The Risk of Paradoxical Embolism score attrib- utable fraction is highly correlated with the RR reduction of device closure compared with medical therapy in randomized trials.568 4. The evidence suggests that PFO closure in appropriately selected patients is superior to aspi- rin, but it is not known whether closure is superior to warfarin. A comparison of device closure and anticoagulation was not a prespecified analysis in the CLOSE trial (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence),563 but a post hoc underpowered analysis of recurrent stroke found no events in the device closure group and 3 events in the warfarin group, which was not a sta- tistically significant difference.561 Similarly, if long- term warfarin treatment is planned, the additional benefit of closure with a transcatheter device for preventing recurrent stroke is unknown. An important consideration is that short-term trials in younger adults do not capture the long-term risk of warfarin or the long-term safety of indwelling PFO closure devices. Knowledge Gaps and Future Research Future research is needed within this area: Trials of closure versus medical management in patients 60 years of age with ESUS.569 Further trials and individual-level meta-analysis of all randomized trial data in patients with ESUS <60 years of age addressing the benefit of PFO closure compared with aspirin in patients with a PFO with- out high-risk anatomic features. Further trials and individual-level meta-analysis of all randomized trial data addressing the benefit of PFO closure compared with long-term anticoagulation. Individual-level meta-analysis of all randomized tri- als to determine whether PFO size is independently associated with response to treatment. 