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Objective  We investigated (1) the associations of pre‐stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional outcome, and (2) whether stroke subtypes modify these associations in first‐ever ischemic stroke.    Methods  This multicenter magnetic resonance imaging (MRI)‐based study included 5,700 consecutive patients with acute first‐ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score‐based augmented inverse probability weighting was performed to estimate adjusted effects of pre‐stroke aspirin use.    Results  The mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre‐stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre‐stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = −5.4%, 95% confidence interval [CI] = −8.9 to −1.9). Thus, pre‐stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3‐month modified Rankin Scale score < 3), particularly in large artery atherosclerosis stroke and cardioembolic stroke (adjusted difference = 7.2%, 95% CI = 1.8 to 12.5 and adjusted difference = 6.4%, 95% CI = 1.7 to 11.1, respectively). Pre‐stroke aspirin use (vs nonuse) was associated with 85% less frequent cerebral thrombus‐related susceptibility vessel sign (SVS) in large artery atherosclerosis stroke (adjusted difference = −1.4%, 95% CI = −2.1 to −0.8,  p  < 0.001) and was associated with ~40% lower SVS volumes, particularly in cardioembolic stroke (adjusted difference = −0.16 cm 3 , 95% CI = −0.29 to −0.02,  p  = 0.03). Moreover, pre‐stroke aspirin use was not significantly associated with hemorrhagic transformation (adjusted difference = −1.1%,  p  = 0.09).    Interpretation  Pre‐stroke aspirin use associates with improved functional independence in patients with first‐ever ischemic large arterial stroke by reducing infarct volume and/or END, likely by decreasing thrombus burden, without increased risk of hemorrhagic transformation. ANN NEUROL 2021;90:763–776

Relation of Pre‐Stroke Aspirin Use With Cerebral Infarct Volume and Functional Outcomes