Uncertainty regarding an optimal antiplatelet regimen still exists in patients with breakthrough
acute ischemic stroke (AIS) while on
aspirin. This study provides an analysis of a prospective multicenter registry between April 2008 and April 2014. Eligible patients were on
aspirin at the time of AIS and treated with antiplatelet regimens (
aspirin,
clopidogrel, or
clopidogrel-
aspirin). Potential factors associated with the choice of each antiplatelet regimen were explored and included a predictive risk score for future vascular events, the Essen
Stroke Risk Score (ESRS). A total of 2348 patients (age, 69 ± 11 years; male, 57.7%) were analyzed, and 55.3%, 25.3% and 19.4% were treated with
clopidogrel-
aspirin,
aspirin and
clopidogrel, respectively. While the likelihood of choosing
clopidogrel-
aspirin increased as the ESRS increased, the likelihood of choosing
aspirin decreased as the ESRS increased (Ptrend < 0.001). The ESRS category (0-1/2-3/ ≥ 4) modified the effect of antiplatelet regimens for 1-year vascular events (Pinteraction < 0.01). Among patients with ESRS ≥ 4,
clopidogrel-
aspirin (HR 0.47 [0.30-0.74]) and
clopidogrel (HR 0.30 [0.15-0.60]) significantly reduced the risk of outcome events. Our study showed that more than half of the patients with
aspirin failure were treated with
clopidogrel-
aspirin. In particular, a higher ESRS, which indicates an increased risk of recurrent
stroke, was associated with the choice of
clopidogrel-
aspirin rather than
aspirin.