Association of <i>CYP2C19</i> Polymorphisms With Clopidogrel Reactivity and Clinical Outcomes in Chronic Ischemic Stroke

Abstract

Background: CYP2C19 variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect of CYP2C19 variants on clinical outcomes in the chronic phase. Methods and Results: In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according to CYP2C19 genotype: extensive metabolizer (EM: *1/*1), intermediate metabolizer (IM: *1/*2 or *1/*3), and poor metabolizer (PM: *2/*2, *2/*3, or *3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. Conclusions: Despite associations between CYP2C19 variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups of CYP2C19 variants.

Platelet Function Test Use for Patients with Coronary Artery Disease in the Early 2020s

“…These results, together with findings that variability in platelet reactivity did not predict ischemic events in stable cardiovascular patients [50,52,70,71], raised the possibility of reducing the intensity of antiplatelet therapy after the acute phase. The TOPIC study included 646 ACS patients treated with aspirin and ticagrelor or prasugrel one month after PCI [72].…”

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial

“… 15 Compared with the trials conducted with patients in the acute phase, the clinical trials in Japanese stroke patients showed that the poor metabolizers were not at greater risk of cerebrovascular events. 16 The addition of cilostazol is expected to further promote the antiplatelet effect of clopidogrel. The combination of aspirin and cilostazol, which have different mechanisms of action, may result in an additive increase in antiplatelet activity.…”

P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study

“…The impact of the CYP2C19 polymorphism on stroke prevention in AIS/TIA has been controversial [6][7][8][9] . Recently, our paper 10) reviewed a difference in the effect of the CYP2C19 PM genotype for cerebrovascular events between the acute and subacute-chronic stroke phase; 10 of 11 (91%) studies recruiting patients during the acute phase (within 1 week after the index stroke) demonstrated a positive effect [11][12][13][14][15][16][17][18][19][20] but all three studies recruiting during the subacute-chronic phase (within ＞2 weeks) showed no significant effect 7,8,10) . Thus, the effect of the CYP2C19 polymorphism on cerebrocardiovascular events appears more pertinent during the acute than chronic stroke phase, an important finding given the difficulty in obtaining genetic testing results in the acute period.…”