the ischemic events. In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect who had cardiothoracic surgery [43]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 11/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limits confidence in the results of this study. GENERAL MANAGEMENT OF PFO-ASSOCIATED STROKE All patients with PFO and ischemic stroke require antithrombotic therapy, cardiovascular risk reduction measures, and other measures to reduce the risk of recurrent stroke and other adverse cardiovascular events. Antithrombotic therapy Agents Antithrombotic therapy is a key component of secondary prevention for all types of ischemic stroke. Patients without an indication for anticoagulation should be treated with antiplatelet therapy whether or not the PFO is successfully closed. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) After PFO closure For most patients who have undergone percutaneous or surgical PFO closure who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation. We treat with aspirin 75 to 81 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 to 81 mg/day). In the CLOSE trial, the antithrombotic regimen after percutaneous PFO closure was aspirin 75 mg/day plus clopidogrel 75 mg/day for three months [12]. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole. Without PFO closure For most patients with a PFO-associated embolic infarct and no other evident source of stroke who do not undergo PFO closure, we suggest antithrombotic therapy with antiplatelet agents rather than anticoagulation. However, anticoagulation therapy is used rather than antiplatelet agents for patients with high risk of venous thromboembolism, as discussed below. Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO-associated ischemic stroke or transient ischemic attack (TIA) is uncertain (see 'Comparative studies' below), high-quality data from randomized trials have established that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin'.) Concurrent indication for anticoagulation Anticoagulation is used for patients with a PFO-associated stroke who have a concurrent indication, such as acute deep venous https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 12/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate thrombosis, pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. Management of these conditions, including the duration of anticoagulation, is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow- up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".) Comparative studies The evidence comparing the benefit of antiplatelet therapy with anticoagulation for stroke prevention among patients with a PFO and ischemic stroke comes mainly from nonrandomized studies or randomized trials with important limitations, as illustrated by the following observations: In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [aHR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, aHR 0.75, 95% CI 0.44-1.27) [44]. In an updated meta-analysis of combined data from four trials (PICSS [45], CLOSE [12], NAVIGATE ESUS [46], and RESPECT ESUS [47]) that included patients with PFO and cryptogenic stroke who were randomly assigned to treatment with anticoagulant or antiplatelet therapy, the risk of recurrent ischemic stroke was similar for anticoagulation versus antiplatelet therapy (odds ratio 0.70, 95% CI 0.43-1.14) [47]. However, confidence in this result is limited by imprecision due to the small number of outcome events and wide confidence interval. Other cardiovascular risk reduction Patients with PFO who have an ischemic stroke or TIA should be treated with all appropriate cardiovascular risk reduction strategies (see above) including lifestyle modification (diet and exercise), blood pressure control, and statin therapy (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Additional preventive measures Certain general measures may be beneficial independent of the therapy chosen for the PFO. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for VTE, we suggest frequent ambulation and calf exercises, avoidance of dehydration or https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 13/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".) RECURRENT ISCHEMIC STROKE As with any stroke, patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients who have undergone PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [48-52]. Alternatively, thrombus may spontaneously form on or adjacent to the PFO device or in the left atrium due to stagnant blood flow [53], particularly given the possible increased risk of atrial arrhythmias (mainly atrial fibrillation) in patients with PFO and/or atrial septal aneurysm [54]. This risk may be augmented after PFO closure [16,17], especially in the first few weeks after device implantation. Recurrent stroke should be treated according to the underlying mechanism, if it can be identified: If the recurrence occurs in a patient who has not had their PFO closed, and the PFO still appears to be the most likely cause of stroke, we suggest PFO closure. (See 'Patient selection for PFO closure' above.) For patients on antiplatelet therapy who have a recurrent PFO-associated stroke (regardless of PFO closure status) and no atrial fibrillation on reevaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet regimen. For patients with recurrent embolic stroke of undetermined source (ESUS), switching to empiric anticoagulant therapy is also a reasonable option. These issues are discussed in detail elsewhere. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 14/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate In rare cases, thrombus formation on the PFO closure device should be treated with anticoagulant therapy; recurrent embolism in this setting may require surgical device removal with defect closure [55]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS Patient selection for PFO closure A causal association between a patent foramen ovale (PFO) and stroke (ie, a PFO-associated stroke) is thought likely in patients with PFO who meet all of the following criteria; patients with PFO who meet all of these criteria are candidates for percutaneous PFO closure: Age 60 years Embolic stroke topography (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Is the stroke embolic?') https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 15/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate No other evident source of stroke despite a comprehensive evaluation (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Exclusion of other sources of ischemic stroke') A possible, probable, or definite likelihood that the stroke was causally related to the PFO according to the PFO-associated stroke causal likelihood (PASCAL) classification system ( table 1), which incorporates the Risk of Paradoxical Embolism (RoPE) score and high-risk features of the PFO on echocardiogram ( table 2) (calculator 1) (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score') No concurrent indication for anticoagulation (see 'Special considerations in anticoagulated patients' above) Decision-making for PFO closure Our approach to management of a patient with an embolic appearing stroke, PFO, and no other identified cause is summarized in the algorithm ( algorithm 1). PFO-associated stroke For most patients without a concurrent indication for anticoagulation who are 60 years of age with a possible, probable, or definite likelihood by PASCAL ( table 1) that the PFO was causally associated with the stroke, we suggest percutaneous PFO device closure in addition to antiplatelet therapy (Grade 2B). For patients who are >60 years of age, we use an individualized treatment approach to PFO closure based upon patient preferences and other risk factors and comorbidities. If otherwise indicated, PFO device closure may be temporarily deferred for patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for patients with an indication for long-term anticoagulation; an individualized approach with shared decision-making is appropriate. (See 'Special considerations in anticoagulated patients' above.) For rare patients who have a concurrent indication for cardiac surgery (eg, valve surgery) and meet PASCAL criteria for PFO causal association, surgical PFO closure is appropriate. For rare patients who have a PFO that is not amenable to percutaneous closure but meet PASCAL criteria for PFO causal association, the benefit of surgical closure is https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 16/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate uncertain. In the absence of a concurrent indication for cardiac surgery, we suggest against surgical closure (Grade 2C). PFO unlikely to be associated with stroke For patients who do not meet criteria for a causal association of PFO with stroke (ie, association unlikely by PASCAL ( table 1)), we suggest against PFO closure (Grade 2C). Benefit of PFO closure PFO device closure is more effective than medical therapy alone for select patients aged 60 years with a PFO-associated stroke (ie, a nonlacunar ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation). Compared with medical therapy, PFO device closure reduces risk of recurrent stroke from approximately 5 to 2 percent over a three- to six-year period. (See 'Benefit' above.) For patients age >60 years, the benefit of PFO device closure is unknown, since these patients were generally excluded from randomized trials of PFO device closure. (See 'Benefit' above.) Choice of antithrombotic agent for PFO-associated stroke Following PFO closure For patients in this setting who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation (Grade 2C). Patients are treated with antiplatelet therapy whether or not the PFO is successfully closed. (See 'Antithrombotic therapy' above.) Without PFO closure For these patients, treatment with antiplatelet therapy is recommended, which is consistent with the recommendations for cryptogenic stroke. (See 'Antithrombotic therapy' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) Concurrent indication for anticoagulation In this setting (eg, usually venous thromboembolism), standard recommendations for anticoagulation apply, and anticoagulation is generally the sole antithrombotic therapy required. Recommendations are provided in separate topic reviews. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Recurrent ischemic stroke Patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 17/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. For patients with a previous PFO-associated stroke treated with antiplatelet therapy but not PFO closure who have a recurrent embolic-appearing stroke with no other identified cause, we suggest PFO closure in addition to antithrombotic therapy (Grade 2C). Switching to another antiplatelet agent or to anticoagulant therapy is a reasonable alternative. (See 'Recurrent ischemic stroke' above.) Use of UpToDate is subject to the Terms of Use. 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Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline. BMJ 2018; 362:k2515. 30. Kasner SE, Rhodes JF, Andersen G, et al. Five-Year Outcomes of PFO Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2021; 384:970. 31. Mess SR, Erus G, Bilello M, et al. Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial. Stroke 2021; 52:3419. 32. Alperi A, Guedeney P, Horlick E, et al. Transcatheter Closure of Patent Foramen Ovale in Older Patients With Cryptogenic Thromboembolic Events. Circ Cardiovasc Interv 2022; 15:e011652. 33. Chen JZ, Thijs VN. Atrial Fibrillation Following Patent Foramen Ovale Closure: Systematic Review and Meta-Analysis of Observational Studies and Clinical Trials. Stroke 2021; 52:1653. 34. Pineda AM, Mihos CG, Singla S, et al. Percutaneous Closure of Intracardiac Defects in Adults: State of the Art. J Invasive Cardiol 2015; 27:561. 35. Moore J, Hegde S, El-Said H, et al. Transcatheter device closure of atrial septal defects: a safety review. JACC Cardiovasc Interv 2013; 6:433. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 20/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 36. Divekar A, Gaamangwe T, Shaikh N, et al. Cardiac perforation after device closure of atrial septal defects with the Amplatzer septal occluder. J Am Coll Cardiol 2005; 45:1213. 37. Scacciatella P, Biava LM, Marra S. Iatrogenic erosion of the septum primum resulting in an atrial septal defect with left-to-right shunt: a rare pitfall of patent foramen ovale percutaneous closure. Catheter Cardiovasc Interv 2014; 84:494. 38. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. 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Eur Heart J 2015; 36:1195. Topic 138296 Version 4.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 22/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate GRAPHICS Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism or deep venous thrombosis preceding Probable Highly probable an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 23/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 24/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri strategies including antithrombotic therapy, blood pressure control, low-density lipoprotein (LDL)-lowering th lifestyle modification, as appropriate. For details regarding the evaluation required for a comprehensive stroke evaluation, choice of antithromboti other factors that impact decision-making for PFO management, refer to appropriate UpToDate topics. PFO: patent foramen ovale; DVT: deep venous thrombosis; PE: pulmonary embolism; RoPE: Risk of Paradoxic PASCAL: PFO-associated stroke causal likelihood; ASA: atrial septal aneurysm. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 25/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate For most patients with an indication for anticoagulation >1 year, PFO closure is not performed, as benefit in uncertain. PFO closure may be an option for selected patients, such as those who experience recurrent embo other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Patients who undergo PFO closure (percutaneous or surgical) are treated with antiplatelet agents. We treat to 81 mg/day) plus clopidogrel (75 mg/day) for three months, followed by continued aspirin therapy. For the rare patient who has a concurrent indication for surgical valve intervention, surgical (rather than pe closure is appropriate. If percutaneous PFO closure is not feasible and there is no concurrent indication for c suggest against surgical PFO closure. For most patients >60 years old, PFO closure is not performed since such patients were excluded from tria and the benefit of closure in this setting is unproven. PFO closure may be an option for selected patients >60 as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Refer to UpToDate topic on cryptogenic stroke. Graphic 138535 Version 1.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 26/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Stephen JD Brecker, MD, FRCP, FESC, FACC Grant/Research/Clinical Trial Support: Medtronic [Transcatheter valves]. Consultant/Advisory Boards: Aortic Innovations LLC [Transcatheter valves]; Medtronic [Transcatheter valves]. Speaker's Bureau: Medtronic [Transcatheter valves]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 27/27