; Clopidogrel; Genotype; Thienopyridine derivative; Antiplatelet agent; Polymorphism
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa0809171

The antiplatelet drug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes. This study shows that CYP polymorphisms that reduce clopidogrel activation result in reduced antiplatelet effect and less clinical benefit in patients with acute coronary syndromes. The antiplatelet drug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes. This study shows that CYP polymorphisms that reduce clopidogrel activation result in reduced antiplatelet effect and less clinical benefit in patients with acute coronary syndromes. Across the spectrum of acute coronary syndromes and in patients undergoing percutaneous coronary interventions (PCI) with stenting, dual antiplatelet therapy with aspirin and clopidogrel, a thienopyridine inhibitor of the platelet P2Y 12 adenosine diphosphate (ADP) receptor, is the standard of care. 1 – 3 However, the pharmacodynamic response to clopidogrel has substantial interpatient variability, 4 – 6 and patients with coronary disease with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for cardiovascular events. 7 – 10 Clopidogrel is a prodrug that requires biotransformation to an active metabolite by cytochrome P-450 (CYP) enzymes (Figure 1 in the Supplementary Appendix, available . . .