Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.
BACKGROUND
Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals.


METHODS
We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites.


RESULTS
In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively.


CONCLUSIONS
Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel.


BACKGROUND
Daiichi Sankyo Company Ltd and Eli Lilly and Company.
Mega
Jessica L
JL
TIMI Study Group, Cardiovascular Division, 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
Walker
Joseph R
JR
Simon
Tabassome
T
Antman
Elliott M
EM
Braunwald
Eugene
E
Sabatine
Marc S
MS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics*; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000209:etiology; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D000068799:Prasugrel Hydrochloride; D016032:Randomized Controlled Trials as Topic; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
N Engl J Med. 2009 Jan 22;360(4):363-75
19106083
Science. 2007 Jan 26;315(5811):525-8
17185560
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8
10716719
Blood. 2006 Oct 1;108(7):2244-7
16772608
Lancet. 2009 Jan 24;373(9660):309-17
19108880
Am Heart J. 2006 Oct;152(4):627-35
16996826
N Engl J Med. 2007 Nov 15;357(20):2001-15
17982182
Eur Heart J. 2009 Apr;30(8):916-22
19193675
Pharmacogenomics. 2007 Mar;8(3):293-305
17324118
J Am Coll Cardiol. 2007 Aug 14;50(7):e1-e157
17692738
J Thromb Haemost. 2007 Oct;5(10):2153-5
17697139
Circulation. 2007 Dec 18;116(25):2923-32
18056526
Circulation. 2003 Jun 17;107(23):2908-13
12796140
Am J Cardiol. 2009 Mar 15;103(6):806-11
19268736
J Am Coll Cardiol. 2006 Nov 7;48(9):1742-50
17084243
J Am Coll Cardiol. 2008 May 20;51(20):1925-34
18482659
N Engl J Med. 2009 Jan 22;360(4):354-62
19106084
Circulation. 2009 Dec 1;120(22):2271-306
19923169
Circulation. 2009 May 19;119(19):2553-60
19414633
Clin Pharmacol Ther. 2002 Apr;71(4):297-303
11956513
Curr Drug Metab. 2008 Oct;9(8):738-84
18855611
J Thromb Haemost. 2007 Dec;5(12):2429-36
17900275
Rapid Commun Mass Spectrom. 2007;21(2):169-79
17154350
Clin Pharmacol Ther. 2006 Nov;80(5):486-501
17112805
Lancet. 2008 Apr 19;371(9621):1353-63
18377975
JACC Cardiovasc Interv. 2008 Dec;1(6):620-7
19463375
JAMA. 2009 Aug 26;302(8):849-57
19706858
Biol Pharm Bull. 2002 Oct;25(10):1356-9
12392094