Beyond Anticoagulation: Understanding the Failure of Medical Therapy in PFO-Related Stroke and the Superiority of Closure

Patent foramen ovale (PFO) is present in roughly one quarter of adults and is over-represented among younger patients with cryptogenic ischemic stroke. The past decade has produced compelling evidence from randomized trials showing that PFO closure is superior to medical therapy in preventing recurrent ischemic stroke in appropriately selected patients. Despite this, anticoagulation continues to be used when closure is not feasible, declined, contraindicated, or considered after recurrent events. The observation that some patients experience “breakthrough” stroke or transient ischemic attack (TIA) despite therapeutic anticoagulation raises a critical question: why does medical therapy fail in PFO-related stroke, and why does closure appear superior? This narrative review synthesizes the latest evidence on the pathophysiology of PFO-associated stroke, with attention to mechanisms that remain incompletely addressed by anticoagulation. It analyzes randomized trial data comparing antiplatelet therapy, anticoagulation, and transcatheter closure. It examines the role of high-risk PFO anatomical characteristics, the Risk of Paradoxical Embolism (RoPE) score, and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification in understanding medical therapy failure. Additionally, the review explores whether PFO “type” predicts anticoagulation failure and highlights future research directions needed to further optimize therapy. The conclusion is clear: in the selected patients with high-risk features closure offers superior stroke prevention beyond what anticoagulation can achieve.