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Ischemic strokes can still occur, however, despite appropriate anticoagulation\u2014an event known as a breakthrough stroke. In this review, we provide an examination of breakthrough stroke through its epidemiology, mechanisms by which breakthrough strokes happen, and a framework for classification. We then propose a systematic, stepwise algorithm to investigate breakthrough stroke, including standardized criteria to identify an ideal population for future clinical trials using the AF-BREACH criteria (Atrial Fibrillation related BReakthrough Embolic Stroke despite appropriate anticoagulation without alternative Cause identified). 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