CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia

Jenkuang Lee, Naichen Cheng, Haochih Tai, Jyhming Jimmy Juang, Chokai Wu, Lianyu Lin, Jueyjen Hwang, Jiunn-Lee Lin, Futien Chiang, Chiati Tsai

Research output: Contribution to journalArticle

Abstract

Objective: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form. This study evaluated the association between the CYP 2C19 genetic polymorphism and clinical outcomes in patients with critical limb ischaemia (CLI) taking clopidogrel after endovascular therapy (EVT). Methods: This was a retrospective study. Patients with CLI who had undergone EVT between August 2014 and January 2017 were included. The study subjects were divided into three groups according to the loss of function (LOF) CYP2C19 alleles: (1) extensive metaboliser (EM); (2) intermediate metaboliser (IM); and (3) poor metaboliser (PM). All patients underwent a platelet function test (VerifyNow). Amputation free survival and all cause mortality were estimated using the Kaplan–Meier method. The association between baseline characteristics and clinical outcomes was assessed with the Cox proportional hazard model. Results: A total of 278 CLI patients (EM: 153, IM: 79, PM: 46) who underwent EVT were included. There were 180/278 (64.7%, EM: 107, IM: 45, PM: 28) patients who completed the 12 month follow up examination. Carriers of at least one CYP2C19 LOF allele (44.9%, 125/278) had diminished pharmacodynamic responses to clopidogrel as measured using VerifyNow (174 ± 27 platelet reactivity units (PRU), 216 ± 21 PRU, and 245 ± 35 PRU for patients with EM, IM, and PM CYP2C19 profiles, respectively; EM vs. IM, p < .0001 and EM vs. PM, p < .0001). The estimated amputation free 12 month survival rates were EM 82.1%, IM 66.1.0%, and PM 56.6% with significant differences between groups (log-rank test p = .0006, p for trend <.0001). The estimated all cause 12 month mortality rates were EM 83.7%, IM 72.2%, and PM 71.3% (log rank test p = .01, p for trend p = .007). The combined group consisting of IM and PM was associated with amputation free survival and all cause mortality based on a univariable analysis (hazard ratio [HR] = 2.23 [1.97–2.46], p = .011; HR = 1.43 [1.05–1.85], p = .043) and remained significant in a multivariable Cox analysis (HR = 2.65 [2.1–2.9], p = .009; HR = 1.39 [1.07–1.74], p = .037). Conclusion: CYP2C19 genetic profiles can significantly influence clinical outcomes (in both amputation free survival and all cause mortality) in CLI patients who are taking only clopidogrel after EVT.

Original languageEnglish
Pages (from-to)373-382
Number of pages10
JournalEuropean Journal of Vascular and Endovascular Surgery
Volume58
Issue number3
DOIs
Publication statusPublished - Sep 1 2019

Fingerprint

clopidogrel
Amputation
Ischemia
Extremities
Cytochrome P-450 Enzyme System
Blood Platelets
Mortality
Survival
Platelet Function Tests
Alleles
Prodrugs
Genetic Polymorphisms
Therapeutics
Cytochrome P-450 CYP2C19
Proportional Hazards Models

Keywords

  • Antiplatelet drug resistance
  • Antiplatelet therapy
  • Clopidogrel
  • CYP2C19 polymorphisms
  • Peripheral artery disease

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia. / Lee, Jenkuang; Cheng, Naichen; Tai, Haochih; Jimmy Juang, Jyhming; Wu, Chokai; Lin, Lianyu; Hwang, Jueyjen; Lin, Jiunn-Lee; Chiang, Futien; Tsai, Chiati.

In: European Journal of Vascular and Endovascular Surgery, Vol. 58, No. 3, 01.09.2019, p. 373-382.

