CYP2C19 Loss-of-Function is Associated with Increased Risk of Ischemic Stroke after Transient Ischemic Attack in Intracranial Atherosclerotic Disease

J Stroke Cerebrovasc Dis. 2021 Feb;30(2):105464. doi: 10.1016/j.jstrokecerebrovasdis.2020.105464. Epub 2020 Nov 24.


Objectives: Intracranial atherosclerotic disease (ICAD) is responsible for 8-10% of acute ischemic strokes, and resistance to antiplatelet therapy is prevalent. CYP2C19 gene loss-of-function (up to 45% of patients) causes clopidogrel resistance. For patients with asymptomatic ICAD and ICAD characterized by transient ischemic attack (TIA), this study measures the effect of CYP2C19 loss-of-function on ischemic stroke risk during clopidogrel therapy.

Materials and methods: From a deidentified database of medical records, patients were selected with ICD-9/10 code for ICAD, availability of CYP2C19 genotype, clopidogrel exposure, and established patient care. Dual-antiplatelet therapy patients were included. Patients with prior ischemic stroke, other neurovascular condition, intracranial angioplasty/stenting, or observation time <1 month were excluded. Time-to-event analysis using Cox regression was conducted to model first-time ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted for age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. Subset analyses were performed for asymptomatic and post-TIA subtypes of ICAD.

Results: A total of 337 patients were included (median age 68, 58% male, 88% Caucasian, 26% CYP2C19 loss-of-function). A total of 161 (47.8%) patients had TIA at time of ICAD diagnosis, while 176 (52.2%) were asymptomatic. First-time ischemic stroke was observed among 20 (12.4%) post-TIA ICAD patients and 17 (9.7%) asymptomatic ICAD patients. Median observation time was 2.82 [IQR 1.13-5.17] years. CYP2C19 loss-of-function allele was associated with ischemic stroke event (HR 2.2, 95% CI 1.1-4.3, p=0.020) after adjustment. Post-TIA ICAD patients had a higher risk of ischemic stroke from CYP2C19 loss-of-function (HR 3.4, 95% CI 1.4-8.2, p=0.006).

Conclusions: CYP2C19 loss-of-function was associated with 3-fold increased risk of first-time ischemic stroke for ICAD patients treated with clopidogrel after TIA. This effect was not observed for asymptomatic ICAD. CYP2C19-guided antiplatelet selection may improve stroke prevention in ICAD after TIA.

Keywords: Antiplatelet; CYP2C19; Clopidogrel; Intracranial atherosclerosis; Intracranial stenosis; Ischemic stroke; Pharmacogenetics.

MeSH terms

  • Aged
  • Clopidogrel / administration & dosage
  • Clopidogrel / adverse effects*
  • Cytochrome P-450 CYP2C19 / genetics*
  • Databases, Factual
  • Drug Resistance / genetics*
  • Female
  • Humans
  • Intracranial Arteriosclerosis / complications
  • Intracranial Arteriosclerosis / diagnostic imaging
  • Intracranial Arteriosclerosis / drug therapy*
  • Ischemic Attack, Transient / diagnostic imaging
  • Ischemic Attack, Transient / etiology
  • Ischemic Attack, Transient / prevention & control*
  • Ischemic Stroke / diagnostic imaging
  • Ischemic Stroke / etiology
  • Ischemic Stroke / prevention & control*
  • Male
  • Middle Aged
  • Pharmacogenomic Variants*
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / adverse effects*
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19