Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype.

Abstract

OBJECTIVES:

The aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to hepatic cytochrome P450 2C19 (CYP2C19) genotype.

BACKGROUND:

Although adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can be free from the effect of CYP2C19 loss-of-function variants (*2/*3).

METHODS:

We randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150 mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California), platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (ΔAgg(max)) between pre-discharge and 30-day follow-up. High on-treatment platelet reactivity (HPR) was defined as 20 μmol/l adenosine diphosphate-induced maximal platelet aggregation (Agg(max)) >59%.

RESULTS:

In noncarriers, despite numerically greater inhibition by adjunctive cilostazol, changes in platelet measures and the rate of HPR did not significantly differ between the 2 groups. In carriers, ΔAgg(max) after 5 and 20 μmol/l adenosine diphosphate stimuli was significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p < 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p < 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple versus high-MD group. Fewer patients in the triple group met the criteria of HPR at 30-day follow-up than in the high-MD group (15.4% vs. 44.7%, p = 0.005).

CONCLUSIONS:

Compared with high-MD clopidogrel, adjunctive cilostazol significantly enhances platelet inhibition and reduces the rate of HPR, especially in AMI patients with CYP2C19 loss-of-function variants. (Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733).

• Authors: In-Suk Kim, Young-Hoon Jeong, Yongwhi Park, Ki-Soo Park, Seong-Eun Yun, Jeong-Rang Park, Seok-Jae Hwang, Eun-Ha Koh, Choong Hwan Kwak, Jin-Yong Hwang, Sunjoo Kim
• Journal: JACC. Cardiovascular interventions (JACC Cardiovasc Interv) Vol. 4 Issue 4 Pg. 381-91 (Apr 2011) ISSN: 1876-7605 [Electronic] United States
• PMID: 21511217 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Platelet Aggregation Inhibitors
• Tetrazoles
• Adenosine Diphosphate
• Clopidogrel
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Cilostazol
• Ticlopidine
• Aspirin

Topics

• Adenosine Diphosphate
• Aged
• Angioplasty, Balloon, Coronary (adverse effects)
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Aspirin (administration & dosage)
• Chi-Square Distribution
• Cilostazol
• Clopidogrel
• Cytochrome P-450 CYP2C19
• Drug Therapy, Combination
• Female
• Genotype
• Humans
• Korea
• Liver (enzymology)
• Male
• Middle Aged
• Myocardial Infarction (blood, therapy)
• Phenotype
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Platelet Function Tests
• Predictive Value of Tests
• Regression Analysis
• Risk Assessment
• Risk Factors
• Tetrazoles (administration & dosage, adverse effects, pharmacokinetics)
• Thrombosis (blood, etiology, prevention & control)
• Ticlopidine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Treatment Outcome