Research output: Contribution to journalArticle

Lee, Jenkuang ; Cheng, Naichen ; Tai, Haochih ; Jimmy Juang, Jyhming ; Wu, Chokai ; Lin, Lianyu ; Hwang, Jueyjen ; Lin, Jiunn-Lee ; Chiang, Futien ; Tsai, Chiati. / CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia. In: European Journal of Vascular and Endovascular Surgery. 2019 ; Vol. 58, No. 3. pp. 373-382.
@article{3bd05cbdb3684c95b455f5fad617aee2,
title = "CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia",
abstract = "Objective: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form. This study evaluated the association between the CYP 2C19 genetic polymorphism and clinical outcomes in patients with critical limb ischaemia (CLI) taking clopidogrel after endovascular therapy (EVT). Methods: This was a retrospective study. Patients with CLI who had undergone EVT between August 2014 and January 2017 were included. The study subjects were divided into three groups according to the loss of function (LOF) CYP2C19 alleles: (1) extensive metaboliser (EM); (2) intermediate metaboliser (IM); and (3) poor metaboliser (PM). All patients underwent a platelet function test (VerifyNow). Amputation free survival and all cause mortality were estimated using the Kaplan–Meier method. The association between baseline characteristics and clinical outcomes was assessed with the Cox proportional hazard model. Results: A total of 278 CLI patients (EM: 153, IM: 79, PM: 46) who underwent EVT were included. There were 180/278 (64.7{\%}, EM: 107, IM: 45, PM: 28) patients who completed the 12 month follow up examination. Carriers of at least one CYP2C19 LOF allele (44.9{\%}, 125/278) had diminished pharmacodynamic responses to clopidogrel as measured using VerifyNow (174 ± 27 platelet reactivity units (PRU), 216 ± 21 PRU, and 245 ± 35 PRU for patients with EM, IM, and PM CYP2C19 profiles, respectively; EM vs. IM, p < .0001 and EM vs. PM, p < .0001). The estimated amputation free 12 month survival rates were EM 82.1{\%}, IM 66.1.0{\%}, and PM 56.6{\%} with significant differences between groups (log-rank test p = .0006, p for trend <.0001). The estimated all cause 12 month mortality rates were EM 83.7{\%}, IM 72.2{\%}, and PM 71.3{\%} (log rank test p = .01, p for trend p = .007). The combined group consisting of IM and PM was associated with amputation free survival and all cause mortality based on a univariable analysis (hazard ratio [HR] = 2.23 [1.97–2.46], p = .011; HR = 1.43 [1.05–1.85], p = .043) and remained significant in a multivariable Cox analysis (HR = 2.65 [2.1–2.9], p = .009; HR = 1.39 [1.07–1.74], p = .037). Conclusion: CYP2C19 genetic profiles can significantly influence clinical outcomes (in both amputation free survival and all cause mortality) in CLI patients who are taking only clopidogrel after EVT.",
keywords = "Antiplatelet drug resistance, Antiplatelet therapy, Clopidogrel, CYP2C19 polymorphisms, Peripheral artery disease",
author = "Jenkuang Lee and Naichen Cheng and Haochih Tai and {Jimmy Juang}, Jyhming and Chokai Wu and Lianyu Lin and Jueyjen Hwang and Jiunn-Lee Lin and Futien Chiang and Chiati Tsai",
year = "2019",
month = "9",
day = "1",
doi = "10.1016/j.ejvs.2019.02.011",
language = "English",
volume = "58",
pages = "373--382",
journal = "European Journal of Vascular and Endovascular Surgery",
issn = "1078-5884",
publisher = "W.B. Saunders Ltd",
number = "3",

