P2Y12 Inhibitor Monotherapy for Secondary Stroke Prevention: Comparative Outcomes of Clopidogrel, Ticagrelor, and Prasugrel

BACKGROUND: Ticagrelor and prasugrel have shown greater efficacy than clopidogrel in acute coronary syndromes; yet, direct comparisons of these agents as monotherapy for secondary stroke prevention remain limited. METHODS: Adults with a prior cerebral infarction who received clopidogrel, ticagrelor, or prasugrel were identified from the TriNetX Research Network. Two separate 1:1 propensity-score–matched comparisons were conducted: clopidogrel versus ticagrelor (n=6144 per group) and clopidogrel versus prasugrel (n=1037 per group). Clinical outcomes at 1 month and 1 year included all-cause mortality, hemorrhagic stroke, acute kidney injury, blood transfusion, and seizures. RESULTS: At both 1 month and 1 year, clopidogrel was associated with significantly lower all-cause mortality versus ticagrelor ( P <0.001) and versus prasugrel ( P =0.021). Prasugrel was associated with higher hemorrhagic stroke rates at 1 year ( P =0.011). Compared with ticagrelor, clopidogrel was linked to lower rates of acute kidney injury ( P =0.001 at 1 month; P =0.011 at 1 year) and blood transfusion ( P <0.001 at both timepoints). Seizure rates did not differ significantly across groups. CONCLUSIONS: In a large, propensity-matched retrospective cohort of adults with prior ischemic stroke on P2Y12 monotherapy, clopidogrel was associated with lower all-cause mortality than both ticagrelor and prasugrel at 1 month and 1 year, along with favorable safety signals for acute kidney injury and transfusion versus ticagrelor and hemorrhagic stroke versus prasugrel. These associations, particularly the consistent mortality finding, should be interpreted with caution given the potential for residual confounding, including unmeasured differences in stroke severity and indication bias. These findings are hypothesis-generating and do not establish a causal benefit or support a preferred agent; prospective, stroke-specific randomized trials are needed to confirm these associations.