Cucchiara, Brett

Antithrombotic therapy plays an important role in reducing stroke recurrence. For noncardioembolic stroke, multiple trials have demonstrated the efficacy of antiplatelet monotherapy for secondary stroke prevention. In select situations, such as short-term treatment in the acute period after a minor stroke or transient ischemic attack, dual-antiplatelet therapy has demonstrated superiority to monotherapy. Multiple trials have tested more aggressive strategies using long-term combination antiplatelet medications or full-dose anticoagulation with limited evidence of a reduction in ischemic events but a relatively consistent increased risk of bleeding. Emerging new agents targeting factor XI/XIa may uncouple necessary hemostasis from pathological thrombosis and offer promise for enhancing secondary prevention of stroke without increasing bleeding. The recently positive OCEANIC-STROKE trial (Oral Factor Eleven A Inhibitor Asundexian as Novel Antithrombotic) testing dual-pathway inhibition with the factor XIa inhibitor asundexian in combination with antiplatelet therapy represents a major advance in antithrombotic therapy for noncardioembolic stroke. This review summarizes the current state of the evidence for antithrombotic therapy in secondary stroke prevention after noncardioembolic stroke and discusses completed and ongoing trials of novel factor XI/XIa inhibitors for stroke prevention.

Plasma neurofilament light is a reliable, uniform marker to estimate neuroaxonal injury and forecast all-cause mortality across major stroke types.

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.