Comparative Outcomes of Clopidogrel, Ticagrelor, and Prasugrel for Secondary Stroke Prevention

Background Ticagrelor and prasugrel have demonstrated superior efficacy compared with clopidogrel in acute coronary syndromes, however, comparative data on their effectiveness as monotherapy for secondary stroke prevention remain limited. Methods This retrospective analysis compared one‐month and one‐year outcomes associated with clopidogrel, ticagrelor, and prasugrel use in patients with prior cerebral infarction. Using the TriNetX Research Network, adults previously diagnosed with cerebral infarction and treated with clopidogrel, ticagrelor, or prasugrel were identified. Propensity score matching (1:1) was performed separately for clopidogrel (n=6132 per group) versus ticagrelor (n=6090 per group) and clopidogrel (n=1032 per group) versus prasugrel (n=1025 per group). Outcomes included all‐cause mortality, hemorrhagic stroke, seizures, acute kidney injury, and blood transfusion. Results Clopidogrel was associated with significantly lower one‐month and one‐year all‐cause mortality compared to both ticagrelor and prasugrel (p<0.001 and p=0.021, respectively). Hemorrhagic stroke recurrence was significantly more frequent with prasugrel at 1‐year (p=0.011). Clopidogrel was associated with reduced acute kidney injury (AKI) (p=0.001, p=0.011) and blood transfusion vs ticagrelor (p<0.001) at both time points. No significant differences were observed in seizure outcomes. Conclusion In this large retrospective cohort, clopidogrel use was associated with lower all‐cause mortality at 1 month and 1 year compared with ticagrelor and prasugrel, alongside lower acute kidney injury and transfusion compared with ticagrelor and lower 1‐year hemorrhagic stroke compared with prasugrel. These associations, particularly the consistent mortality benefit, support consideration of clopidogrel's continued therapeutic use for secondary stroke prevention. Prospective studies are needed to confirm these findings and investigate underlying mechanisms.