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Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

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ABSTRACT

The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19*2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE.

No MeSH data available.


MACE-free survival in patients stratified by CYP2C19 metabolizer status. (A) EM vs. IM vs. PM; (B) EM vs. IM+PM. Differences were compared using the log-rank test.
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Figure 4: MACE-free survival in patients stratified by CYP2C19 metabolizer status. (A) EM vs. IM vs. PM; (B) EM vs. IM+PM. Differences were compared using the log-rank test.

Mentions: One-year follow-up was completed in 559 patients. The total clinical outcomes are shown in Figure 3. During the follow-up period, 69 patients (13.3%) experienced adverse cardiovascular events (1 cardiac death, 9 myocardial infarction and 59 unstable angina). The total frequency of MACE was different among EM, IM and PM patient groups (7.8% vs. 17.8% vs. 11.8%, P = 0.009). The frequency of unstable angina differed among EM, IM and PM patients (6.6% vs. 15.4% vs. 9.8%, P = 0.014). We observed a strong trend toward higher frequency of unstable angina and MACE in IM patients, compared to PM patients. Comparison of the total frequencies of MACE and unstable angina in EM and IM+PM groups additionally revealed significant differences (Table 3). MACE-free survival was further analyzed in patients groups stratified by CYP2C19 metabolizer status. As shown in Figure 4, CYP2C19 EM patients exhibited significantly lower rates of MACE, compared with patients in the IM, PM, and combined IM+PM groups.


Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention
MACE-free survival in patients stratified by CYP2C19 metabolizer status. (A) EM vs. IM vs. PM; (B) EM vs. IM+PM. Differences were compared using the log-rank test.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: MACE-free survival in patients stratified by CYP2C19 metabolizer status. (A) EM vs. IM vs. PM; (B) EM vs. IM+PM. Differences were compared using the log-rank test.
Mentions: One-year follow-up was completed in 559 patients. The total clinical outcomes are shown in Figure 3. During the follow-up period, 69 patients (13.3%) experienced adverse cardiovascular events (1 cardiac death, 9 myocardial infarction and 59 unstable angina). The total frequency of MACE was different among EM, IM and PM patient groups (7.8% vs. 17.8% vs. 11.8%, P = 0.009). The frequency of unstable angina differed among EM, IM and PM patients (6.6% vs. 15.4% vs. 9.8%, P = 0.014). We observed a strong trend toward higher frequency of unstable angina and MACE in IM patients, compared to PM patients. Comparison of the total frequencies of MACE and unstable angina in EM and IM+PM groups additionally revealed significant differences (Table 3). MACE-free survival was further analyzed in patients groups stratified by CYP2C19 metabolizer status. As shown in Figure 4, CYP2C19 EM patients exhibited significantly lower rates of MACE, compared with patients in the IM, PM, and combined IM+PM groups.

View Article: PubMed Central - PubMed

ABSTRACT

The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19*2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE.

No MeSH data available.