Amlodipine, clopidogrel and CYP3A5 genetic variability: effects on platelet reactivity and clinical outcomes after percutaneous coronary intervention.
OBJECTIVE
To test the effect of a loss-of-function variation of the cytochrome P450 (CYP) 3A5 on drug-drug interaction between amlodipine and clopidogrel. Amlodipine is a well-known inhibitor of CYP 3A4, an isoenzyme of CYP3A that activates clopidogrel. However, controversy exists regarding whether amlodipine adversely affects clopidogrel response and clinical outcome after percutaneous coronary intervention (PCI). In the presence of CYP3A4 inhibitors such as amlodipine, the genetic variation of CYP3A5, the isoenzyme responsible for the backup CYP3A activity, may play an important role in clopidogrel activation.


METHODS
Post hoc analysis of a prospectively enrolled cohort.


METHODS
Patients enrolled in the CROSS-VERIFY cohort from June 2006 to June 2010, with successful genotyping of CYP3A5.


METHODS
The pharmacodynamic analysis end point was clopidogrel on-treatment platelet reactivity (OPR) and the clinical analysis end point was the composite of cardiac death, non-fatal myocardial infarction, ischaemic stroke and stent thrombosis at 12 months post-PCI.


RESULTS
1258 patients had successful genotyping and were categorised as CYP3A5 non-expressers (749 patients) and expressers (509 patients) according to the CYP3A5 genotype. Amlodipine users showed higher OPR versus non-users only in CYP3A5 non-expressers (249 ± 83 vs 228 ± 84 P2Y12 reaction units, p=0.013). These findings was corroborated by clinical outcomes, in which amlodipine users had a higher incidence of events compared with non-users only in CYP3A5 non-expressers (4.6% vs 0.6%, HR 7.731, CI 2.042 to 29.264, p=0.004).


CONCLUSIONS
Treatment with amlodipine is associated with increased clopidogrel OPR and increased risk of thrombotic events after PCI, which is dependent on the CYP3A5 genetic status.
Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Korea.
Kyung Woo
KW
Park
Jeehoon
J
Kang
Jin Joo
JJ
Park
Han-Mo
HM
Yang
Hae-Young
HY
Lee
Hyun-Jae
HJ
Kang
Bon-Kwon
BK
Koo
Byung-Hee
BH
Oh
Young-Bae
YB
Park
Hyo-Soo
HS
Kim
D000368:Aged; D017311:Amlodipine / Q000494:pharmacology*; D015906:Angioplasty, Balloon, Coronary; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D005260:Female; D006083:Graft Occlusion, Vascular / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D020521:Stroke / Q000209:etiology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D017311:Amlodipine; D000077144:Clopidogrel; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine