In contrast, the RESPECT showed significant interactions between treatment and both larger shunt size (>20 micro- bubbles) and atrial septal aneurysm, with benefit shown only when either was present. A pooled individual patient data analysis from medically treated patients from 2 observational studies and 2 clinical trials found that atrial septal aneurysm, but not shunt size, was independently associ- ated with recurrent stroke.557 A meta-analysis of PFO closure trials found benefit for closure only for patients with high-risk anatomic features.561 However, this finding may have resulted from con- founding because trials that showed benefit had a higher proportion of high-risk features and limited the alternative therapy to antiplatelet therapy only, not antiplatelets or anticoagulants.567 3. If the PFO is considered low risk on the basis of anatomic features, it is particularly important to consider the other clinical features in deciding whether PFO is likely related to the stroke or is incidental. The Risk of Paradoxical Embolism an index to stratify patients with crypto- genic stroke with PFO by their likelihood that the PFO is stroke related, may be helpful for patient selection. Factors in the score indicative of a higher likelihood of a PFO-dependent stroke mechanism are absence of hypertension, diabetes, prior stroke, or TIA; cortical infarct on imaging; and younger age group. Scores range from 0 to 10, with the esti- mated attributable fraction or probability that the PFO is stroke related ranging from 0% (95% CI, 0 4) for a Risk of Paradoxical Embolism score of 10. 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. 