Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial

Abstract

Background and Purpose: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. Methods: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. Results: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P =0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P =0.25) among noncarriers. There was no significant interaction by genotype for major ischemia ( P =0.36) or stroke ( P =0.33). Conclusions: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.

Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020

“…Pharmacogenetic testing can identify patients with clopidogrel resistance, however, its clinical implications for stroke prevention practice are unclear at this time. [38][39][40] Another short-term dual antiplatelet treatment option is the combination of daily low-dose aspirin and ticagrelor, a P2Y12 antagonist most often used in coronary artery disease. The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial tested a 30-d course of the aspirin-ticagrelor combination starting within 24 h of a high-risk TIA or minor ischemic stroke.…”

Integrated care for optimizing the management of stroke and associated heart disease: a position paper of the European Society of Cardiology Council on Stroke

“…In the POINT trial, presence of a clopidogrel slow metabolizer genetic variant was not associated with a significant reduction in efficacy, but there was a trend towards lower efficacy in these patients, although this did not reach significance due to the small sample size. 37 Following the results of these two trials, the combination of aspirin and clopidogrel is now recommended for patients with recent minor (NIHSS score ≤3) noncardioembolic IS or high-risk TIA (ABCD2 score ≥4). It should be started early (ideally within 12–24 h of symptom onset and at least within 7 days of onset) and continued for 21–90 days.…”

A Narrative Review on Translational Research in Acute Brain Injury

“…CYP2C19 allele status is considered as a possible determinant of the clopidogrel efficacy but still the relation is not yet clearly established. 44,45 Neuroinflammation is considered an important pathophysiological mechanism of cerebral damage in AIS. Experimental studies related to inflammation-modulating agents have shown promising results but failed in clinical trials.…”