Cytochrome p-450 polymorphisms and response to clopidogrel.
BACKGROUND
Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function.


METHODS
We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.


RESULTS
In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02).


CONCLUSIONS
Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Mega
Jessica L
JL
Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. jmega@partners.org
Close
Sandra L
SL
Wiviott
Stephen D
SD
Shen
Lei
L
Hockett
Richard D
RD
Brandt
John T
JT
Walker
Joseph R
JR
Antman
Elliott M
EM
Macias
William
W
Braunwald
Eugene
E
Sabatine
Marc S
MS
D054058:Acute Coronary Syndrome / Q000628:therapy*; D000328:Adult; D015906:Angioplasty, Balloon, Coronary; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D000077144:Clopidogrel; D003131:Combined Modality Therapy; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D015607:Stents; D013927:Thrombosis / Q000453:epidemiology / Q000235:genetics; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine