Angiotensin-Converting Enzyme Inhibitors' Influence on Antiplatelet Therapy of Clopidogrel in ACS.
BACKGROUND
Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel.


METHODS
We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay.


RESULTS
It showed that the allele frequency of CES1 c.428A was 0% in these patients. 45.22% (227/502) of these patients were carriers of CYP2C19*2 or CYP2C9*3 loss-of-function alleles. Among them, 57.71% (131/227) of the patients with CYP2C19 variants received ACEIs therapy. In a total of 502 patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between the ACEIs group and non-ACEIs group [56.26 ± 14.55% versus 57.76 ± 13.56%, p = 0.241; 0 (0 - 2) Ω vs. 0 (0 - 2) Ω, p = 0.856]. In the CYP2C19 variant patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between ACEIs group and non-ACEIs group [57.24 ± 15.12% versus 58.07 ± 13.90%, p = 0.667; 0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.536]. In the subgroups of ACS patients (unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction), there was no difference in the VASP-PRI between the ACEIs group and non-ACEIs group [55.81 ± 15.24% versus 58.37 ± 13.31%, p = 0.103; 55.76 ± 15.20% versus 49.09 ± 15.22%, p = 0.098; 58.13 ± 11.48% versus 61.87 ± 10.34%, p = 0.221], and there was no difference in the impedance whole blood platelet aggregation assay between ACEIs group and non-ACEIs group [0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.936; 0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.625; 0 (0 - 1.25) Ω versus 0 (0 - 1.5) Ω, p = 0.788].


CONCLUSIONS
In our study, when ACEIs were used with clopidogrel, platelet response to clopidogrel was not affected. These findings suggest that the drug interaction between clopidogrel and ACEI is of little relevance in platelet function.
Shuo
S
Yang
Chanjuan
C
Cui
Jie
J
Zhang
Rui
R
Qiao
D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D000077144:Clopidogrel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D013988:Ticlopidine