Jenkuang Lee1, Naichen Cheng2, Haochih Tai2, Jyhming Jimmy Juang3, Chokai Wu4, Lianyu Lin3, Jueyjen Hwang3, Jiunnlee Lin3, Futien Chiang3, Chiati Tsai5. 1. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Telehealth Centre, National Taiwan University Hospital, Taipei, Taiwan. 2. Division of Plastic Surgery, Department of Surgery, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. 3. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. 4. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. Electronic address: wuchokai@gmail.com. 5. Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. Electronic address: fang31@ms39.hinet.net.
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.
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.
Authors: Shu Huang; Seonkyeong Yang; Shirly Ly; Ryan H Yoo; Wei-Hsuan Lo-Ciganic; Michael T Eadon; Titus Schleyer; Elizabeth Whipple; Khoa Anh Nguyen Journal: Eur J Clin Pharmacol Date: 2022-06-03 Impact factor: 3.064