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

Abstract

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). 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. 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). 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.