}

TY - JOUR

T1 - CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia

AU - Lee, Jenkuang

AU - Cheng, Naichen

AU - Tai, Haochih

AU - Jimmy Juang, Jyhming

AU - Wu, Chokai

AU - Lin, Lianyu

AU - Hwang, Jueyjen

AU - Lin, Jiunn-Lee

AU - Chiang, Futien

AU - Tsai, Chiati

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Objective: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form. This study evaluated the association between the CYP 2C19 genetic polymorphism and clinical outcomes in patients with critical limb ischaemia (CLI) taking clopidogrel after endovascular therapy (EVT). Methods: This was a retrospective study. Patients with CLI who had undergone EVT between August 2014 and January 2017 were included. The study subjects were divided into three groups according to the loss of function (LOF) CYP2C19 alleles: (1) extensive metaboliser (EM); (2) intermediate metaboliser (IM); and (3) poor metaboliser (PM). All patients underwent a platelet function test (VerifyNow). Amputation free survival and all cause mortality were estimated using the Kaplan–Meier method. The association between baseline characteristics and clinical outcomes was assessed with the Cox proportional hazard model. Results: A total of 278 CLI patients (EM: 153, IM: 79, PM: 46) who underwent EVT were included. There were 180/278 (64.7%, EM: 107, IM: 45, PM: 28) patients who completed the 12 month follow up examination. Carriers of at least one CYP2C19 LOF allele (44.9%, 125/278) had diminished pharmacodynamic responses to clopidogrel as measured using VerifyNow (174 ± 27 platelet reactivity units (PRU), 216 ± 21 PRU, and 245 ± 35 PRU for patients with EM, IM, and PM CYP2C19 profiles, respectively; EM vs. IM, p < .0001 and EM vs. PM, p < .0001). The estimated amputation free 12 month survival rates were EM 82.1%, IM 66.1.0%, and PM 56.6% with significant differences between groups (log-rank test p = .0006, p for trend <.0001). The estimated all cause 12 month mortality rates were EM 83.7%, IM 72.2%, and PM 71.3% (log rank test p = .01, p for trend p = .007). The combined group consisting of IM and PM was associated with amputation free survival and all cause mortality based on a univariable analysis (hazard ratio [HR] = 2.23 [1.97–2.46], p = .011; HR = 1.43 [1.05–1.85], p = .043) and remained significant in a multivariable Cox analysis (HR = 2.65 [2.1–2.9], p = .009; HR = 1.39 [1.07–1.74], p = .037). Conclusion: CYP2C19 genetic profiles can significantly influence clinical outcomes (in both amputation free survival and all cause mortality) in CLI patients who are taking only clopidogrel after EVT.

AB - Objective: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form. This study evaluated the association between the CYP 2C19 genetic polymorphism and clinical outcomes in patients with critical limb ischaemia (CLI) taking clopidogrel after endovascular therapy (EVT). Methods: This was a retrospective study. Patients with CLI who had undergone EVT between August 2014 and January 2017 were included. The study subjects were divided into three groups according to the loss of function (LOF) CYP2C19 alleles: (1) extensive metaboliser (EM); (2) intermediate metaboliser (IM); and (3) poor metaboliser (PM). All patients underwent a platelet function test (VerifyNow). Amputation free survival and all cause mortality were estimated using the Kaplan–Meier method. The association between baseline characteristics and clinical outcomes was assessed with the Cox proportional hazard model. Results: A total of 278 CLI patients (EM: 153, IM: 79, PM: 46) who underwent EVT were included. There were 180/278 (64.7%, EM: 107, IM: 45, PM: 28) patients who completed the 12 month follow up examination. Carriers of at least one CYP2C19 LOF allele (44.9%, 125/278) had diminished pharmacodynamic responses to clopidogrel as measured using VerifyNow (174 ± 27 platelet reactivity units (PRU), 216 ± 21 PRU, and 245 ± 35 PRU for patients with EM, IM, and PM CYP2C19 profiles, respectively; EM vs. IM, p < .0001 and EM vs. PM, p < .0001). The estimated amputation free 12 month survival rates were EM 82.1%, IM 66.1.0%, and PM 56.6% with significant differences between groups (log-rank test p = .0006, p for trend <.0001). The estimated all cause 12 month mortality rates were EM 83.7%, IM 72.2%, and PM 71.3% (log rank test p = .01, p for trend p = .007). The combined group consisting of IM and PM was associated with amputation free survival and all cause mortality based on a univariable analysis (hazard ratio [HR] = 2.23 [1.97–2.46], p = .011; HR = 1.43 [1.05–1.85], p = .043) and remained significant in a multivariable Cox analysis (HR = 2.65 [2.1–2.9], p = .009; HR = 1.39 [1.07–1.74], p = .037). Conclusion: CYP2C19 genetic profiles can significantly influence clinical outcomes (in both amputation free survival and all cause mortality) in CLI patients who are taking only clopidogrel after EVT.

KW - Antiplatelet drug resistance

KW - Antiplatelet therapy

KW - Clopidogrel

KW - CYP2C19 polymorphisms

KW - Peripheral artery disease

UR - http://www.scopus.com/inward/record.url?scp=85071707672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071707672&partnerID=8YFLogxK

U2 - 10.1016/j.ejvs.2019.02.011

DO - 10.1016/j.ejvs.2019.02.011

M3 - Article

C2 - 31395432

AN - SCOPUS:85071707672

VL - 58

SP - 373

EP - 382

JO - European Journal of Vascular and Endovascular Surgery

JF - European Journal of Vascular and Endovascular Surgery

SN - 1078-5884

IS - 3

ER -