Clopidogrel: CYP2C19, CYP1A2 effects in some post-MI patients
Daniel Zambrano (University of Florida College of Pharmacy PharmD Candidate, Class of 2015)
A recent large study showed associations between both loss-of-function and gain-of-function CYP polymorphisms and poor outcomes post-acute myocardial infarction (MI) in patients treated with clopidogrel, with specific effects varying by population and polymorphism. The loss-of-function CYP2C19*2 allele was associated with increased 1-year mortality and bleeding risk in Caucasian patients; 1-year mortality and bleeding risk were increased in African American patients carrying CYP2C19*17 and CYP1A2*1C polymorphisms.
Clopidogrel is a prodrug that has variable effects, related in part to genetic polymorphisms of the CYP450 enzymes involved in its activation. Clopidogrel acts by inhibiting the platelet P2Y12 adenosine diphosphate receptor after being activated by CYP2C19, CYP1A2, CYP2B6, CYP2C9, and CYP3A5. Genetic variability among these enzymes exists at varied rates among individuals of different races. Additional data are needed regarding clinical implications of this variability in different populations.
Cresci et al retrospectively reviewed data for 1,632 Caucasians and 430 African American patients enrolled in the TRIUMPH study who were discharged on clopidogrel for treatment of acute myocardial infarction. The aim of the current analysis was to evaluate associations among CYP variants and one-year mortality in patients discharged on clopidogrel. Investigators also evaluated associations among previously-reported genetic variants in genes encoding proteins involved in clopidogrel metabolism.
Caucasian patients carrying the CYP2C19*2 loss of function allele had an increase in all-cause mortality compared with patients possessing the *1/*1 allele (adjusted hazard ratio [HR] 1.70; 95% CI 1.01–2.86, p = 0.046). African American patients carrying the CYP2C19*17 gain of function allele had a significant increase in mortality and bleeding events compared with *1/*1 patients (p<0.05 for both *1/*17 vs. *1/*1 and *17*/17 vs. *1/*1 comparisons). Presence of the CYP1A2*1C allele was also associated with significantly increased 1-year mortality and bleeding risk in African American patients. Notably, homozygous CYP2C19*17 and CYP1A2*1C patients had higher risk of mortality and bleeding events than their respective heterozygous patient counterparts.
Study results are notable as this the first large study to investigate associations between genetic variants and outcomes among African American patients taking clopidogrel after acute MI. Previous studies reporting effects of genetic variability with clopidogrel in this patient group have been conducted primarily in Caucasian and Asian population groups.
Current Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide guidance for CYP2C19-guided clopidogrel therapy in patients with acute coronary syndromes undergoing PCI. Within these guidelines, authors acknowledge that conflicting evidence exists surrounding possible effects of variability in the CYP2C19*17 allele, with discordant study results possibly being attributed to linkage disequilibrium between *17 and *2. Guideline authors conclude that evidence of an independent effect of *17 is insufficient to recommend clopidogrel dosage adjustment in patients with variant CYP2C19*1/*17 and CYP2C19 *17/*17 alleles.
Although study results supported a significant association between CYP1A2 variability and outcomes in African American patients, further investigation is needed to better determine effects of CYP1A2 polymorphisms in this and other patient populations. Currently the Pharmacogenomics Knowledgebase (www.pharmgkb.org) provides a clinical annotation for CYP1A2 polymorphism effects on platelet reactivity with clopidogrel (evidence level = 3 [low]).
Consistent with the level of supporting evidence, FDA-approved labeling for clopidogrel currently recommends that clinicians consider alternate treatment strategies in patients with some CYP2C19 (but not CYP1A2) polymorphisms.
Cresci S et al. Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel Treated Patients Following Acute Myocardial Infarction. Circ Cardiovasc Genet. 2014; [Epub ahead of print].